Ƙananan neuroplasticity wanda ke haifar da kwayoyin halitta a cikin ƙananan ƙananan hanyoyi na tasiri na halitta da kuma sakamako na sakamako (2014)

COMMENTS: The Nazarin DeltaFosB mu sau da yawa suna kiran duk abin da aka mayar da hankali kan da ƙananan haɓaka (cibiyar lada), kuma sun gano cewa jima'i suna tafiya da yawa irin tsarin kwakwalwar kamar meth & cocaine. Daga babban binciken wannan mai binciken (Ka'idojin Kwayoyin Halitta da Hanyoyin Drug a Dokar Kasuwancin Kasuwanci ta Kasa da ΔFosB a matsayin Mai Mahimmanci Mai Mahimmanci (2013)):

Sabili da haka, ladabi na halitta da na magani ba wai kawai sun haɗu a kan hanya ɗaya ba, suna haɗuwa a kan masu yin sulhu guda ɗaya na kwayar halitta, kuma mai yiwuwa a cikin ƙananan ƙwayoyin cuta guda ɗaya a cikin Nucleus Accumbens, don yin tasiri a kan himma mai daɗi da “son” nau'ikan lada biyu.

Kashewa: Meth, cocaine, da jima'i duk suna yin abubuwan da suke da mahimmanci guda daya a cikin asibiti a cikin gidan lada (ƙananan haɓaka), duk abin da zasu iya yi daban-daban a cikin kwakwalwa. Wannan ya rushe tsohuwar magana da cewa sakamakon ladabi da kwayoyi sun bambanta a cikin hanyoyin da tasiri.

Wannan sabon binciken yayi nazarin abin da jima'i yake yiwa VTA. VTA shine inda ƙwayoyin jijiyoyin da ke samar da kwayar halitta ke farawa - kuma suna reshe zuwa ƙananan ƙwayoyin cuta, cortex na gaba, da amygdala. Ainihin VTA shine tushen (asalin) yawancin yawancin dopamine. Duba wadannan hotunan 2 na da'irar lada: Pic1, Pic2

Masu bincike sun gano cewa jima'i (mafi girma) yana sa jikin kwayoyin halitta a cikin VTA su dakata na dan lokaci (cikin maza). Kwayoyin salula da dendrites sun hada da ƙwayar launