Neurosci Biobehav Rev. 2011 UJan; 35 (3): 939-55. i-doi: 10.1016 / j.neubiorev.2010.10.014. I-Epub 2010 Nov 2.
- 1Bernard B. Brodie Department of Neuroscience, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, CA, Italy. [i-imeyili ivikelwe]
UKUQALA
I-Oxytocin iyinhlawulo enamandla ye-penile erection lapho ijojelwa kwisistimu yenzwa yomphakathi. Ezingwini zamadoda, indawo engqondo ebucayi kakhulu yomphumela we-pro-erectile we-oxytocin yi-nucleus yomsindo we-hypothalamus. Le nucleus nezifunda ezungezile ziqukethe imizimba yamangqamuzana azo zonke i-oxytocinergic neurons eyenza izindawo ezingaphezulu ze-hypothalamic nobuchopho bomgogodla. Lokhu kubuyekezwa kubonisa ukuthi i-oxytocin iveza ukukhishwa kwe-penile futhi uma injected kwezinye zalezi zindawo (isb. Indawo ye-ventral tegmental, i-ventral subiculum ye-hippocampus, i-nucleus yangaphambili ye-cortic ye-amygdala ne-thoraco-lumbar intambo yomgogodla). Ucwaningo lwe-microinjection oluhlangene ne-microdialysis lwangaphakathi kwe-intra-cerebral nezifundo ezimbili ze-immunofluorescence ziphakamisa ukuthi i-oxytocin kulezi zindawo isebenza ngokuqondile noma ngokungaqondile (ngokuyinhloko nge-glutamic acid) ne-mesolimbic ne-neoponic neurons. I-dopamine ekhishwe ku-nucleus accumbens iphinde isebenze izindlela ze-neural eziholela ekusebenziseni i-incerto-hypothalamic ne-dopaminergic neurons ku-nucleus ephambili. Lokhu kuvuselela izinkinga ze-oxytocinergic kuphela ezenza umgogodla uphinde uqondise ukulungiswa kwe-penile, kodwa nalabo ababhekisela ezindaweni ezingenhla ze-hypothalamic, ukuhambisa ngokuqondile noma ngokungaqondile (ngokusebenzisa i-glutamic acid) umsebenzi we-mesolimbic dopaminergic neurons olawula isisusa nomvuzo. Ngokubili lezi zindlela ze-neural zingase zenze isifunda esiyinkimbinkimbi, esenza indima hhayi kuphela esigabeni sokuqeda umsebenzi wezocansi (umsebenzi we-erectile nokubambisana), kodwa futhi nezici ezishukumisayo nezivuzayo zesigaba sokulindela sokuziphatha ngokobulili.
I-1.Indlelo
Ukwakhiwa kwe-Penile kuyisenzo esithinta abantu ngokocansi esithinta indima ebalulekile ekukhiqizeni izidalwa ezincelisayo ezibandakanya umuntu, futhi lokho kungabonwa nakwezinye izimo ezihlukile kulabo abahlobene ngokuqondile nokukhiqiza. Kuye umongo lapho penile ukwakhiwa kwenzeka, ezahlukene kwemizwa emaphakathi kanye neuropathy kanye / noma izindlela humoral iqhaza isiqondiso yayo (bheka Meisel futhi Sachs, 1994; Argiolas futhi Melis, 1995, 2004, 2005; Sachs, 2000, 2007; McKenna, 2000; Giuliano noRampin, 2000, 2004; Andersson, 2001; Melis no-Argiolas, 1995a, 2003; Hull et al., 2002). Phakathi kwama-neurotransmitter kanye nama-neuropeptides alawulayo ukulawula i-penile erection, eyaziwayo kakhulu i-dopamine, i-serotonin, ama-amino acidatory, i-nitric oxide, i-adrenocorticotropin, i-oxytocin ne-opioid peptides. Zingenza noma zivimbele ukukhishwa kwe-penile ngokusebenza ezindaweni eziningana zobuchopho, okungukuthi, indawo yangaphambili yomphakathi, i-nucleus yomsindo we hypothalamus, indawo ye-ventral, i-hippocampus, i-amygdala, i-nucleus yombhede we-stria terminalis, i-nucleus accumbens, i-medulla oblongata nomthambo womgogodla (Ithebula 1) (bheka Meisel futhi Sachs, 1994; Witt futhi Insel, 1994; Stancampiano et al, 1994;. Argiolas futhi Melis, 1995, 2005; Argiolas, 1999; Bancila et al, 2002;. Giuliano futhi Rampin, 2000, McKenna, 2000; Andersson, 2001; Hull et al., 2002; Coolen et al., 2004).
Oxytocin, le peptide neurohypophyseal eyaziwa kahle indima yayo hormone e lactation futhi parturition, kuyisici esihlupha nabesifazane kanye nabesilisa, hhayi kuphela e izinzwa ne cell emizimbeni ise paraventricular futhi supraoptic nuclei ka hypothalamus projecting kuya neurohypophysis, kodwa futhi izinzwa projecting kusukela ku-nucleus ephambili kanye nezinhlaka ezizungezile eziza ezindaweni zokucubungula (ie, i-septum, i-ventral tegmental, i-hippocampus, i-amygdala, i-medulla oblongata kanye nomgogodla). Lezi zineurons zicatshangelwa ukuthi zihilelekile emisebenzini eminingi ephakathi, njengememori, ukufunda, ukusebenzisana kanye nokuziphatha komzimba, okubandakanya ukukhishwa kwe-penile nokuziphatha okuphambene nomzimba (bheka i-Buijs, i-1978; i-Sofroniew, i-1983; i-Argiolas no-Gessa, i-1991; i-Pedersen et al 1992; Carter, 1992; Wagner noClemens, 1993; i-Ivell no-Russel, i- 1995; i-Carter et al., I-1997; i-Tang et al., I-1998; i-Veronneau-Longueville et al., I-1999). Ngempela, oxytocin kusiza Erectile umsebenzi futhi wesilisa yokuziphatha ngokocansi amagundane, amagundane, onogwaja nezinkawu (bheka Argiolas futhi Gessa, 1991; Carter 1992;. Pedersen et al, 1992; Argiolas futhi Melis, 1995, 2004; Argiolas, 1999). Lokhu kungase kwenzeke nakubantu, ngoba i-plasma oxytocin yanda ngenxa yocansi, ikakhulukazi ejaculation (i-Carmichael et al., I-1987; i-Murphy et al., I-1987) nokuphathwa kabi kwebele ne-genitalia, evame ukuqhubeka ngesikhathi sezocansi ubulili (Tindall, 1974).
Umphumela omuhle we-oxytocin ekuziphatheni ngokocansi kwaba ngowokuqala kuboniswa amandla okwenza i-oxytocin ekwenzeni ukuncipha kwe-latency kuze kuqale ukujula nokuvimbela ukukhwabanisa ngokobulili kwamanogwaja abesilisa abanjwe nabesifazane abamukelayo (uMelin no-Kihlstrom, i-1963). Kodwa-ke, imiphumela yezocansi ye-oxytocin yayigcinwa ngokucacile kuphela eminyakeni engamashumi ayisishiyagalolunye. I-Oxytocin eyanikezwa ngokuyinhloko ngamanani we-nanogram yatholwa yikwazi ukudala i-penile erection (i-Argiolas et al., 1985, i-1986) nokuthuthukisa ukuziphatha okuphambene (Arletti et al., 1985) kwamagundane angamadoda, nokwandisa i-lordosis kumazinyane ezinsikazi (i-Arletti futhi Bertolini, 1985;. Caldwell et al, 1986), ngokusobala ngokwenza lesizalo-uhlobo receptor oxytocinergic (bheka Argiolas futhi Melis, 1995, 2004; Argiolas, 1999; Melis futhi Argiolas, 2003; nezinkomba therein). I-Oxytocin ithuthukisa ukuziphatha ngokocansi hhayi kuphela ezingodini zesilisa ezithokozelayo ngokobulili (Arletti et al., 1985) kodwa nasezintuthweni ezindala ezingamadoda (Arletti et al., 1990), futhi ikakhulukazi, kodwa hhayi ngaphansi, izimbongolo zezinsikazi (i-Winslow neInsel , I-1991).
Umphumela we-pro-erectile we-oxytocin yi-dependto-dependon-dependent, njengoba uqedwa yi-hypophysectomy nokuxoshwa, futhi ubuyiselwe ngokungezwa nge-testosterone noma i-metabolites, i-estradiol ne-5_-dihydro-testosterone enikezwe ndawonye (Melis et al., 1994a). Indawo ebucayi kakhulu ebuchosheni yokufakelwa kwe-penile erection yi-oktotocin yi-nucleus ebonakalayo ye-hypothalamus (i-Melis et al., I-1986), lapho zonke izilinganiso ze-oxytocinergic ezivela ngaphandle zivela khona (bheka ngenhla). Lapha, i-oxytocin itholakale ukuthi ikwazi ukudala i-penile erection (kanye nokweqa) lapho injected at amanani aphansi njengoba 3 pmol (bheka Isigaba 2.1 ngezansi). Oxytocin eyenga penile ukwakhiwa futhi lapho injected bilaterally phakathi CA1 emkhakheni hippocampus, kodwa hhayi subiculum amaphiko (bheka isigaba 2.3 ngezansi), i-septum lateral, nucleus caudate, le medial endaweni preoptic, nucleus ventromedial ka hypothalamus kanye i-nucleus ephezulu (Melis et al., 1986). Ngokuqondene nendlela i-oxytocin eyenza ngayo i-nucleus ebonakalayo ukuze idale le mpendulo yezocansi, ucwaningo oluningi lubonisa ukuthi i-oxytocin isebenza nge-neurons yayo. Ngokuvumelana nalesi sizathu, ukuxhumana kocansi kwandisa i-FOS, umkhiqizo wegenesis we-gene othomathikhi c-fos ema-neuron e-oxytocinergic avela emaphandleni afaka umgogodla, ohilelekile ekulawuleni ukukhishwa kwe-penile (bheka i-Witt ne-Insel, i-1994 nezinkomba lapho), nokuntuleka kocansi (isib. ukungakwazi komlingani omdala omdala ukubhekana ne-ovariectomized estrogen-progesteroneprimed female receptive) kuye kwahlanganiswa kumlenze wesilisa onamazinga aphansi e-oxytocin mRNA ku-nucleus ye-hypothalamus (Arletti et i-al., i-1997).
Kungakhathaliseki i-oxytocin ithonya isigaba sokulindela noma isigaba sokuqeda ukuziphatha ngokocansi akucaci njengamanje. Njengoba i-oxytocin yenza i-penile erection futhi umphumela oyinhloko we-oxytocin ekuziphatheni komzimba ukunciphisa isikhathi sokumisa esikhwameni samadoda (Arletti et al., 1985), kunengqondo ukucabanga ukuthi i-peptide ithuthukisa ukusebenza kocansi. Kodwa-ke, njengoba i-oxytocin iphinde ikhulise ukuxhumana komphakathi nokucansi (bheka i-Pedersen et al., I-1992; i-Carter et al., I-1997; i-Ivell no-Russel, i-1995), kanye ne-oxytocin receptor antagonists zivimbela ukungahambisani nokungathintana (Melis et al., 1999a), kubhekwa njengezinkomba zokuvusa ngocansi (bheka amaSachs, 1997, 2000, 2007; Melis et al., 1998, 1999b kanye nezinkomba ezikulo), indima enokwenzeka ye-oxytocin ekuvusweni ngokobulili nokugqugquzela ngokocansi ayikwazi ukukhishwa.
Lokhu kubukeza kufingqa imiphumela eshicilelwe futhi engashicilelwa yezifundo zamuva, ezibonisa lokho i-oxytocin iveza i-penile erection hhayi kuphela lapho ijojelwa engxenyeni yomsindo we-hypothalamus, kodwa nakwezinye izingxenye zengqondo ezingaphezu kwe-hypothalamic, njenge-ventral tegmental endaweni (Melis et al., 2007, 2009a; Succu et al., 2008), ti-subiculum ye-ventral ye-hippocampus ne-nucleus yangemva kwe-amygdala (I-Melis et al., 2009b, i-2010), okuyizinto ezibalulekile ze-limbic system futhi kucatshangwa ukuthi idlala indima ebalulekile ekugqugquzelweni nasezinkambisweni zokuvuza. Lezi zifundo zenza ukuthi i-oxytocin ihlanganyele emiphakathini ye-neural, ehlanganisa nezinye izinzwa ze-neurotransmitters, njenge-dopamine ne-glutamic acid, nezinye izindawo zobuchopho ngaphandle kwe-nucleus yombono, isibonelo, indawo ye-ventral tegmental, i-nucleus accumbens, i-hippocampus nezindawo ezizobe zikhona kukhonjisiwe. Lezi zifunda zingase zixhumanise ukuxhumana phakathi kwe-mesolimbic kanye ne-incerto-hypothalamic dopaminergic system, nokudlala indima hhayi kuphela kwisigaba sokuphela kwesenzo sokuziphatha ngokobulili (isib. Ukukhishwa kwe-penile nokuxubana), kodwa futhi nesisusa socansi kanye nesondo ukuvusa, ngakho-ke ukuhlinzeka nge-neural substrate ekuchazeni izindawo ezishukumisayo nezokuvuza zomsebenzi wobulili.
I-2. I-Oxytocin ithonya i-penile erection ngokusebenza ezindaweni ezahlukene zobuchopho
I-2.1. I-nucleus yomsindo we hypothalamus
Njengoba kukhulunywe ngenhla kwe-nucleus yomsindo we-hypothalamus ngokushesha yavezwa njengendawo yechungechunge ezwela kakhulu umphumela we-pro-erectile we-oxytocin. Uma ijowe unilaterally kule nucleus, i-oxytocin itholakale isebenza ngokulinganisa njenge-3 Ng (3 pmol) (Melis et al., 1986). Ucwaningo lwama-structural-activity luveze ukuthi ukwakhiwa kwe-penile okwenziwe i-oxytocin kwakulinganiselwe yi-uterinetype oxytocin receptors, kuhlanganise ne-Ca2 + influx emzimbeni wesiguli se-oxytocinergic neurons eyenza izindawo ezingaphezu kwe-hypothalamic zobuchopho nokusebenza kwe-nitric oxide-synthase. I-oxide ye-nitri ngokusebenza njengesithunywa se-intracellular nge-mechanism engaziwa (engabandakanyi i-guanylate cyclase) iholela ekusebenziseni kwe-neuron ye-oxytocinergic eyenza umgogodla kanye nezindawo ezingqondweni ze-brain-hypothalamic, okwenza ukuthi i-penile erection (Fig. 1) ibone ngezansi no-Argiolas noMelis, 1995, 2004, 2005 kanye nezinkomba kulo). Ikhono le-oxytocin ukuvuselela i-neurons yayo
I-Fig. 1. (UKUKHUMA) Ukumelwa kwesimiso se-oxytocinergic neurons, okuvela engxenyeni ye-hypothalamus ne-projection ezindaweni ezingaphezulu ze-hypothalamic, njenge-spinal cord, i-VTA, i-hippocampus, i-amygdala, njll. Ukusebenza kwala ma-neurons i-dopamine, ama-amino acidatory, i-oxytocin ngokwayo, i-hexarelin peptides analogue kanye nama-peptide athola i-VGF aholela e-penile erection, enganciphisa futhi / noma isuswe ngokugqugquzelwa kwe-GABAergic, i-opioid ne-cannabinoid CB1 receptors. Ukusetshenziselwa kwe-oxytocinergic neurons kuyesibili ekusebenziseni kwe-nitric oxide-synthase okwamanje kulezi neurons. Ngempela i-nitric oxide engapheli eyakhiwe yi-dopamine, ama-amino acitatory noma ama-oxytocin receptors noma i-nitric oxide engavamile, njengoba eyatholakala kuma-nitric oxide abanikeli abanikezwa ngqo kwi-nucleus ebonakalayo, ivuselela i-oxytocinergic neurons ngendlela engaziwa, okusobala ayihlobene ukugqugquzela guanylate cyclase. Lokhu kubangela ukuthi kukhululwe i-oxytocin emgodleni wokugogodla nakwezinye izindawo ezingqondweni ze-hypothalamic. Eminye imininingwane mayelana nendlela i-oxytocin eyenza ngayo i-penile erection lapho ikhululwa kulezi zindawo, isib. I-VTA, i-subralulum ye-ventral kanye ne-amygdala ichazwe ezindaweni eziphathelene nobuchopho. Lapha, i-oxytocin yenza izithandwa zayo futhi yandisa akukho ukukhiqizwa, okuholela ekwakheni i-penile njengoba kutholakala ku-PVN. Nokho, ngokungafani ne-PVN, ku-VTA caudal akukho ukusebenza kwe-guanylate cyclase. Lokhu kubangela ukwanda komgogodla we-cGMP oholela ekusebenziseni ama-neuron angu-mesolimbic ne-penile erection. Ku-VS CHA ayisebenzisi i-neurons ye-glutamatergic eyenza izindawo ezingaphezulu ze-hippocampal, kuhlanganise ne-VTA. I-Glutamic acid ku-VTA ivuselela ama-neuron e-mesolimbic ne-dopaminergic etholakala nge-oxytocin. Izindlela ezifana nalazo ezichazwe ngenhla zingase zisebenze futhi uma ukukhishwa kwe-penile kwenzeka ezimweni zomzimba, okufana nokuthi lapho ama-rats abesilisa abekwe phambi kwenkinga engatholakali yabesifazane (isib.
kwi-nucleus yombangazwe yayisekelwe yizifundo ezibonisa ukuthi: (1) i-oxytocin receptors zikhona kule nucleus ye-hypothalamic (Freund-Mercier et al., 1987; Freund-Mercier noStekelkel, 1995); (2) i-oxytocin yenza kube lula ukukhululwa ku-vitro nase-vivo (Freund-Mercier noRichard, 1981, 1984; Moos et al., 1984); futhi (I-3) i-oxytocin ivuselela i-neurons yayo ngokwenza i-nucleus ebonakalayo (Yamashita et al., 1987). Ngaphezu kwalokho, ukuxhunyaniswa kwe-oxytocinergic okugxila emzimbeni wesiguli sama-magnocellular oxytocinergic neurons kuye kwaboniswa nucleus ne-supraoptic nucleus ye-hypothalamus (Theodosis, 1985). Okokugcina, ukubhujiswa kwama-neuron e-oxytocinergic ephakathi ngamagciwane e-electrolytic noma amakhemikhali e-excitotoxic we-nucleus ephambili, okuqeda ngokuphelele okuqukethwe kwe-oxytocin kuyo yonke isimiso sezinzwa zomgogodla kanye nomgogodla, awuqedi nje kuphela umphumela we-pro-erectile we-oxytocin, kodwa futhi uphazamisa izidakamizwa ezenziwe ukukhishwa kwe-penile kanye nokuvinjelwa okungahambisani (bheka ngezansi no-Argiolas et al., 1987a, b; Liu et al., 1997 kanye nezinkomba kulo). Imiphumela efana nalabo abathola izilonda ze-nucleus ezibonakalayo zitholakala ngeziphikisana ezinamandla futhi ezikhethwe yi-oxytocin receptor. Ngempela, lezi zinhlanganisela ezifakwe ngaphakathi kwe-nucleus ezibonakalayo ezilinganisweni ze-nanogram zivinjelwe ukwakhiwa kwe-penile e-oxytocin ngokuphelele, kuyilapho lapho kunikezwa ama-ventricles lateral, akuvimbeli kuphela ama-penile erections okwenziwe i-oxytocin ngokwayo, kodwa futhi i-penile erection eyenziwe yizidakamizwa (bheka iSigaba 3 ngezansi kanye no-Argiolas noMelis, 1995, 2004, 2005 kanye nezinkomba zalo) kanye nokungahambisani nokungavumelani (Melis et al., 1999a), futhi ngaphezu kwalokho kuphumelela ngokweqile ukuphazamisa ukuziphatha okuphambene kwamagundane angamadoda (Argiolas et al., 1988). Ngaphezu kwalokho, ukusebenzisana ngokocansi kwandisa i-FOS, umkhiqizo wegenesis we-geni esheshayo c-fos ema-neuron e-oxytocinergic ahlinzekela umgogodla ohilelekile ekulawulweni kwe-penile erection (bheka i-Witt ne-Insel, i-1994 nezinkomba kulo). Okokugcina, ukungabi namandla ngokocansi (isib. ukungakwazi komlingani omdala omdala ukulingana nesifazane westerrogene-progesteroneprimed receptive) hnjengoba futhi kuhlotshaniswa kumvuthongo wesilisa onamazinga aphansi e-oxytocin mRNA kanye ne-nitric-oxide synthase ku-nucleus ephambili ye-hypothalamus (Benelli et al., 1995; Arletti et al., 1997) (ukubuyekezwa okubanzi kwalezi zifundo bheka i-Argiolas, i-1999; i-Argiolas no-Melis, i-2004, i-2005).
I-2.2. Indawo ye-ventral tegmental
Indawo yendawo ye-ventral yatholwa maduzane nje njengesayithi lobuchopho lapho i-oxytocin yenza khona ukukhishwa kwe-penile. Le ndawo iqukethe ukuphela kwe-nerveus ne-oxytocin receptors (Freund-Mercier et al., 1987; Vaccari et al., 1998). Ngokuqondile, i-oxytocin itholakele engakwazi ukukwenzaukuhlenga i-penile erection uma injected unilaterally ibe caudal, kodwa hhayi endaweni rostral ventral tegmental ngendlela exhomeke kumthamo (Melis et al., 2007). Ukulinganisa okusebenzayo kwakungaphezu kwalawo okudingekayo uma kujowelwa yinucleus yomsindo futhi kufana nalabo abancenga ukukhishwa kwe-penile uma bejova ngaphakathi kwe-subiculum ye-ventral ye-hippocampus noma kwi-nucleus ye-cortical postticomal ye-amygdala (bheka ngezansi). Ngokusobala, umphumela we-pro-erectile uhambelana nokusebenza kwama-neuron angu-mesolimbic e-dopaminergic evulela igobolondo ye-nucleus accumbens, ebuye isebenze namanje izindlela ezingaziwayo ze-neural eziholela ezingxenyeni ze-incerto-hypothalamic dopaminergic ezithinta ama-neuron e-oxytocinergic aphikisanayo aphikisana ne-penile erection (Melis et al., 2007, 2009a).
Ngokuqondene nendlela i-oxytocin eyenza ngayo i-dopaminergic neurotransmission endaweni ye-ventral tegmental, idatha etholakalayo ibonisa ukuthi i-oxytocin ivuselela ama-oxytocinergic receptors esitholakala emzimbeni wesiguli se-mesolimbic ne-dopaminergic neurons. Lokhu kwandisa umxhwele we-Ca2 + ngaphakathi kwamagciwane esithombeni se-dopaminergic neurons, ngaleyo ndlela kusebenze i-nitric oxide-synthase (i-Succu et al., I-2008). Ngokungafani ne-nucleus ebonakalayo (bheka i-Section 3 ngezansi), i-nitric oxide ivuselela i-guanylate cyclase, ngaleyo ndlela ikhulisa ukuhlushwa kwe-GMP ye-cyclic. Ngokuhambisana nale ndlela, i-d (CH2) i-5Tyr (Me) i-2-Orn8-vasotocin, umphikisi omkhulu we-oxytocin, noma i-S-methyl-thio-l-citrulline, inhibitor enamandla ye-neuronal nitric oxide-synthase, efakwe indawo ye-ventral tegmental ngaphambi kwe-oxytocin, isusa i-penile erection kanye nokwanda kwe-dopamine engxenyeni eyengeziwe ye-dopamine kugobolondo le-nucleus accumbens elibangelwa i-oxytocin. Ngaphezu kwalokho, i-8-bromo-cyclic GMP, i-analogue esebenzayo ye-phosphodiesterase esebenzayo ye-phosphodiesterase, ikhuthaza ukukhishwa kwe-penile uma ijoqwe endaweni ye-caural ye-ventral futhi ikhulise ukuhlushwa kwe-dopamine engaphezulu kwesikhumba se-nucleus accumbens, etholakala nge-oxytocin injected into indawo ye-ventral tegmental (Succu et al., 2008; Melis et al., 2009a) (bheka futhi uFi. 2).
Ngokuvumelana njalo nale ndlela, i-haloperidol, i-dopamine enamandla kakhulu ye-D2 receptor antagonist, injected in igobolondo ye-nucleus accumbens yenza kunciphise i-penile erection eyenziwe i-oxytocin injected endaweni ye-ventral tegmental (Melis et al., 2007). Le ndlela engenhla ibuye isetshenziswe izifundo ezimbili zokuzivivinya i-immuno-fluorescence, ebonisa ukuthi ama-oxytocin fibers afaka emithanjeni yamangqamuzana e-dopaminergic neurons endaweni ye-ventral tegmental, eyayibhalwe ngaphambilini nge-retrograde tracer i-Fluorogold ejojelwe kugobolondo le-nucleus accumbens ( Melis et al., 2007; Succu et al., 2008). Ukusebenza kwalezi zinkinga ze-dopaminergic kanye ne-dopamine receptors ku-nucleus accumbens kuholela ekusebenziseni izindlela ze-neural ezingakabonakali, okukhuthaza i-incerto-hypothalamic ne-neoponeric neurons ukukhulula i-dopamine ku-nucleus ephambili, ngaleyo ndlela isebenze i-oxytocinergic neurons eyenza umgogodla kanye nokuxhumanisa ukulungiswa kwe-penile (bheka ngenhla noMelis et al., 2007; Succu et al., 2007, 2008). Ngempela, i-oxytocin injected in the caudal tegmental endaweni emkhakheni owabangela ukukhishwa kwe-penile, kwanda ukuhlushwa kwe-dopamine engaphezulu kweselula ku-dialysate engatholakali kuphela kwi-nucleus accumbens, kodwa futhi kusukela enkampanini yomsindo (Succu et al., 2007).
I-2.3. I-hippocampus
Insimu ye-CA1 ye-hippocampus yilapho enye indawo yobuchopho ecebile emafetheni e-oxytocinergic kanye nama-receptors ahlonishwe yizifundo zangaphambili lapho umjovo we-oxytocin wenza u-penile erection (bona uBuis, 1978; Sofroniew, 1983). Kodwa-ke, ngokungafani nucleus yendawo, lapha i-oxytocin itholakale inamandla okunciphisa ukukhishwa kwe-penile kuphela lapho ijojowe ngama-bilaterally nangamazinga aphezulu kunelabo abatholakalayo esebenzayo kwinucleus (Melis et al., 1986; Chen et al., 1992). Ukufakwe kwe-oxytocin ku-subiculum kwakutholakalanga kulezi zifundo zangaphambili. Noma kunjalo, izifundo zamuva kanye nokucophelela ezincane ezincane ziholela ekudaleni a isifunda se-subiculum ye-ventral lapho umjovo we-oxytocin wawunamandla okunciphisa ukukhishwa kwe-penile ngendlela exhomeke emtheni (Melis et al., 2009b). Umphumela we-pro-erectile we-oxytocin ojojelwe kulolu chungechunge lwendawo ubuye wabonwa ngamanani afana nalawo atholakalayo esebenza endaweni ye-ventral ngemuva kokujola okungahlanganisi (Melis et al., 2007), njengoba kutholakala ku-nucleus ephambili. Ngokusobala, i-oxytocin injected into subiculum ventral iholela e-penile erection ngokuvuselela oxytocinergic receptors in neurons aqukethe nitric oxide-synthase, okwenza ukwanda nitric oxide ukukhiqizwa. I-oxide ye-nitri ngokusebenza njenge-intercellular isithunywa isebenzisa i-glutamic acid neurotransmission, eholele ekusenikeni kwe-penile, mhlawumbe ngokusebenzisa ama-neural (glutamatergic) ama-projection avela ku-ventral subiculum ezindaweni ezingaphezulu ze-hippocampal eziqondisa umsebenzi we-mesolimbic ne-neuron (i-ventral tegmental, i-prefrontal cortex, i-nucleus ebonakalayo) (bheka ngezansi noMelis, 2007, 2009b; Succu et al., 2008).
Le ndlela yokusebenza isekelwa ukuhlolwa kwe-microdialysis ye-intra-cerebral, okubonisa ukuthi i-oxytocin injected into subiculum ye-ventral emithini yokwenza i-penile erection, ikhiqiza ukukhiqizwa kwe-nitric oxide kanye nokuhlushwa kwe-extracellular glutamic acid ku-dialysate evela e-ventral subiculum (i-melis et al. , I-2010) ne-dopamine ye-extracellular ku-nucleus accumbens (i-Melis et al., I-2007). Lezimpendulo zazingenwa yi-oxytocin receptor antagonist d (CH2) 5Tyr (Me) 2-Orn8-vasotocin, kodwa futhi ne-neuronal oxide-synthase inhibitor S-methyl-thio-lcitrulline kanye ne-nitric oxide scavenger hemoglobin eyanikezwa ungene emgodini we-subiculum ambalwa ambalwa ngaphambi kwe-oxytocin (Melis et al., 2010).
Ngaphezu kwalokho, ngokuhambisana nalendlela yokusebenza, ukuvuselelwa kwe-neurotransmission ye-glutamatergic yi-NMDA engeniswe ngaphakathi kwe-subiculum ye-ventral kudala i-penile erection (Melis et al., 2010). I-phenotype ye-projection eqondile evela ku-subralulum ye-ventral, eyenza ukuthi kusebenze i-nelionic eyelimbic ne-dopaminergic kanye nokwanda kwe-dopamine engaphezulu kweselula ku-nucleus accumbens, engaziwa okwamanje. Kodwa-ke, njengoba ukukhishwa kwe-penile okubangelwa i-oxytocin egayelwe ngaphakathi kwe-subiculum ye-ventral kwenzeka ngokuvumelana nokukhula kwe-extra-cellular glutamic acid ku-dialysate kusuka endaweni ye-ventral, kodwa hhayi ku-nucleus accumbens futhi ihlanjululwe yi-+ + MK-801, umphikisi onamandla ongeyena onokuncintisana we-excitatory amino acid receptors we-NMDA subtype (Woodruff et al., 1987), egxilwe endaweni ye-ventral, kodwa hhayi ku-nucleus accumbens (bheka Fig. 2 noMelis et al., 2009b) , kungenzeka ukuthi lezi zilinganiso ziholela ekusebenziseni i-neurotransmission ye-glutamatergism endaweni ye-ventral tegmental, okwenza kusebenze i-mesolimbic ne-dopaminergic neurons eyenza i-nucleus accumbens. Kungakhathaliseki ukuthi i-glutamic acid ekhuphukile etholakala endaweni ye-ventral ye-ventral ngemva kwe-oxytocin injection ibe yi-ventral subiculum ikhishwa kuma-neurons avela ku-subiculum noma kwezinye izindawo zobuchopho (isib. I-prefrontal cortex) engaziwa okwamanje. Noma kunjalo, lokhu kubangela ukusebenza kwe-nelioni ye-mesolimbic ne-dopaminergic nokukhululwa okwedlulele kwe-dopamine ku-nucleus accumbens. Lapha ukusebenza kwe-dopamine receptors kuholela ekusebenziseni i-incerto-hypothalamic neurons ne-dopaminergic, ukukhulula i-dopamine engxenyeni ye-pearl, ngaleyo ndlela kusebenze i-oxytocinergic neurons eyenza umgogodla nokuxazulula ukwakhiwa kwe-penile (bheka ngenhla noMelis et al., 2007, 2009a; Succu et al., 2008).
I-2.4. I-amygdala
I-amygdala ingenye indawo yobuchopho egcwele ama-oxytocin fibers kanye nama-receiptors (bona i-Freund-Mercier et al., I-1987; i-Vaccari et al., I-1998; i-Uhl-Bronner et al., I-2005). I-Oxytocin lapha kucatshangwa ukuthi ihileleke emisebenzini ehlukene, kusuka ekukhathaolysis, ekukhunjweni komphakathi nasekuqondeni, ekufundeni kwezenhlalo, ukuzwelana ngokomzwelo, ukuphathwa komuntu ngokomzwelo nokwesaba kubantu ekusebenzeni kwe-erectile nokuziphatha ngokocansi (bheka iKondo et al., 1998; iDominguez et al., 2001; i-Ebner et al., i-2005; i-Huber et al., i-2005; i-Domes et al., i-2007; i-Petrovic et al., i-2008; i-Lee et al., i-2009; i-Donaldson ne-Young, i- 2009; i-Hurlemann et al. , I-2010). Kodwa-ke, ikhono le-oxytocin lokwenza ukukhishwa kwe-penile kwamantongomane uma kukhishwa kwinucleyal cortical nucleus ye-amygdala yatholwa maduzane (Melis et al., 2009b). Le mpendulo yenzeke ngokuvumelana nokunyuka kokuhlushwa kwe-dopamine engaphezulu kwamaselula ku-dialysate etholakala kugobolondo le-nucleus accumbens, etholakala ngemva kwe-oxytocin injection ngaphakathi kwe-subralulum ye-ventral (i-Melis et al., I-2009b). Indlela okwakhiwa ngayo i-oxytocin engxenyeni ye-cortical posteromedial ye-amygdala eyenza i-penile erection engaziwa okwamanje. Idatha etholakalayo ibonisa ukuthi kokubili ukukhishwa kwe-penile kanye nokwanda kwe-dopamine engxenyeni eyengeziwe ye-dopamine ku-dialysate etholakala ku-nucleus accumbens ixhunyaniswa ngokusebenza kwe-oxytocinergic receptors, njengoba kokubili izimpendulo zaqedwa umphikisi we-oxytocin receptor d (CH2) 5Tyr ( Mina) I-2-Orn8-vasotocin injected in the amygdala nucleus amaminithi ambalwa ngaphambi kwe-oxytocin (Melis et al., 2009b).
Noma yikuphi indlela i-oxytocin esebenzayo ku-nucleus ehamba phambili ye-corycle ye-amygdala, ukusabela kocansi okubangelwa i-peptide kuqedwa ngokuvinjelwa kwazo zonke izidakamizwa ze-dopaminergic ezine-cis-flupenthixol ezijojelwe kugobolondo le-nucleus accumbens kanye nokuvinjelwa kwe-NMDA receptors nge ( +) I-MK-801 igxilwe endaweni ye-ventral tegmental, kodwa ingenayo i-nucleus accumbens, etholakala ekuhanjisweni kwe-penile eyenziwe i-oxytocin injected into subralulum ye-ventral (Melis et al., 2009b). Lokhu kusikisela ukuthi i-oxytocin injected in the nucleus posteromedial ye-amygdala isebenza nge-neurotransmission ye-glutamic in endaweni ye-ventral tegmental. Lokhu kubangela ukuvuselelwa kwama-neuron e-mesolimbic ne-dopaminergic, okuholela ekwakheni kwe-penile. Ngenxa yezifundo ezibonisa izindlela ze-neural ezixhuma le nucleus ye-amygdala ne-subralulum ye-ventral (i-Canteras et al., I-1995; isiFulentshi ne-Totterdell, i-2003), lokhu okutholakele kuphakamisa ukuthi kungenzeka ukuthi kungenzeka ukuxhumana phakathi kwalezi zindawo ezimbili zobuchopho, nakuba ziqondana ngqo Izindlela ezivela ku-amygdala noma kwi-nucleus accumbens noma endaweni ye-ventral tegmental zichazwe (Kelley noDomesick, 1982; Witter, 2006).
I-2.5. Umgogodla
Umthambo womgogodla ungenye indawo yesistimu yezinzwa ezisemkhatsini oqukethe i-oxytocinergic fibers kanye ne-receptors (i-Freund-Mercier et al., I-1987; i-Uhl-Bronner et al., I-2005), lapho i-oxytocin iholela khona ekuhambeni kwe-penile (Tang et al., 1998 ; Veronneau-Longueville et al., 1999; Giuliano noRampin, 2000; Giuliano et al., 2001). Njengoba kukhulunywe ngenhla, lezi zinkimbinkimbi ze-oxytocinergic zivela engxenyeni yomsindo we hypothalamus futhi zibambe iqhaza ekuhlahleni izindlela ezilawula izinzwa ze-spinal autonomic eziphakathi kwe-penile erection. Ngempela lezi zinkimbinkimbi zenza oxhumana nabo base-synaptic emacilini e-scandal sympathetic kanye ne-parasympathetic cell in the thoraco-lumbar ne-lumbo-sacral ne-spinal neurons ezingenasisindo se-penile cavernous corpora (Marson noMcKenna, 1996; Giuliano noRampin, 2000; Giuliano et al. , I-2001). Lawa ma-synaptic oxhumana nabo aboniswa ngokubhalwa kwe-neurons yomgogodla evela emthonjeni bese efinyelela umthambo womgogodla ngamathrekhi abuyele e-cavernous corpora, kuhlanganiswe nokuhlolwa kwe-immuno-fluorescence kabili kanye nokuhlolwa kwe-microscopy laser (Tang et al., 1998; Veronneau-Longueville futhi al., 1999). Ngokuvumelana nalezi zifundo, ekufakweni kwama-rats angama-intrathecal angamadoda angasetshenziselwa ukulinganisa ama-oxytocin e-lumbo-sacral, kodwa hhayi ezingeni le-thoraco-lumbar, kwenza ukuba ingcindezi engapheliyo iphakame ngendlela exhomeke kuyo. Lezi zimphumela zaqedwa ngokuvinjelwa kwe-oxytocinergic receptor nge-d (CH2) i-5Tyr (Me) i-2-Orn8-vasotocin nangesigaba sezinzwa zomzimba (Giuliano noRampin, i-2000; i-Giuliano et al., I-2001). Le miphumela ibonisa ukuthi i-oxytocin, esebenza emthonjeni we-spinal lumbo-sacral, yandisa ukucindezela okungenamandla, futhi iphakamisa ukuthi i-oxytocin, ekhishwe ngesikhathi sokusebenza komzimba we-nucleus ebonakalayo iyisisusa esinamandla se-spinal pro-erectile neurons eyenza i-cavernous corpora. Kuyathakazelisa ukuthi lezi zinzwa ze-pro-erectile zomgogodla ezisebenza nge-oxytocin zenza umphumela wayo we-pro-erectile, futhi zithola oxhumana nabo be-synaptic kusuka ku-neoton ye-serotoninergic evela ku-nucleus paragigantocellularis yokwakheka kwe-medulla oblongata (i-Marson no-McKenna, i-1992; i-Tang et al ., 1998). Ukubhujiswa kwalezi zinzwa ze-serotoninergic kusiza ukujula nokucubungula kwe-penile kumagundane angamadoda (Marson noMcKenna, 1992; Yells et al., 1992). Njengoba imithi ukufukula 5HT2C receptor lula penile ukwakhiwa lapho unikezwa intracerebroventricularly, kodwa hhayi ku-nucleus paraventricular, nezidakamizwa ukuthi receptor block 5HT2C ukunciphisa futhi Dopamine agonistand oxytocin olubangelwa penile ukwakhiwa, kuyilapho Dopamine abamelene musa ukwehlisa 5HT2C agonist olubangelwa penile ukwakhiwa ( bheka i-Stancampiano et al., i-1994 nezinkomba kulo), kuye kwaphakanyiswa ukuthi i-oxytocin yenza kube lula ukutholwa kwe-pro-erectile 5HT2C receptors ezingeni lezintambo ze-lumbo-sacral (Stancampiano et al., 1994). Ngaphandle kwalokho, i-oxytocin ingase ithonye umsebenzi we-neuron we-serotoninergic ehla emgodini ngokusebenza ngokuqondile ku-nucleus paragigantocellularis, lapho lezi zinezi zitholakala khona (bheka iSancancampiano et al., 1994).
I-3. Ukusebenzisana phakathi kwe-oxytocin, i-dopamine ne-glutamic acid esimisweni se-central central kanye ne-penile erection
Njengoba kukhonjiswe eSigabeni 1, zonke izinzwa ze-oxytocinergic ezikhona ohlelweni lwezinzwa ezisemkhathini zivela enkampanini yomsindo kanye nezakhiwo ezizungezile. Umsebenzi walezi neuron ungaphansi kokulawulwa kwama-neurotransmitter ahlukahlukene kanye / noma ama-neuropeptides. Phakathi kwalabo abafundiswa kakhulu ezingeni elibonakalayo kukhona i-dopamine, i-glutamic acid, i-gamma-aminobutyric acid (i-GABA), i-nitric oxide, i-endocannabinoids, i-peptide yama-opioid, i-peptides yokukhulisa i-hormone-ukukhululwa, i-peptide ehlobene ne-VGF ne-oxytocin ngokwayo. I-dopamine, i-glutamic acid, i-hormone yokukhula ekhulula ama-peptide, ama-peptide athola i-VGF kanye ne-oxytocin avuselela, isibonelo, lezi zinhlanganisela kanye nama-agonists enza lula ukukhipha i-penile erection uma ijojelwa ku-nucleus ephambili, kanti i-GABA, i-opioid peptides ne-endocannabinoids ingavimbela, isib. noma ama-agonists abo avimbela ukukhishwa kwe-penile (bheka i-Meisel no-Sachs, i-1994; i-Witt ne-Insel, i-1994; i-Argiolas no-Melis, i-1995, i-2004, i-2005; i-Giuliano no-Rampin, i-2000, i- 2004; i-McNenna, i-2000; i-Andersonson, i- 2001; i-Hull et al., i-2002).
Imikhakha eminingana yobufakazi bokuhlola iphakamisa ukuthi lezi neuron oxytocinergic kanye neurotransmitters engenhla kanye neuropeptides zihilelekile ekulawuleni umsebenzi we-erectile nokuziphatha ngokobulili ngezimo ezihlukahlukene zomzimba. Ngaphezu kwalokho, i-oxytocin ekhishwe ezindaweni ezingaphezu kwengqondo ze-hypothalamic, njenge-ventral tegmental, i-hippocampus nezindawo zayo, i-amygdala kanye nomgogodla ungathonya umsebenzi walezo neurons lapho i-syntoses i-oxytocinergic impinge. Okwamanje, i-neurons kuphela edingekayo ukuze i-penile erection lapho i-oxytocinergic synapses impinge, ekhonjiswe ngokuqinisekisiwe, yizidumbu ze-mesolimbic dopaminergic neurons yendawo ye-ventral tegmental eyenza igobolondo le-nucleus accumbens (Melis et al., 2007 ; Succu et al., 2008), kanye ne-neurctile ne-neurons e-pro-erectile ephuma esiteshini se-lumbo-sacral eya e-cavernous corpora (bheka i-Giuliano no-Rampin, i-2000; i-Giuliano et al., I-2001) (bheka futhi izingxenye 2.2 no-2.5) . Ngempela, nakuba ama-synapses e-oxytocineric kanye nama-receptors abuye ahlonishwa ngaphakathi kwe-subiculum ye-ventral, i-amygdala kanye nomgogodla, izindawo ezibaluleke kakhulu ukuze kulungiswe i-penile (bheka ngenhla), kulezi zindawo uhlobo lwe-neurotransmitter / s lunezinkanyezi okuyinto yokuphela kwengcindezi ye-oxytocineric impinge, ayisaziwa.
Lesi sigaba sokubukeza sichaza ngokufingqiwe izincwadi zamuva ngezindlela ezenza umphumela we-proto erectile we-oxytocin uvinjelwe endaweni ye-ventral tegmental, i-ventral subiculum ye-hippocampus kanye nentambo yomgogodla. Ukunakwa okukhethekile kuhlinzekwa ekuxhumaneni kwe-peptide ne-dopamine ne-glutamic acid kulezi zindawo futhi nendima lokhu kusebenzisana kungadlala ekulawuleni okuphakathi komsebenzi we-erectile. Ukufingqa okufingqiwe kwemiphumela ye-dopamine ne-glutamic acid e-oxytocinergic neurons ku-nucleus ye-paraventricular, ebuye iqhaza indima ebalulekile emsebenzini we-erectile inikezwa kuqala, ukuze wenze umfundi azi isimo sokucwaninga zakuqala kule nkambu, lezi zifundo sezivele zibuyekezwa kakhulu (bheka u-Argiolas noMelis, 1995, 2004, 2005; uMelis no-Argiolas, 2003). Futhi kulokhu, ukunakwa okunikeziwe emiphumeleni yakamuva kakhulu, okuphakamisa indima ebalulekile kokubili isixhumanisi se-dopamine-oxytocin kanye nesixhumanisi se-glutamic acid-oxytocin hhayi kuphela ekusebenzeni ngokobulili (ukukhishwa kwe-penile nokukopisha), kodwa nakwezocansi ukuvuselela nokugqugquzela ngokocansi.
I-3.1. Ukusebenzisana kwe-Dopamine-oxytocin ku-nucleus ephambili
The ikhono lama-dopamine agonists ukudala u-penile erection ngokuvuselela ama-neuron e-oxytocinergic ephakathi kwaphakanyiswa ngokushesha ngemuva kokutholakala ukuthi i-apomorphine ihoxisa ukukhishwa kwe-penile uma ijoyiwe ku-nucleus ephambili (Melis et al., 1987) lapho i-oxytocin receptor antagonist d (CH2) 5Tyr (Me) 2-Orn8-vasotocin injected intracerebroventricularly (icv) itholakala ekwazi ukunciphisa cishe i-penile erection eyenziwe nge-oxytocin kuphela, kodwa futhi nge-apomorphine, eyanikezwa ngezansi (Argiolas et al., 1987b). Le miphumela yalandelwa yilezi ezinye izifundo ezibonisa imiphumela efanayo uma i (CH2) i-5Tyr (Me) i-2-Orn8-vasotocin inikezwa i-icv ne-apomorphine yanikezwa ngqo kwi-nucleus ephambili (Melis et al., 1989b), lukuqala ukuphakamisa ukuthi i-dopamine agonists idala i-penile erection ngokusebenzisa izinzwa ze-oxytocinergic ezibonakalayo eziholela ezindaweni ezingaphezulu ze-brainpress futhi ikakhulukazi emthonjeni womgogodla (bona u-Argiolas noMelis, 1995, 2004, 2005). Ngokuvumelana nalesi sizathu, emagatsini angenasisekelo, ukuvinjelwa kwe-lumbo-sacral oxytocinergic receptors yi-non-peptide receptor antagonist ongewona i-peptide osanda kutholakala akwazi ukuqeda ukukhuphuka kwe-apomorphine ekukhusweni kwe-intracavernous okubangelwa i-dopamine agonist apomorphine, okunikeza ubufakazi umzila we-paraventriculo-spinal oxytocinergic ohilelekile ekuhanjisweni kwe-penile (Baskerville et al., 2009).
Izifundo ezihloswe ku ukuhlonza i-dopamine receptor obhekene nokufakwa kwe-penile erection, kwembulwe ukuthi nasezikhungweni ze-nucleus dopamine receptor agonists ezenza ukuba i-penile erection ibenze nge-dopamine receptors yomndeni wakwa-D2, njengoba kutholakala nge-dopamine receptor agonists enikezwa uhlelo (bheka uMelis et al., 1987; Eaton et al., 1991; Melis no-Argiolas, 1995a). Ngakho-ke, i-apomorphine, i-aponorrine, i-D1 / D2 receptor receptor, futhi i-quinpirole enamandla kakhulu, i-agonist ekhethiwe kakhulu ye-D2receptor, kodwa hhayi i-SKF 38393, i-D1 receptor receptor receptor, i-nucleus etholakale ibe yinto exhomeke ekudleni , futhi ukuphendula ngokocansi okubangelwa yi-D2 receptor agonists kwaqedwa abaphikisi be-D2 abamukelayo, njenge-haloperidol ne-l-sulpiride, kodwa hhayi ngo-SCH 23390, ophikisanayo we-D1 receptor (i-Melis et al., 1987). Ikhono le-apomorphine lokubangela ukukhishwa kwe-penile uma ijojelwe ku-nucleus ebonakalayo nayo yaqinisekiswa yizicwaningo ze-telemetry ezibonisa ukuthi i-dopamine agonist eyanikezwa i-nucleus ebonakalayo iyakwazi ukwandisa ukucindezeleka okungenasisindo ekuvuthweni kwamagundane angamadoda ngaphandle kokushintsha ukucindezeleka kwegazi (Chen et al. , I-1999; i-Giuliano ne-Allard, i-2001), etholakala ngemuva kokujova kwesistimu (Bernabè et al., 1999). Lezi zifundo nazo iqinisekisile indima eyinhloko ye-receptors ye-D2, njengoba i-D1 receptor receptor ngokuvamile ifunwa ukuthi ayikwazi ukwandisa ukucindezeleka okungenayo i-intracavernous uma ijojowe kwi-nucleus ephambili (Chen et al., 1999).
Kunezingqinamba eziningana zobufakazi bokuhlola ezabe zitholakala zikhomba ukuthi ama-receptor angama-D2, avuselela ama-penile erection, atholakala emzimbeni wesiguli se-oxytocinergic neurons. Okwokuqala, i-nucleus ebonakalayo iqukethe i-dopaminergic nerve terminals engezansi okuthiwa i-incertohypothalamic ne-dopaminergic neurons. Amaseli esilaya alawa neurons asezindaweni ze-A13 ne-A14 I-Dahlstrom ne-Fuxe (1964), iphikisana kakhulu nezinhlaka eziningi ze-hypothalamic, ezibandakanya ne-neonic oxtocinergic neurons eziholela ekwenzeni i-neurohypophysis kanye / noma ezindaweni eziningi zobuchopho (Buijs et al., 1984; Lindvall et al., 1984).
Ukubandakanyeka kwalezi zinkinga ze-dopaminergic ezingeni lesiphakamiso ekulawulweni kwe-penile erection kanye nokuxubungula kusekelwa izifundo ze-microdialysis ezibonisa ukuthi izingxube ze-extracellular dopamine ne-3,4-dihydroxyphenylacetic acid (i-DOPAC), i-metabolite yayo eyinhloko, yanda ku-dialysate etholakala i-nucleus ebonakalayo yamantombazane abesilisa abesilisa ocansini abonisa ukungahambisani nokungavumelani lapho efakwa phambi kwe-estrogen + i-proroterone-eyayihlonishwayo owesifazane (Melis et al., 2003).
Ukwanda kwe-dopamine kanye ne-DOPAC ukugxila kwakuphakeme nakakhulu uma ukuxubana nomfazi owamukelayo kuvunyelwe (i-Melis et al., I-2003), etholakala endaweni yangaphambili ye-preoptic (Hull et al., 1995) naku-nucleus accumbens (Pfaus no-Everitt, i-1995). Okwesibili, izifundo eziningana zibonisa ukuthi ukukhishwa kwe-penile okubangelwa ukugqugquzelwa kwe-D2 receptors, kuhanjiswa yi-oxytocin ekhishwe kulezi zindawo. Ngakho-ke, i-apomorphine eyanikezwa ngamanani okwenza i-penile erection, itholakale yandisa ukwanda kwe-oxytocin, hhayi kuphela e-plasma yamagundane nezinkawu (Melis et al., 1989a; Cameron et al., 1992), kodwa nangokwengeziwe kwengqondo izindawo, njenge-hippocampus (Melis et al., 1990). Ngokuvumelana nale miphumela, i-apomorphine injected in nucleus ezibonakalayo esenzweni esenza ukuba i-penile erection yamuva iboniswe ukuthi iyakwazi nokwandisa ukuhlushwa kwe-dopamine engaphezulu kwamaselula ku-nucleus accumbens, umphumela wehliswe yi-oxytocin receptor antagonist d (CH2) I-5Tyr (Me) i-2-Orn8-vasotocin injected endaweni ye-ventral tegmental (Succu et al., 2007; Melis et al., 2009a) (bheka futhi iSigaba 4). Okwesithathu, izilonda zogesi eziphakathi kwamanye ama-nucleus angama-pearl, ezicishe ziqede ngokuphelele i-oxytocin ezivela ezindaweni ezingqondweni ze-extra-hypothalamic (i-Hawthorn et al., I-1985), ziqede ukulungiswa kwe-penile (i-Argiolas et al., I-1987a) ye-apomorphine, ne-electrolytic receptor antagonists okunikezwa ngaphakathi kwezingxenyeni zangasese, kodwa hhayi ngaphansi kwe-nucleus ebonakalayo, ukunciphisa ukukhishwa kwe-penile e-apomorphineinduced ehambisana ne-potency efana naleyo yalezi zinhlanganisela ezivimbela i-oxytocin receptors (Melis et al., 1989b). Ama-oxytocin receptor antagonists nawo anamandla kakhulu ekunciphiseni ukugqugquzelwa kokuziphatha ngokocansi okwenziwe ngabantu hhayi kuphela yi-oxytocin, kodwa futhi nge-apomorphine (i-Argiolas et al., I-1988, i-1989).
Ngokuqondene nendlela i-D2 receptors eyenziwa ngayo i-dopamine noma i-dopamine receptor agonists, ukwandisa umsebenzi we-neurosic oxygen, ngaleyo ndlela ikhulule i-oxytocin ezindaweni ezingokwengqondo ze-extrahypothalamic nasendlini yomgogodla, idatha eminingi yokuhlolaukusekela inkolelo yokuthi ukuvuselelwa kwama-receptors e-D2 kwandisa ukuxilongwa kwe-Ca2 + i-intracellular ngaphakathi kwezingqamuzana ze-oxytocinergic neurons, okuholela ekusebenziseni i-nitric oxide-synthase, i-enzyme encike ku-CaxNUMX + -calmodulin, ekhona kulezi zitho zemizimba (i-Vincent no-Kimura, i-2; i-Torres et al., i-1992; i-Sanchez et al., i-1993; i-Sato-Suzuki et al., i-1994). Ukwanda kwe-nitric oxide ukukhiqiza kubangela ukuvuselelwa kwe-oxytocinergic neurons. Ngakho-ke, i-1998) i-apomorphineindation erection erection ivinjelwe izivimbela ze-calcium eziphilayo kanye ne -_-conotoxin GVIA, i-blocker enamandla futhi ekhethiwe yeziteshi ze-Ca1 + ezisekelwe ku-N-Mc (i-McCleskey et al., 2) enamandla, ezinikezwe esigabeni sokuqala i-nucleus (bheka i-Argiolas et al., i-1987, nezinkomba kulo); (1990) ukukhishwa kwe-penile eyenziwe nge-apomorphine kwavinjelwa yi-nitric oxide-synthase inhibitors enikezwe kwi-nucleus ephambili (Melis et al., 2c); futhi (i-1994) i-apomorphine namanye ama-agonists abamukela i-D3 anikezwe ngamanani awenza ukukhishwa kwe-penile kwanda ukukhiqizwa kwe-nitric oxide ekudonseni kwe-paraventricular etholakala yi-microdialysis yangaphakathi-cerebral, ukwanda okwenziwe ngama-inhibitors we-nitric oxide-synthase ayenziwe nge-nitric oxide I-D2 receptor i-ponte erection ehlanganisiwe (Melis et al., 2). Indlela yokwenza i-nitric oxide eyenza i-neuron ne-oxytocinergic neurons, ayisaziwa, nakuba idatha etholakalayo ibonisa ukuthi i-nitric oxide iyisithunywa se-intracellular nokuthi i-guanylate cyclase ayihilelekile. Ngempela, i-analogue esebenzayo ye-phosphodiesteraseresistant ye-cyclic GMP, i-1996-bromo-cyclic GMP, itholakala ukuthi ayikwazi ukudala ukukhishwa kwe-penile uma ihlinzekwa kwi-nucleus ephambili (Fig. 8) (bheka uMelis no-Argiolas, i-2b kanye nezinkomba).
Ukuhunyushwa ngenhla kuye kwavame ukubhekwa njengokungacabangi, ikakhulukazi ngoba ukugqugquzelwa kwe-Dopamine D2 receptors kuvame ukuhlanganiswa nokuvinjelwa kunokuba kunxushunxuswe kwamalungu esitokisi ama-neurons aqukethe lawa ma-receptors ngokusebenzisa izindlela ezihlukahlukene ze-protein ze-G (bheka uSokoloff noSchwartz, i-1995). Kodwa-ke, incazelo ecacile yalokhu kungavumelani, okuhambisana nokugqugquzelwa okuqondile kwe-neurosoni ye-oxytocinergic ne-dopamine, kuye kwaphakanyiswa kamuva nje ngokuthola I-protein-ehlangene i-dopamine i-D4 i-receptor, ilungu lomndeni we-D2 receptor (D2, D3 no-D4), ukugqugquzelwa okwandisa i-Ca2 + influx emasilini amaseli ane-cloned version yalesi subtype receptor (Moreland et al., 2004). Okubaluleke nakakhulu, i-D4 receptor receptor agonist (isib. ABT 724) (i-N-methyl-4- (2-cyanophenyl) piperazynil-3methylbenzamide i-maleate) itholakale inamandla okunciphisa ukukhishwa kwe-penile kwamagundane wesilisa lapho kunikezwa uhlelo (Brioni et al., I-2004). Le mphumela ayitholakalanga ne-D2 receptor subtype agonist ye-PNU-95666E ekhethiwe (R-5,6-dihydro-N, N-dimethyl-4Himidazo [4,5,1-i] quinolin-5-amine) (i-Hsieh et al., I-2004), futhi ayikwazanga ukwandisa umkhuhlane we-Ca2 + kumalungiselelo eseli equkethe uhlobo oluhlanganisiwe lwe-D4 receptor subtype (i-Brioni et al., i-2004; i-Moreland et al., i-2004). Ngokuvumelana nalokho okushiwo ngenhla kanye nokuthola, i-PD 168,077 (i-N-methyl-4- (2-cyanophenyl) piperazynil-3methylbenzamide i-maleate), i-PIP-3EA (2- [4- (2-methoxyphenyl) piperazin-1-ylmethyl] imidazo [1,2-a] pyridine) namanye ama-agonists akhethwe yi-D4 receptor (Heier et al., 1997; Melis et al., 2006b; Löber et al., 2009), atholakale akwazi ukukhipha i-penile erection uma ejowe ngendlela ehlelekile, i-nucleus ebonakalayo, nakuba ingaphumelela kakhulu kune-apomorphine. Umphumela we-pro-erectile walawa ma-agonist we-D4 receptor uvinjelwe yi-L-745,870 (3- (4- [chlorophenyl] piperazin-1-yl) -methyl-1H-pyrrolo [2,3-B] pyridine trihydrochloride), i-receptor ekhethiwe ye-D4 umphikisi (Patel et al., 1997; Melis et al., 2005, 2006b; Löber et al., 2009).
Ekugcineni, umphumela we-pro-erectile wama-agonists angenhla we-D4 wancishiswa nge-nitric oxide-synthase inhibitors, eyanikezwa i-nucleus ephambili, ne-d (CH2) i-5Tyr (Me) i-2-Orn8-vasotocin, umphikisi we-oxytocin we-receptor antagonist unikezwa i-icv kodwa hhayi kwi-nucleus ebonakalayo. Le miphumela ihambisana nalokho okushiwo ukuthi i-D4 receptor agonists ivuselela neuron oxytocineric ngokusebenzisa i-nitric oxide-synthase, futhi ikhulule i-oxytocin ezindaweni ezingqondweni ze-extrahypothalamic, okwenza kube lula ukuvuselelwa kwe-penile, njengoba kuboniswe i-apomorphine kanye ne-classic D2 agonists (Melis et al ., 2005, 2006b; Löber et al., 2009).
Lokhu okutholakala ngenhla futhi kusekela ukucabanga ukuthi i-dopamine idala ukulungiswa kwe-penile ngokusebenza kuma-receptors e-D4 asezigungwini zezingqamuzana ze-neuron e-oxytocinergic, futhi okubangela ukwanda kwe-Ca2 + emzimbeni wesiguli se-oxytocinergic neurons, okuholela ekhiqizweni kwe-nitric oxide production. I-oxide ye-nitric isebenzisa i-oxytocineric neurons ukuze ikhulule i-oxytocin ezindaweni ezingaphezulu ze-hypothalamic nobuchopho bomgogodla, njengoba kuxoxe ngakho kakade. Mayelana nalokhu, Kuyaphawuleka ukuthi i-dopamine receptors iye yabonakala emzimbeni wesiguli se-oxytocinergic neurons ku-nucleus ephambili Ucwaningo lwama-immuno-fluorescence lwakamuva nje kuphela olwenziwe ngama-D2, D3 kanye ne-D4 receptor antibodies kanye nama-oxytocin antibodies. Lezi zifundo zibonise ukubonakaliswa kwazo zonke ezintathu ze-D2receptor subtypes (i-D2, i-D3 ne-D4), ezakhiwe ngokuhlukana emzimbeni wesiguli se-oxytocinergic neurons ku-nucleus ephambili (nakwe-nucleus ephezulu kanye nendawo yangaphambili ye-preoptic) (Baskerville noDouglas, 2008; Baskerville et al., 2009).
Lokhu kunikeza ukuxhaswa okunamandla kwe-neuroanatomical ukuthi kungenzeka ukuthi i-dopamine ne-dopamine receptor agonists yohlobo lwe-D2 lenza i-penile erection ngokusebenzisa i-neuron e-oxytocinergic ngokuqondile eyenza ezindaweni ezibucayi ze-extrahypothalamic ezikhulunywe ngenhla, isib, intambo yomgogodla, indawo ye-ventral tegmental, i-hippocampus kanye ne-amygdala. Noma kunjalo, lokhu okutholakele akuhlinzeki nganoma yiluphi usizo lokuhlonza i-subXpe / s samukeli ye-D2, okuvuselelwa kwayo okubangelwa impendulo erectile. Ngeshwa, akukho usizo olutholakala ngisho nasezifundweni ezihloswe ekuboneni i-oxytocinergic neurons eyenziwa yi-dopamine receptor agonists ku-nucleus ephambili. Ngempela, naphezu umsebenzi ohlukile ahlukahlukene Dopamine yokwamukela subtypes, noma okuxubile Dopamine yokwamukela agonists (isib, apomorphine), noma abakhethayo D2 yokwamukela agonists (isib, quinpirole, okuyinto ethatha kuwo wonke D2 yokwamukela subtypes) noma abakhethayo D4 yokwamukela agonists kubangele ukusetshenziselwa kwe-oxytocinergic neurons, njengoba kulinganiswa ukwanda kwamaprotheyini e-FOS kuma-neurons e-parvocellular oxytocinergic we-nucleus ephambili (Bitner et al., 2006). Kodwa-ke, lokhu kutholakala kusanda kubuzwa, njengoba amaprotheni we-FOS akhula kuma-neuron e-oxytocinergic avela kuphela lapho kukhishwa i-penile okwenziwa yi-quinerolane, eyenza ngokuyinhloko kwi-D2 ne-D3 receptor subtypes, kodwa hhayi nge-PD 168077, i-D4 receptor agonist, kungakhathaliseki ukuthi ikhono lazo zombili izidakamizwa zenza ukuphendula ngokocansi (Baskerville et al., 2009).
Ukuhlolwa okwengeziwe kwama-agonists akhethiwe kwamanye ama-subtypes e-D2 receptor (ngokuyinhloko i-D2 ne-D3) ayadingeka ukuze abone indima eqondile ye-dopamine receptor subtype ekulawuleni umsebenzi we-erectile ezingeni lesiphakamiso. Kulokhu, njengoba sekukhulunywe ngaphambili, i-apomorphine, eyenza ngokucophelela kuwo wonke ama-dopamine receptor subtypes (bheka uBrioni et al., 2004, nezinkomba zayo), iphumelela kangcono kunama-receptors e-D4 ekunciphiseni i-penile erection uma ijojelwe ibe yombonisi i-nucleus. Lokhu kungase zingachazwa ngezinqubo ziyezwana ephakeme ka apomorphine ku D4 receptor uma iqhathaniswa nalokho ihlolwe D4 yokwamukela agonists, nomake, D4 yokwamukela agonists bangase benze njengokungathi D4 yokwamukela agonists ngokwengxenye, noma ukuqalisa concomitant ezahlukene Dopamine yokwamukela subtypes ngu apomorphine may ukhiqiza ukusebenza okuphezulu kwe-oxytocinergic neurons ephikisana nokukhishwa kwe-penile, kunokusebenza kwe-D2 receptor agonists ye-D4 receptor subtype kuphela.
Ukusebenzisana phakathi kwe-dopamine D1 kanye ne-D2 receptors kakade kuchazwe ekulawuleni ukuziphatha ngokobulili ezingeni le-preoptic endaweni yangaphakathi (bheka iHull et al., 1989). Uma kwenzeka ukuthi ukuhluleka kwe-D2 receptor agonists ukudala i-penile erection (i-Hsieh et al., I-2004) izoqinisekiswa (kodwa bheka i-Depoortère et al., I-2009), isibonelo ngisho nangemva kokujova kwalezi zinhlanganisela ku-nucleus ephambili , indima enkulu yama-receptors e-D3 yedwa noma kanye neyama-receptors e-D4 ekusebenziseni i-oxytocinergic neurons ephikisana ne-penile erection kufanele ihlaziywe ngokuningiliziwe (bheka iBaskerville et al., 2009). Ngeshwa, ama-agonist akhethiwe we-D2 ne-D3 (isib., Okungafani nokuhlangana kwabo kulawa ma-subpipes amabili we-receptor subtypes okungenani ama-oda amane / amahlanu we-in vitro) ayitholakali okwamanje. Ngenxa yalesi sizathu, isiphakamiso samuva ukuthi ama-receptors e-D3 asebenzisana nokuhlelwa kwe-penile okwenziwa yi-classic D2 receptor agonists, esekelwe ngokuyinhloko ekwenzeni abaphikisi be-D3 abaphikisanayo abavame ukuhlolwa kwe-vitro, ukunciphisa ukukhishwa kwe-penile eyenziwe ngama-agonists e-classical D2, i-apomorphine, i-quinpirole ne-pramipexole, eyenza ngokusheshisa yonke i-dopamine i-D2 receptor subtypes (i-Collins et al., i-2009), idinga ngokuqinisekile ukuqinisekiswa nezinye izivivinyo. Lokhu kuqinisekiswa kuyadingeka futhi ngoba akukho mthelela we-D4 receptor agonists e-penile erection etholakala kulolu cwaningo, ngokuphambene okuphawulekayo nemiphumela yezifundo okukhulunywe ngenhla, okubonisa umphumela we-pro-erectile wama-agonist we-receptor receptor. Ngempela, ngisho nekhono le-apomorphine lokwenza i-penile erection (kanye nokukhwabanisa) ku-D4 i-receptor i-knockout amagundane nge-potency efana nalokho okubonwa kuzinhlobo ze-D4 ze-recipor receptor mouse kanye nekhono labamelene nabe-D3 abathintekayo ekuqedeni impendulo ye-apomorphine kulezi zilwane ( I-Collins et al., I-2009) ayikwazi ukubhekwa njengobufakazi obucacile bendima ekhethiwe ye-subXpe ye-receptor ye-D3 ku-e-penile erection e-D2 eyamukelayo i-agonist. Lesitshalo umehluko ngaphandle, wafundela neurotransmitter / neuropeptide kanye / noma neurotransmitter / neuropeptide yokwamukela isakhi sofuzo ablation (neurotransmitter / neuropeptide kanye / noma neurotransmitter / neuropeptide izilwane yokwamukela Knockout) baye ngokuvamile wanezela ukudideka eminye kanye nezinkinga ku isiqinisekiso indima ngokobulili putative ka neurotransmitters futhi / noma ama-neuropeptide nama-receptors awo. Ngokufanayo, i-oxytocin gene ablation ikhiqiza i-oxytocin ikhiphe amantongomane futhi ilandele ngendlela evamile, njengokungathi i-oxytocin ayidingekile ekukhuliseni nasekuhlanganyeleni. Futhi i-homozygous female oxytocin knockout amagundane ibonisa ukuvuthwa okuvamile nokuhlukanisa, nakuba kunesisindo esibonakalayo sokuyeka ubisi (Nishimori et al., 1996; Young et al., 1996). Ukuxoshwa kwegesi okufake i-neuronal nitric oxide synthase ne-nitric oxide synthase, futhi kuveza i-nitric oxide synthase inqamule amagundane ukuthi umlingani uphinde ulandele ngokujwayelekile (Huang et al., 1993). Noma kunjalo, lokhu okutholakele kubonisa mhlawumbe isici esibalulekile sokuzivocavoca umzimba, okungukuthi, ukuhlukaniswa kwezinhlelo ezihilelekile ekulawuleni kwazo ezingeni eliphakathi nendawo.
Ukwehlukana okunjalo ngokuqinisekile kuvela emvelaphi yokuziphendukela kwemvelo, ngoba kuqinisekisa ukuthi izakhi zofuzo zizovela esizukulwaneni esilandelayo ukuze kusinde izinyoni. Ngakho-ke, iqiniso lokuthi ukususwa kwe-genetic receptor gene akushintshi umphumela we-pro-erectile we-apomorphine, kuphakamisa ukuthi ama-receptors e-D4, afana ne-oxytocin ne-nitric oxide, abambalwa abalamuleli abasebenza ezinkambini ezilawula umsebenzi we-erectile, kunokuba ukuphakamisa ukuthi ayikho indima kulaba bantu abamukelayo ekulawuleni ukukhishwa kwe-penile nokuziphatha kocansi. Ukuhluleka kwama-agonists e-D4 ukudala ukukhishwa kwe-penile uma kunikelwa ngendlela ehlelekile kumagundane angamadoda wezinkinga ezahlukene kusanda kubikwe esinye isifundo (Depoortère et al., 4). Nokho, ngokungafani nomsebenzi kaColins et al. (I-2009), futhi ukwenza isithombe ngendima ye-D2009 receptor subtypes ekulawuleni ukukhishwa kwe-penile ephazamisayo nakakhulu, lolu cwaningo lubonisa nokuthi ukukhetha abaphikisanayo be-D2 abaphikisayo abahlinzekiwe ngokwezifiso abazange bakwazi ukunciphisa ukufakwa kwe-penile e-apomorphine ama-rats angamadoda ehlukumeza kakhulu umphumela we-pro-erectile we-apomorphine, kuyilapho ukuphendula ngokocansi (kanye nokweqa) kwakuphikisana nomphikisi ophikisayo we-D3 L-2 (741,626 - [[3- (4-chlorophenyl) -4-hydroxypiperidin -4-yl] i-methyl-1H-indole), eholela abalobi ukuba bakhombise ukuthi abamukeli be-D1, esikhundleni se-D2 kanye ne-D3 receptors, yibo abadlala indima enkulu ku-Penile erection e-D4 eyenziwe nge-agonist (Depoortère et al., 2). Okokugcina, kungenzeka ukuthi umphumela wokuzijabulisa we-dopamine receptor agonists ema-oxytocinergic neurons ephikisana nokuhlelwa kwe-penile, okungenani ngeyingxenye, awuqondile ngaphandle kokuqondisa, isib. Ukukhulumisana noma ukuthonywa izinguquko emsebenzini wezinye izinzwa ze-neurotransmitters ze-neuropeptides ezikwazi ukuhlunga umsebenzi i-oxytocinergic neurons e-nucleus ephambili, ayikwazi ukukhishwa ngokuphelele.
I-3.2. Ukusebenzisana kwe-Glutamic acid-oxytocin ku-nucleus ephambili
I-nucleus ebonakalayo ye-hypothalamus inomcebo kakhulu ngama-synapses aqukethe i-amino acid exitatory njenge-neurotransmitter (isib. I-glutamic acid ne-aspartic acid) (UVan Pol, i-1991). Ama-amino acidative kule nucleus ahileleke emisebenzini eminingi, kufaka phakathi ukukhishwa kwe-penile nokuziphatha kocansi (Roeling et al., 1991; Melis et al., 1994b, 2000, 2004b). Ngakho-ke, i-N-methyl-d-aspartic acid (i-NMDA), i-agonist ekhethiwe ye-NMDA receptor subtype, kodwa hhayi (±) -_- amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) , i-agonist ekhethiwe ye-AMPA receptor subtype noma (±) -trans (1) -amino-1,3-cyclopentane dicarboxilic acid (ACPD), i-agonist ekhethiwe ye-subtype ye-receptor receptor, itholakala enamandla okunciphisa i-penile erection uma injected into i-nucleus yomsindo yamagundane ahamba ngokukhululekile (Melis et al., 1994b). Umphumela we-pro-erectile we-948 MR Melis, A. Argiolas / Neuroscience kanye nokubuyekezwa kwe-Biobehavioral 35 (2011) i-939-955 NMDA ivinjelwe (+) MK-801, umphikisi we-NMDA ongaphikisanga (Woodruff et al., 1987 ), injected in the nucleus paraventricular (Melis et al., 1994b). Ngokuvumelana nale miphumela, ekuhloleni kwe-telemetry okuhloswe ukuqapha ukucindezelwa okungenayo, i-NMDA itholakale isebenza kakhulu kunama-agonists enye i-excitatory amino acid receptor subtypes uma ijojelwe engxenyeni yomsindo ekukhuleni kwengcindezi ye-intracavernosal ephapheme noma ehlambulukile amantombazane wesilisa (Zahran et i-al., i-2000; u-Chen no-Chang, i-2003).
Njengoba kuphakanyisiwe ngenhla ye-oxytocin ne-dopamine, kungenzeka ukuthi abamukeli be-NMDA abaxazulula ukukhishwa kwe-penile bahlala emithanjeni yamangqamuzana e-oxytocinergic neurons, njengoba ukuphelelwa yisikhathi kwe-amino acid nesiphetho se-impinge ku-oxytocinergic cells body in the nucleus (Van Den Pol, 1991). Ngo Isifaniso nalokho zatholakala Dopamine yokwamukela agonists, umphumela pro-Erectile ka NMDA is ngokusobala ayengumlamuleli waso ukusebenza neurotransmission oxytocinergic, kokuba ezaqedwa yi d oxytocin omelene (CH2) 5Tyr (Me) 2-Orn8-vasotocin ICV unikezwa, kodwa hhayi engqungqutheleni ye-nucleus (bheka i-Argiolas no-Melis, i-1995, i-2004, i-2005 kanye nezinkomba zayo). Ngokufanayo, ukuvuselelwa kwe-NMDA eyenziwe nge-oxytocinergic neurotransmission nakho kuyisimangaliso ekusebenziseni i-nitric oxide-synthase, ngoba i-NMDA eyenziwe nge-penile erection ivinjelwe yi-nitric oxide-synthase inhibitors (i-N-Nitro-N-methyll-arginine methyl ester ne-N- methyl-thio-l-citrulline) unikelwe nucleus paraventricular, futhi NMDA injected nucleus paraventricular at ngemithamo ukuthi ntombazane penile ukwakhiwa, kwandisa ukukhiqizwa nitric oxide nucleus hypothalamic (bheka Argiolas futhi Melis, 1995, 2004, 2005 nezinkomba therein ). Mayelana ne-dopamine receptor agonists, i-NMDA eyenza ukuthi kusebenze i-nitric oxidesynthase ingase ibe yinkimbinkimbi ekwandeni kwe-Ca2 + emithonjeni ye-oxytocinergic cell through the receptors ehambisana ne-Ca2 + yesiteshi, njengoba kuboniswe emalungiselelweni amaningana ama-neural (okubukezwayo abone uSnyder, 1992; I-Southam no-Garthwaite, i-1993; i-Schuman no-Madison, i-1994 kanye nezinkomba zayo). I-oxide ye-nitri ivulela i-oxytocinergic neurotransmission (bheka ngenhla). Imvelaphi yezinhlobonhlobo ze-glutamatergic ezenza i-neuronic neuron yochungechunge ephikisana ne-penile erection ingaziwa, nakuba ubufakazi obunye bokuthi i-neuroanatomical ne-electrophysiological bubonisa ukuthi bangase baqale emlonyeni we-hippocampus (uSaphier noFeldman, 1987; Chen et al., 1992) . Nakuba kudingekile ukusebenza okuqhubekayo ukuze kuvezwe kangcono umsuka wezinto ezibonakalayo ze-glutamatergic ku-nucleus ephambili, ukubandakanywa kwe-glutamic acid ku-nucleus ebonakalayo ekulawuleni ukukhishwa kwe-penile kanye nokuziphatha ngokocansi kusekelwa ngokucacile izifundo ze-microdialysis. Ngakho-ke, ukubhekwa kwamagciwane amaningi e-glutamic acid kanye ne-aspartic acid kwandiswe ku-dialysate etholakala enkampanini yomsindo yamagundane angamadoda okubonisa ukungahambisani nokungavumelani uma ufakwa phambi kwamagundane ama-estrogen + ama-progesterone-amathandayo angenakufinyeleleka (Melis et al., I-2004b), ama-penile erections aphinde ahanjiswe ngokusungulwa kwe-transmission central oxytocinergic (Melis et al., 1999a, b). Ukunyuka okunjalo kutholakale nakakhulu uma ukuhlangana nomfazi okwamukelayo kuvunyelwe (Melis et al., 2004a). Ngokuvumelana nenkolelo yokuthi umsebenzi owandisiwe we-amino acidative exitatory kwenzeka enyakatho ye-nucleus ngenkathi i-penile erection ne-copulation, kokubili ukungahambisani nokungalingani nokuziphatha okuphambene nakho (ngesikhathi lapho kutholakala khona ukukhishwa kwe-copula penile) kunciphisa ukuvinjelwa kwama-receptors we-NMDA ku-nucleus ephambili , futhi lokhu kuncishiswa kulandelwa ukwehla kokukhiqizwa kwe-nitric oxide ukukhiqizwa okwenzeka kule nucleus hypothalamic kulezi zimo zomzimba (Melis et al., 2000). Ukwenyuka extracellular glutamic acid lokuhlushwa yesibili kuya kwehle Gaba ukukhululwa GABAergic kwalapho impinging ku excitatory acid acidergic synapse juxtaposed ukuba oxytocinergic emizimbeni cell, kwatholakala nucleus paraventricular ngemva nokuvinjelwa cannabinoid CB1 receptor yi CB1 omelene SR 141761A, okunikezwa ngaphakathi kwe-ventricles lateral noma ngokuqondile kwi-nucleus ebonakalayo emithini eyenza i-penile erection (bheka i-Succu et al., i-2006; i-Castelli et al., i-2007). Ukwanda okunjalo kwaholela ekusungulweni kwe-nitric oxide-synthase emzimbeni wesiguli se-oxytocinergic neurons, okwandisa ukwenziwa kwe-nitric oxide. I-oxide ye-nitri ivule ama-neuron e-oxytocinergic ehlanganisa ukulungiswa kwe-penile njengoba kuchaziwe ngenhla. Ngokuhambisana nale ndlela, i-SR 141761A eyabangela ukukhishwa kwe-penile yanciphisa ngokuvinjelwa kwama-receptors e-NMDA nangama-inhibitors we-nitric oxide-synthase, kodwa hhayi ngokuvinjelwa kwe-dopamine noma i-oxytocin receptors ku-nucleus ephambili, ngesikhathi ivinjelwe ukuvinjelwa I-central oxytocin receptors yi-oxytocin receptor antagonists enikezwa i-icv
I-3.3. Ukusebenzisana kwe-Oxytocin-dopamine endaweni ye-ventral tegmental
I-Oxytocin iveza ukukhishwa kwe-penile uma ijoqwe engxenyeni ye-caudal ye-ventral tegmental endaweni encike ekutheni (Melis et al., 2007). I-dose esebenzayo ephansi kakhulu injected unilaterally kwaba 20 Ng, kuyilapho isilinganiso esiphezulu ihlolwe kwaba 100 ng. Umphumela we-oxytocin uhlotshaniswa nokusebenza kwe-oxytocinergic receptors, njengoba ukusabela ngokobulili kupheliswa umjovo wangaphambi komphikisi we-oxytocin d (CH2) 5Tyr (Me) 2-Orn8-vasotocin endaweni ye-ventral tegmental. Lezi zitholampilo zitholakala emzimbeni wesiguli se-dopaminergic neurons, okuyinto iphrojekthi enkulu kakhulu kwigobolondo le-nucleus accumbens. Ngakho-ke, (1) izifundo ezimbili ze-immuno-fluorescence zibonisa ukuthi endaweni ye-ventral tegmental indawo ye-oxytocinergic fibers isondelene kakhulu namagciwane esithombeni se-dopaminergic neurons, iningi lawo elibhalwe kahle nge-tyrosine-hydroxylase futhi liqukethe i-retrograde tracer Fluorogold ngaphambili ukujova kugobolondo le-nucleus accumbens (i-Melis et al., 2007), kanye ne-2 endaweni yokwakhiwa kwe-oxytocin eyenziwe nge-penile erection eyenzeka ngokuvumelana ngokunyuka kokuxilongwa kwe-dopamine engaphezulu kweselula ku-dialysate etholakala egobolondo i-nucleus accumbens (i-Melis et al., i-2007). Ukwakhiwa kwe-penile ekwenzeni i-Oxytocin kwenzeka futhi ngokuhambisana nokwanda kwe-nitric oxide production endaweni yendawo ye-ventral, yizo zombili izimpendulo ezingenayo kuphela i-d (CH2) 5Tyr (Me) i-2-Orn8-vasotocin kanye ne-nitric oxide synthase inhibitor S- i-methyl-thio-l-citrulline, kodwa futhi yi-_-conotoxin, i-blocker ye-Ca2 + ethintekayo yombane, futhi i-ODQ (1H- [1,2,4] oxadiazole [4,3-a] quinoxalin-1-one), inhibitor enamandla ye-guanylate i-cyclase, konke okunikezwe endaweni ye-ventral tegmental ngaphambi kwe-oxytocin (i-Succu et al., i-2008). Njengoba iningi lamagciwane e-Dopaminergic ebizwa ngokuthi i-dopaminergic cells ahlangene namafayili e-oxytocinergic, atholakala ukuthi anesifiso sokuthi i-tyrosine hydroxylase endaweni ye-ventral tegmental, yayibhalwe kahle nge-nitric oxide-synthase ne-guanylate cyclase (i-Succu et al., I-2008), i-oxytocin -uped erection penile kungenziwa ukukhulumisana le ndlela elandelayo. Ukusetshenziselwa kwama-oxytocinergic receptors emithombeni ye-dopaminergic cell nge-peptide kwandisa imithwalo ye-Ca2 + ngaphakathi kwamagciwane esithombeni se-dopaminergic neurons. Lokhu kusebenze i-nitric oxide-synthase, i-CaxNUMX + -calmodulin encike enzyme, futhi ngokwandisa ukukhiqizwa kwe-nitric oxide. I-oxide ye-nitri isebenza ngokugcwele ku-guanylate cyclase, okuholela ekwenzeni ukwanda kwe-GMP ye-cyclic. I-Cyclic GMP isebenza nge-neurons e-dopaminergic eyenza i-nucleus accumbens. Indima ye-cyclic GMP ekwakheni i-penile eyenziwe i-oxytocin injected endaweni ye-caural tegmental yendawo iphinde isekelwe amandla we-8-bromo-cyclic GMP, i-analogue ephikisanayo ye-phosphodiesterase ye-cyclic GMP, ukuze kuqhutshwe ukukhishwa kwe-penile uma ijojowe indawo ye-ventral tegmental, nokwandisa i-dopamine engaphezulu kweselula ku-dialysate evela ku-nucleus accumbens (i-Succu et al., i-2008; i-Melis et al., i-2009a). Lokhu kuhluke ngendlela umthamo we-nitric oxide owenza ngayo ama-neuron e-oxytocinergic kwi-nucleus ephambili, i-8-bromo-cyclic GMP engakwazi ukukhipha i-penile erection uma injected kule nucleus (uMelis no-Argiolas, i-1995b) (Fig. 2). Ngokuphathelene nemigwaqo ye-neural esebenze yi-dopamine ku-nucleus accumbens eholela ekwenzeni i-penile, lezi zisaziwa. Noma kunjalo, idatha etholakalayo ibonisa ukuthi lezi zindlela zivuselela i-dopamine neurotransmission kuyi-nucleus ye-hypothalamus. Ngakho-ke, ukwakhiwa kwe-penile e-oxytocin eyenziwe nge-oxytocin kwenzeka ngokungahambisani nokunyuka kwe-dopamine engaphezulu kweselula hhayi kuphela i-nucleus accumbens, kodwa futhi ku-nucleus ebonakalayo, futhi ivinjiswe yi-dopamine receptor antiagonist haloperidol egxilwe engxenyeni yomsindo (Melis et al., 2007). AKuzobambisana, le miphumela isekela umqondo wokuthi i-oxytocinergic neurons evela kwinucleus yomsindo futhi iqhubekela phambili endaweni ye-ventral tegmental, lapho i-oxytocin evuliwe khona, futhi isebenze uhlelo lwe-NO-cyclic lokusayina uhlelo, okuyinto futhi kusebenze mesolimbic ne-neurons dopaminergic (Melis et al., 2007, 2009a; Succu et al., 2008). I-dopamine ekhishwe ku-nucleus accumbens iphinde isebenze izindlela ze-neural eziholela ekusebenziseni i-incerto-hypothalamic neoponergic neurons, evuselela ama-neuron e-oxygenic ne-pearl evulela umgogodla ophikisana ne-penile erection. Ngesikhathi esifanayo, i-dopamine ekhishwe kwi-nucleus ebonakalayo ingase isebenze ne-oxytocinergic neurons eyenza izindawo ezingqondweni ze-hypothalamic ezifana ne-ventral tegmental, i-hippocampus, i-amygdala futhi mhlawumbe nezinye izindawo zobuchopho.
Njengoba kukhulunywe ngenhla, ngokuvumelana nalesi sizathu, i-apomorphine injected in nucleus yombangazwe emthamo owenza i-penile erection iphinde ikhulise ukuhlushwa kwe-dopamine engaphezu kwamaselula ku-nucleus accumbens, umphumela wehliswe yi-oxytocin receptor antagonist d (CH2) 5Tyr (Me ) I-2-Orn8-vasotocin injected endaweni ye-ventral tegmental (i-Succu et al., I-2007; i-Melis et al., I-2009a). Ngamanye, izindlela ezingenhla ze-neural zingase zenze i-neuraltransmitters (hypothetical neuraltransmitry) ehlanganisa i-neopterine, i-oxytocin nezinye izifo ze-neurotransmitters (isib. I-glutamic acid, bheka ngezansi) ingathonya ukusebenza kocansi kuphela, kodwa nesisusa socansi nokuzijabulisa ngokocansi (bheka iSigaba 4).
I-3.4. Ukusebenzisana kwe-Oxytocin-glutamic acid ku-subiculum ye-ventral ye-hippocampus
I-oxytocin iveza ukukhishwa kwe-penile uma ijojelwe ngaphakathi, kepha hhayi kwi-subiculum ye-dorsal, ngendlela encike ekutheni (Melis et al., 2009b). Impendulo yezocansi ihambelana nokuvuselelwa kwe-oxytocin receptors, ekuqedeni umjovo wangaphambili we-d (CH2) i-5Tyr (Me) i-2-Orn8-vasotocini enikezwe endaweni efanayo ye-oxytocin, etholakala kwezinye izindawo zobuchopho (bheka ngenhla) . Ngokuqondene nokwaziswa kwala ma-receptors, idatha etholakalayo ibonisa ukuthi zitholakala emzimbeni wesiguli se-neurons esine-nitric oxide-synthase.
Ngakho-ke, ucwaningo lwe-microdialysis lubonisa ukuthi ukukhishwa kwe-penile eyenziwa nge-oxytocin kwenzeka ngokuhambisana nokwanda kwe-nitric oxide ukukhiqizwa kwe-subralulum ye-ventral, futhi lokhu kwanda kupheliswa nje kuphela ngenxa yokujova kwangaphambili kwe-nitric oxidesynthase inhibitor S-methyl-thio-l-citrulline kanye ne-nitric oxide scavenger hemoglobin, kodwa futhi nge-d (CH2) i-5Tyr (Me) i-2-Orn8-vasotocin, konke okunikezwe endaweni efanayo ye-oxytocin emithonjeni ephikisana ne-penile erection (Melis et al., 2010). Okubaluleke nakakhulu, ukwakhiwa kwe-penile eyenziwe nge-oxytocin kwenzeka futhi ngokuhambisana nokwanda kwe-glutamic acid engaphezu kwamaseli ngaphakathi kwe-subiculum ye-ventral, ephikisana kancane ne-non-competitive NMDA receptor antagonist (+) MK-801 enikezwe i-ventral subiculum (i-Melis et al., i-2010). Ngokubodwa, le miphumela iphakamisa ukuthi i-nitric oxide esanda kusungulwa, ngokwenza isithunywa se-intercellular, ivuselela i-glutamic acid neurotransmission eholele ekutheni i-penile erection, mhlawumbe ngokusebenzisa izilinganiso ze-neural effect i-subiculum ezindaweni ezingaphezulu ze-hippocampal. Ngokuvumelana nalesi sizathu, I-NMDA injected into subiculum ventral iholela e-penile erection ngendlela exhomeke emthamo, futhi lokhu nomphumela uvinjiswe ngokuphelele umjovo wangaphambili endaweni efanayo (+) MK-801, kodwa hhayi S-methyl-thio-l-citrulline , i-hemoglobin noma i-(CH2) i-5Tyr (Me) i-2-i-Orn8-vasotocin (i-Melis et al., i-2010). Ngokuqondene nezindlela ze-neural ezihamba phambili ezibhekisela ezindaweni ezingaphezulu ze-hippocampal ezicutshungulwa yi-amino acids (okuwukuthi, i-glutamic acid) e-subralulum ye-ventral, kungenzeka ukuthi lena yi-glutamatergic, njengoba iningi lama-hippocampal asebenza kahle. Okwamanje, kungase kuphakanyiswe kuphela ukuthi lezi zilinganiso ziqondisa umsebenzi we-mesolimbic ne-neurons we-dopaminergic, okwenza ukuthi ihambise umsebenzi we-incerto-hypothalamic ne-dopaminergic neurons ku-nucleus ephambili, okuholela ekusebenzeni kwe-oxytocinergic neurons ukuxhumanisa ukulungiswa kwe-penile njengoba sekuxoxwe kakade (bheka ngenhla).
Ngakho-ke ukukhishwa kwe-penile okubangelwa yi-ventral subiculum oxytocin kwenzeka ngokuhambisana nokunyuka kwe-dopamine engaphezulu kweselula kugobolondo le-nucleus accumbens, futhi lokhu kwanda, njenge-penile erection, kuqedwa nguD (CH2) 5Tyr (Me) 2- I-Orn8-vasotocin inikwe i-subiculum yangaphakathi ngaphambi kwe-oxytocin (i-Melis et al., I-2009b). Ngaphezu kwalokho, njengoba i-ventral subiculum oxytocin eyenza i-penile erection iyancishiswa (+) i-MK-801 injected endaweni ye-ventral tegmental, kodwa hhayi ku-nucleus accumbens (i-Melis et al., I-2009b) futhi iyenzeka ngokuvumelana nokwanda kwama-cell-extra i-glutamic acid endaweni ye-ventral, kodwa hhayi ku-nucleus accumbens, njengoba kokubili izimpendulo eziqedwe ngu-d (CH2) 5Tyr (Me) -Orn8-vasotocin, injected subiculum ventral ngaphambi oxytocin (bheka Fig. 3), kungenzeka ukuthi ukuvuselelwa kwama-neurons we-mesolimbic ne-dopaminergic kungokwesibini kwi-neurotransmission ye-glutamatergic eyandayo endaweni yangasese ye-ventral. Lokhu kusikisela ukuthi ukusebenzisana kwe-acutamic acid-dopamine elawula ukukhishwa kwe-penile kukhona endaweni ye-ventral tegmental. Ucwaningo olwengeziwe luyadingeka ukuze kuqinisekiswe ukuthi indlela ehamba phambili ye-pro-erectile ehambisana ne-subiculum eya endaweni ye-ventral iqondisa ngqo noma engaqondile, okungukuthi, nge-prefrontal cortex noma kwezinye izindawo zobuchopho (bheka uMelis et al., 2009b kanye nezinkomba zalo). Njengoba i-nucleus eyimvelo ibuye ilandelwe iziqhumane ze-glutamatergic kusukela ku-hippocampus (bheka ngenhla futhi uSaphier noFeldman, 1987), futhi i-glutamic acid isebenza nge-neurons e-oxytocinergic eneziqhumane ezibandakanya labo abaya endaweni ye-ventral tegmental (bheka u-Argiolas noMelis, i-2005 kanye nezinkomba kulo), futhi i-oxytocin endaweni ye-ventral tegmental yenza i-penile erection iphinde ikhulise umsebenzi we-mesolimbic dopaminergic neurons (bheka ngenhla), kuyamangalisa ukucabanga ukuthi pI-neurons yama-aravinicular i-oxytocinergic ingase ibandakanyeke futhi, okungenani ingxenye, ekusebenziseni kwe-nelions ye-mesolimbic ne-dopaminergic nge-oxytocin egayelwe ngaphakathi kwe-subiculum ye-ventral (bheka iSigaba 4).
I-4. Amazwi okuphetha
Ucwaningo olwenziwe ngenhla luqinisekisa futhi lwandise iziphumo zakuqala ezibonisa ukuthi emagodini amaduna i-oxytocin idlala indima ebalulekile ekulawuleni okuphakathi kwe-penile erection ezingeni le-nucleus ye-hypothalamus ne-spinal cord. Ikakhulukazi, iningi kakhuluAmaphesenti ayishumi abonisa ukuthi i-oxytocin ithonya i-penile erection futhi ngokwenza kwezinye izindawo zobuchopho, okungukuthi, indawo ye-ventral, i-subralulum ye-ventral, ne-nucleus e-posteromedial cortical ye-amygdala.
Esikhathini esiphezulu, ukutholakala okusha okubaluleke kunazo zonke mhlawumbe ukutholakala kwenkulumo yazo zonke izidakamizwa ze-dopamine zomndeni we-D2 (D2, D3 no-D4) emzimbeni wesiguli se-oxytocinergic neurons ku-nucleus ephambili (nase-nucleus ephezulu indawo yangaphambili ye-preoptic) (Baskerville noDouglas, 2008; Baskerville et al., 2009). Lokhu kunikeza nge-neuroanatomical eqinile ukusekela ekucatshangweni ukuthi i-dopamine ne-dopamine receptor agonists ingase isebenze ngokuqondile i-oxytocinergic neurons ehilelekile ekusebenzeni kwe-erectile futhi ingaphangeli nje kuphela emthonjeni womgogodla, kodwa nakwezinye izindawo ezingqondweni ze-hypothalamic. Kulokhu, kubalulekile ukutholakala ukuthi ukunyuka kwe-dopamine receptor-okwenziwe ukwanda kwe-intracavernous yancipha ngokuvinjelwa kwama-oxytocinergic receptors ku-lumbo-sacral intambo yomgogodla (Baskerville et al., 2009). Ngempela, nakuba ubufakazi obunjalo bufunyenwe kumantombazane angamaduna angenasisindo, lokhu kutholakala kuqinisekisa ukusebenza kwe-paraventriculo-spinal oxytocineric endleleni ehilelekile ekubandakanyekeni kwe-dopamine receptor-induced penile erection. HKodwa-ke, kusadingeka kuqinisekiswe ukuthi ukukhishwa kwe-penile okubangelwa ukuvuselelwa kwama-dopamine receptors akhona emzimbeni wamaseli e-oxytocinergic kungokwesibini ekusebenziseni i-dopamine receptor subtype yomndeni we-D2 (D2, D3 noma i-D4) noma uma lezi-receptor subtypes zisebenzisana ekunciphiseni impendulo ye-erectile, mhlawumbe ngezindlela ezehlukene kuye ngokuthi umongo wenziwe kuphi i-penile (bheka i-Moreland et al., 2004; Enguehard-Gueiffier et al., 2006; Melis et al., 2006a, b; Löber et al., 2009; Collins et al., 2009; Depoortère et al., 2009; Baskerville et al., 2009).
Okunye okubalulekile okutholayo ukuthi i-oxytocin yenza ukukhishwa kwe-penile uma kungenwa kuphela ku-nucleus ebonakalayo noma insimu ye-CA1 ye-hippocampus, kodwa futhi endaweni yangasese ye-ventral, i-ventral subiculum, kanye ne-nucleus yangemva kwe-corycle yama-amygdala. Lezi zindawo zobuchopho azihlolwanga ezincwadini zokuqala ezibonisa ukuthi i-oxytocin yanda iziqephu zepenile erection ezinqoleni zamadoda, nakuba zithola njenge-lumbo-sacral yomgogodla we-oxytocinergic projections kusuka ku-nucleus ephambili. I-Oxytocin yatholakala ukuthi iyakwazi ukwandisa izigameko zesikhumba esiphambukayo, ezivela kumagundane amaduna amakhulu lapho kungekho khona isenzo socansi, njengalezo ezivela ekubeni khona kwe-estrogen-progesterone eyamukelekayo (ratrogen-progesterone primed) isimiso se-ovariectomized female noma ukuxhaphazwa kwama-genitalia, lapho kujoqwelwa enkampanini yomsindo kanye nensimu ye-CA1 ye-hippocampus, kodwa hhayi kwi-subiculum ye-dorsal, i-septum lateral, i-nucleus ye-caudate, indawo engaphambili ye-preoptic, i-nucleus ye-ventrom ne-nucleus enkulu (Melis et al. , I-1986). Kuzo zonke lezi zifundo u-penile erection wayevame ukubalwa lapho i-penis iphuma emgodini we-penile ngumuntu obuka amehlo owayengazi ngokunakekelwa okwenziwe ngokuqondile ngenkathi kuhlolwa noma kamuva ngokubheka ukuhlolwa okuqoshwe ku-videotape nge-camera camera apparatus. Isiqephu ngasinye se-penile erection siphelela i-0.5-1 min futhi ngokuvamile sihambisana nokuzilungisa kwe-penile kanye / noma ukukhishwa kwe-hip. Akekho ukuhlolwa okuvame ukuwenziwa kulezi ziphutha ukuze kuqinisekiswe ukuthi umphumela wesipiliyoni, ubudala noma uma lezi zimpondo zingahlukaniswa nabaphenduli abaphansi noma abaphezulu ekusebenzeni kwe-pro-erectile ye-oxytocin egayelwe ezindaweni ezahlukene zobuchopho. Lokhu kusebenza naseziningi zezifundo ngomphumela we-pro-erectile wamanye ama-neuropeptides nezidakamizwa ezikhulisa iziqephu ze-penile erection zesikhashana, kuhlanganise ne-dopamine agonists, ama-amino acidatory, ACTH-MSH, i-hexarelin ne-VGF peptides. Kodwa-ke, umphumela we-pro-erectile walezi zinhlanganisela uye waqinisekiswa ngokuphindaphindiwe ngezindlela ze-telemetry, ezenza kube khona okwakhiwa kwe-penile ngokukhuphuka kwengcindezi ye-intracavernous eyenzeka ngokuzenzekelayo noma emva kokuphathwa kwalezi zinhlanganisela ngezindlela ezihlukene, okusho ukuthi, ngokuhlelekile, ngokwemvelo noma ngqo ku-brain nuclei ethile, emva kokufakelwa kwengcindezi ye-microtransducer ngqo kwi-corvernous corpora (bheka uBernabè et al., 1999). Esikhathini se-ventral tegmental, i-subralulum ye-ventral kanye nucleus posteromedial ye-amygdala futhi i-oxytocin iholela ekutheni i-penile erection ibenze nge-oxytocinergic receptors. Lokhu kuholela ekusebenziseni kwe-neurons ye-mesolimbic ne-dopaminergic evela endaweni ye-ventral tegmental futhi ekhombisa igobolondo le-nucleus accumbens, njengoba kulinganiswa ukunyuka kweminye ukuhlushwa kwe-dopamine engxenyeni eyengeziwe etholakala kwigobolondo ye-nucleus accumbens kanye nokunciphisa impendulo erectile eyenziwe yi-peptide ejojelwe kulezi zindawo ezingaphezu kwe-hypothalamic, etholakala ngemuva kokuvinjelwa kwama-receptor e-dopaminergic i-nucleus accumbens (bheka ngezansi). Ngokuqondene nezinqubo ezenziwa ukuvuselelwa kwe-oxytocinergic receptors kulezi zindawo zobuchopho, okuholela ekusebenziseni kwe-nelions ne-penile ye-mesolimbic ne-penile erection, okucaciswa kakhulu yilokho okwenzeka endaweni ye-ventral tegmental. Ngempela, lapha imiphumela yezokwelapha kanye ne-immuno-fluorescence ibonisa ukuthi i-oxytocin isiphetho sesiphetho esithinta imizimba yamaseli we-dopaminergic neurons eyenza igobolondo le-nucleus accumbens (Melis et al., 2007, 2009a; Succu et al., 2008). Eziningi zalezi zi-neuron zicebile ku-nitric oxide synthase naku-guanylate cyclase. Ukuvuselelwa kwama-oxytocinergic receptors emithanjeni yamangqamuzana alawa ne-dopaminergic neurons kubangela ukuthi kusebenze i-nitric oxide synthase eholela ekwenzeni ukwanda kwe-nitric oxide production. I-oxide ye-nitri ivule amandla i-guanylate cyclase, ngaleyo ndlela yandisa ukuhlushwa kwe-GMP ye-cyclic, okuholela ekusetshenzisweni kwe-nelions eyelimbic dopaminergic nokukhululwa kwe-dopamine ku-nucleus accumbens, njengoba kulinganiswa ukwanda kwe-dopamine engaphezulu kweselula ku-dialysate evela ku-nucleus accumbens etholakala yi-microdialysis yangaphakathi-cerebral (Succu et al., 2008 ). I-dopamine ekhishwe ku-nucleus accumbens iphinde isebenze izindlela ze-neural eziholela e-penile erection. Lokhu kusekelwa ikhono le-dopamine receptor abaphikisana ne-haloperidol kanye / noma i-cis-flupentixol injected in the nucleus accumbens ukunciphisa indawo ye-ventral tegmental eyakhiwe i-penile erection (Succu et al., 2008). Enye yezinqubo ze-pro-erectile ibonakala isebenzise i-incerto-hypothalamic neoponergic neurons, ikakhulukazi leyo eyenza imizimba yamangqamuzana e-neuron e-oxytocinergic ephikisayo. Ngempela i-oxytocin injected endaweni ye-caural tegmental yandisa i-extracellular dopamine hhayi kuphela ku-nucleus accumbens kodwa futhi ku-nucleus ebonakalayo, nokuvinjelwa kwama-dopamine receptors ku-nucleus ye-paravista kunciphisa indawo enkulu ye-ventral tegmental endaweni ye-penile erection (Succu et al. , 2007, 2008; Melis et al., 2007, 2009a). Ukutholakala kwalezi nucleus kuhlanganisa i-dopamine-yombhalo wecopamine-yombonakaliso we-oxytocin-ventral endaweni ye-oxytocin-dopamine links kuphakanyiswa futhi ikhono le-pro-erectile dose ye-apomorphine kanye ne-D4 receptor agonist PD 168077 efakwe engxenyeni yomsindo ukuze kwandiswe i-dopamine engaphezulu kweselula kugobolondo le-nucleus accumbens (i-Succu et al., i-2007), impendulo okupheliswa ngu-d (CH2) i-5Tyr (Me) -Orn8-vasotocin enikezwe endaweni ye-ventral tegmental (Melis et al., 2009a, bheka futhi ngezansi). Noma kunjalo, umsebenzi oqhubekayo kuyadingeka ukukhomba izindlela ze-neural ezihlanganisa i-nucleus accumbens ohlelweni lwe-incerto-hypothalamic dopaminergic.
Indlela yokwenza i-oxytocin yenza i-penile erection iphinde isebenze i-nelions i-mesolimbic i-dopaminergic neurons uma ijojwe ngaphakathi kwe-subiculum ye-ventral noma i-nucleus ye-posteromedial ye-amygdala iqondakala kancane okwamanje. Kulezi zindawo futhi, i-oxytocin isebenza ngokwezifiso zayo eziholela ekusebenzeni kwe-nitric oxide-synthase, ngaleyo ndlela yandisa ukukhiqizwa kwe-nitric oxide. I-oxide ye-nitri ivule amandla okungaqondakali okungaziwa kahle, okubonakala ukuthi kwandisa i-glutamatergic neurotransmission endaweni ye-ventral tegmental. I-glutamic acid ivuselela i-mesolimbic ne-dopaminergic neurons eholela e-penile erection. Le ngqondo ixhaswa ngokuyinhloko ngekhono le-oxytocin egayelwe ngaphakathi kwe-subralulum ye-ventral ukwandisa i-glutamic acid engaphezulu kwamasendaweni endaweni ye-ventral (Fig. I-3), kanye ne-NMDA ye-receptor antagonist (+) i-MK-801 engenayo yokuncintisana endaweni ye-ventral tegmental, kodwa hhayi ku-nucleus accumbens, ukunciphisa ukukhishwa kwe-penile okubangelwa i-oxytocin injected noma i-subralulum ye-ventral noma i-nucleus ye-posteromedial of the amygdala (Melis et al., 2009b). Okwamanje, imininingwane eyengeziwe iyatholakala kwi-penile erection subiculum e-oxytocin. Lapha ukukhishwa kwe-penile eyenziwe nge-oxytocin kubonakala sengathi kusetshenziselwa ukuvuselelwa kwe-oxytocinergic receptors etholakala emzimbeni wesiguli se-nitric oxide-synthase-containing neurons. Lokhu kubangela ukwandisa ekukhiqizeni i-nitric oxide, eyenza i-neurotransmission ye-glutamatergic ngokwenza isithunywa se-intercellular ngenqubo efanayo naleyo echazwe amandla okuhlala isikhathi eside (bona uSnyder, 1992; uSoutham noGarbetite, 1993; Schuman no Madison, 2004) . Ngokuvumelana nalesi sizathu sokuthi i-penile erection eyenziwe i-oxytocin eyenziwa yi-concomitantly ngokunyuka kwe-extracellular glutamic acid ku-dialysate evela ku-subralulum ye-ventral, nokuvuselelwa kwe-amino acid receptors kwi-subralulum ye-ventral yi-NMDA, kudala i-penile erection. I-glutamic acid ivuselela izilinganiso ze-neural efferent, eziholela ekusebenziseni i-nelions ye-mesolimbic ne-dopaminergic endaweni ye-ventral tegmental, njengoba kubikiwe ngenhla. Uma lezi zindlela zisebenza futhi kule nucleus posteromedial ye-amygdala aziwa okwamanje. Ngaphezu kwalokho, kudingeke ucwaningo olwengeziwe ukuze kufakazele ukuthi (i-1) i-oxytocinergic nerve endings kanye ne-receptors kwi-subiculum ye-ventral nasesikhungweni se-amygdala se-posteromedial sitholakala endaweni yesiguli se-neurons equkethe i-nitric oxide-synthase, (2) uma lezi zineurons zigcina ngaphansi kokulawulwa kwe-amino acid (glutamatergic) synapses kanye (3) ukukhomba uhlelo lokubonisa olwenziwa yi-nitric oxide. Kulokhu, kuyaphawuleka ukuthi ikhono le-oxytocin landa umsebenzi we-nitric oxide-synthase emithanjeni yamangqamuzana e-dopaminergic neurons endaweni ye-ventral tegmental kanye ne-neurons engaziwa ngaphakathi kwe-subiculum ye-ventral kanye ne-nucleus ye-postyomedial ye-amygdala, ekhumbula ikhono le-oxytocin ukwenza kusebenze i-nitric oxide-synthase emzimbeni wesiguli se-oxytocinergic neurons ku-nucleus ephambili (Melis et al., 1997). Kodwa-ke, ngenkathi endaweni yokucwaninga kwemvelo ukukhiqizwa okwandisiwe kwe-nitric oxide emithanjeni yamangqamuzana e-dopaminergic neurons kuholela ekusebenziseni lawa ne-neuron ngokusebenzisa i-guanylate cyclase nokunyuka kwe-GMP ye-cyclic, lokhu akukwenzeka kwi-nucleus ephambili. Ngakho-ke, i-8-bromo-cyclic GMP injected in i-nucleus ezibonakalayo ayikwenzanga ukukhishwa kwe-penile, kuyilapho yenza kanjalo lapho ijoqwe endaweni engena endaweni ye-ventral. Enye indlela yokubonisa indlela ehlukile ye-nitric oxidecyclic system GMP ibandakanyeka ezingeni elibonakalayo ekusebenziseni i-oxytocinergic neurons ephikisana nokuphakanyiswa kwe-penile nge-nitric oxide engapheliyo noma / noma engavamile (uMelis no-Argiolas, i-1995b; i-Melis et al., I-1997). . 1). Ngakolunye uhlangothi, i-cyclic GMP endaweni ye-ventral tegmental ibonakala idlala indima ebalulekile ekusebenziseni i-nelions ye-mesolimbic ne-dopaminergic kanye nokwanda kwe-dopamine engaphezulu kweselula eyenzeka ku-dialysate etholakala kwigobolondo le-nucleus accumbens yamagundane angamadoda okhethiwe ukubonisa noma ukungabonisi okwenziwe okungahambisani ne-penile uma ufakwa phambi kwe-ovariectomized receptive (isrogen + progesterone ephathwayo). Kulezi zimo zokuhlola, emagodini abesilisa abonisa ukungavumelani okungahambisani nawo, ukwanda kweminye yokuhlushwa kwe-dopamine yeselula kutholakala njengoba kulindeleke, futhi lokhu kwanda kwanda, nakuba ngokuzithoba, ngama-inhibitors e-phosphodiesterase anikezwe endaweni ye-ventral tegmental (Sanna et i-al., i-2009).
Ikhono le-oxytocin lijojelwe endaweni ye-ventral tegmental, kwi-subiculum ye-ventral nase-nucleus ye-cortic posteromedial ye-amygdala, kanye ne-dopamine agonists injected in the nucleus paraventricular, ukudala i-penile erection nokuvuselela i-mesolimbic ne-dopaminergic neurons ifanele ukuphawula . Okokuqala, izindlela ezifana nalabo okukhulunywe ngenhla zingase zisebenze uma ukukhishwa kwe-penile kwenzeka ezimweni zomzimba, njengesikhathi sokuqhuma (lapho ku-copula penile erections) noma ngesikhathi sokungahambisani nokuphikisana kwama-penile. Lezi ziphazamiso ziyi-perile erections e-interrections-mediated erections engaqondaniswa nalabo abathonywa izidakamizwa noma i-oxytocin, eyenzeka lapho ama-rats angamadoda avela ngokobulili abekwe phambi kwe-inaccessible receptive (ovariectomized estrogen + progesterone primed). i-arousal (i-Sachs, i-1997, i-2007). Ngempela, nakuba le miphumela ingabonakali ukuthi i-oxytocin kulezi zindawo ibambe iqhaza ekukhulisweni kwepenile ezenzeka ezimweni zomzimba noma emva kokuphathwa kwezidakamizwa, zengeza amandla engeziwe ekutholeni okutholakala kusengaphambili zikhomba ukuthi lezi zindawo zobuchopho zingezona lapho okwenziwe khona i-oxytocin ezenzweni ezinkulu hhayi kuphela iziqephu zesikhombiso se-penile erection ezibonwa ngemuva kwezidakamizwa ze-pro-erectile, kodwa futhi nokuthuthukisa ukuziphatha kwabantu ngokobulili (nabesifazane) (bona i-Argiolas no-Melis, i-2004 kanye nezinkomba zalo). Ngakho-ke, ukugxiliswa kwe-oxytocin kwanda kwi-hippocampus yamagundane angamadoda aphathwe nge-pro-erectile dose ye-apomorphine, i-classical dopamine agonist (Melis et al., 1990) no d (CH2) 5Tyr (Me) -Orn8-vasotocin, evimba i-oxytocin i-receptors, iphumelela ngokuphumelelayo hhayi kuphela ekudambiseni ukuziphatha okuphambene nomzimba (Argiolas et al., 1987a) kodwa futhi nomphumela wokugqugquzela we-apomorphine ekuziphatheni okwenziwe ngamadoda (Argiolas et al., 1987b) emagatsheni abesilisa abesilisa ocansini, ngesikhathi lapho ku-copula penile erection kwenzeka. d (CH2) i-5Tyr (Me) -Orn8-vasotocin iphinde ibe namandla kakhulu ekunciphiseni ukuvinjelwa okungavumelani kwamagundane abesilisa, uma kunikwa inani le-nanogram kuma-ventricles, kodwa hhayi ku-PVN (Melis et al., 1999a).
Okwesibili, i-nelions e-mesolimbic ne-dopaminergic idlala indima ebalulekile ezindaweni ezishukumisayo nezomvuzo zokuqinisa imvelo, njengokudla, amanzi nokusebenza kocansi (Fibiger no-Phillips, i-1988; i-Wise ne-Rompre, i-1989; i-Everitt, i-1990). Ngokuyinhloko, i-dopamine ekhishwe kulezi zine-neuron kucatshangwa ukuthi iqondise ukuguqulwa kwezici ezishukumisayo zemvelo yemvelo ibe ngumgomo wokuziphatha okuqondiswayo, isibonelo esimweni socansi, ukufuna umlingani wesondo nocansi ukufinyelela umvuzo nokwaneliseka (Goto no-Grace, i-2005). Ngakho-ke, i-extracellular concentration ye-dopamine yanda ekukhuliseni okuvela kwi-nucleus accumbens yamagundane angamadoda ayenziwa ngokocansi ngenkathi evezwa yi-isrogen + ye-proroterone-primed-earmed female rat rat, futhi ukwanda okunjalo kwaphakama nakakhulu uma isilwane sesilisa sivunyelwe ukuba silingane ne-female receptive (Pfaus no-Everitt, i-1995).
Okwesithathu, imiphumela yamanje isekela ukucabanga ukuthi isifunda se-neural sixhuma i-nucleus ebonakalayo ngendawo ye-ventral ngokuqondile noma ngokungaqondile (ngokusebenzisa i-subiculum ye-ventral kanye / noma i-nucleus yesikhombandlela ye-amygdala) kanye ne-nucleus accumbens, kusukela lapha kungaziwa indlela yokubuyela emuva ku-nucleus ebonakalayo ukulawula umsebenzi we-neurosol oxygencinic oholela emthonjeni womgogodla odlulisa i-penile erection kanye ne-oxytocinergic neurons eyenza indawo ye-ventral, i-subralulum ye-ventral ne-posteromedial nucleus ye-amygdala, ehambisa ngale ndlela umsebenzi we-mesolimbic ne-dopaminergic neurons (Fig. 4). Lesi sifunda esiyinkimbinkimbi se-neural singabamba iqhaza ekwenzeni imisebenzi ye-neural ehilelekile ekulawuleni ukuphelisa (erectile-ejaculatory) kanye nokulindela (okugqugquzelayo nokuvuza) izici zokuziphatha ngokobulili zesilisa ezimweni zomzimba. Ngempela, i-dopamine eyengeziwe yamandla iyanda kwi-nucleus accumbens (i-Pfaus no-Everitt, i-1995) nasesikhungweni sezintambo zamantombazane abesilisa ocansini ngesikhathi sibhekene nesilinganiso samantombazane esamukelekayo, lapho kungavunyelwanga khona, futhi ngisho nangaphezulu uma kuvunyelwe ukuvumelanisa, isib, lapho kukhishwa ama-pulale erections (Melis et al., 2003). Ngakho-ke, nakuba izifundo ezengeziwe zidingekile ukuze kucaciswe indima ye-oxytocin engapheli endaweni ye-ventral tegmental, i-subralulum ye-ventral kanye ne-amygdala ngesikhathi sokungahambisani nokuziphatha ngokobulili, kungase kube khona ukucabanga ukuthi lesi siteshi sesimo se-neural, ngenkathi sinikeza izici zokuqeda ukuziphatha ngokobulili, ngesikhathi esifanayo kungase kusebenze uhlelo lwe-mesolimbic dopaminergic oluhlinzeka nge-neural substrate ekuchazeni izindawo ezivuzayo zocansi (Everitt, 1990; Pfaus no Everitt, 1995). Kulokhu, kuyaphawuleka ukuthi isimiso se-mesolimbic dopaminergic esasungulwa yi-oxytocin egxilwe endaweni ye-ventral tegmental senziwa ngokufanayo nezidakamizwa zokuhlukunyezwa ezifana nama-opiates, i-cannabinoids, i-amphetamine, i-cocaine ne-alcohol (Tanda et al., 1997), futhi ukuthi i-oxytocin itholakala ekwazi ukunciphisa ukubekezelelana nokuxhomeka kwe-cocaine, i-morphine, i-alcohol kanye ne-cannabinoids (i-Kovacs et al., i-1998; i-Cui et al., i-2001). Ekuphetheni, kubonakala sengathi i-oxytocin ayikhishwe kuphela endaweni ye-ventral, kodwa futhi ku-subiculum ye-ventral ne-posteromedial nucleus ye-amygdala, ingenza i-mesolimbic neoponergic neurons isebenze, okungenzeka ibandakanyeke emiphumeleni ekhuthazayo nenomvuzo yokusebenza ngokobulili . Ukusetshenziselwa kwe-nelionic eyelimbic ne-dopaminergic kungase kube ngqo, ngokusebenzisa ama-receptor e-oxytocinergic emzimbeni wesiguli se-mesolimbic ne-neoponergic neurons, noma ngokungaqondile ngokusebenzisa i-glutamic acid neurotransmission endaweni ye-ventral tegmental.
I-dopamine ekhishwe esikhunjeni se-nucleus accumbens igxilisa umsebenzi we-incerto-hypothalamic neoponergic neurons e-nucleus ebonakalayo eyenza i-penile erection (nge-activation ye-oxytocinergic neurons eyenza umgogodla), noma isisusa socansi nomvuzo (ngokusebenzisa ukusebenza kwe-oxytocinergic i-neurons eyenza indawo ye-ventral tegmental, i-subiculum ye-ventral noma i-nucleus yangemva kwe-cortical ye-amygdala). Njengoba i-dopamine ikhishwa futhi kugobolondo le-nucleus accumbens nasendlini ye-nucleus ephambili lapho i-penile erection kwenzeka ezindaweni zomzimba (isib. Ukungahambisani nokuphikisana) (Succu et al., 2007; Melis et al., 2003, 2007), kuba cishe ukuthi ama-neuron aphakathi kwe-oxytocinergic ahlanganyela emiphakathini ye-neural ehlanganisa ukuxhumana phakathi kwe-mesolimbic kanye ne-incerto-hypothalamic dopaminergic system. Lezi zifunda ze-neural zingadlala indima hhayi kuphela kwisigaba sokuphela kokuziphatha ngokobulili (isib. Ukulungiswa kwe-penile nokukopiselana), kodwa futhi nasisisusa socansi, ukuvuswa kocansi kanye nomvuzo wobulili.
Ukumelwa kweSimeth of a circuit of hypothetical circuitry okubandakanya i-oxytocin ethonya isisusa socansi, ukuvuza nokusebenza ngokocansi, njengoba kuphakanyiswe imiphumela yalesi sahluko nemibiko yangaphambilini. Ama-neurons oxytocinergic avela ku-nucleus ephambili futhi aqhubekele emthonjeni we-umgogodla uma kusetshenziselwa isibonelo nge-dopamine ne-glutamic acid (kodwa futhi namanye ama-neurotransmitter kanye / noma ama-neuropeptides), ukwenza kube lula ukukhishwa kwe-penile nokusebenza kocansi ngokusebenzisa i-oxytocinergic neurons eyenza umgogodla. I-dopamine ne-glutamic acid (kodwa futhi nama-neurotransmitters nama-neuropeptide) ku-nucleus ephambene nayo ivuselela i-oxytocinergic neurons eyenza indawo ye-ventral tegmental, ngaleyo ndlela isebenzise i-nelionic eyelimbic neurons eyenza i-nucleus accumbens, igxile isisusa socansi nomvuzo. I-Dopamine ekhishwe ku-nucleus accumbens (NAs) isebenza ngendlela engaziwayo ye-neural, eyandisa umsebenzi we-incerto-hypothalamic neoponergic neurons (ezivela kumaqembu a-A13-A14 we-Dahlstrom no-Fuxe) okungaxhunyiwe kwi-neurons ye-oxytocinergic, kuhlanganise nalawo asebenzayo umthambo womgogodla, oholela ekukhuleni kwe-penile. Lezi zindawo zingasetshenziswa futhi yi-oxytocin injected hhayi kuphela endaweni ye-ventral tegmental, kodwa futhi nase-subiculum ye-ventral nase-amygdala, ebuye ithole ukungena kwe-oxytocinergic kusuka ku-nucleus ebonakalayo, mhlawumbe ngokusebenzisa i-glutamatergic eqondile noma engaqondakali ephumelelayo kwi-ventral indawo ye-tegmental, okuholela ekuguquleni kokubili isisusa socansi kanye nokwakhiwa kwe-penile. Okokugcina, amasifunda angenhla angase asetshenziswe futhi yi-stimuli nama-pheromone, njengoba i-dopamine engaphezulu kweselula ne-glutamic acid ekwandeni kwe-nucleus (nasendaweni yangaphambili ye-preoptic) ngesikhathi se-pheromone-mediated erections and interulation (for reference references see Uhlu lwezinkomba).
Ukubonga Lo msebenzi wawuxhaswe ngokuxhaswe yi-grant evela eMnyangweni we-Italy we-University kanye noCwaningo kuya ku-AA no-MRM
Okubhekwayo
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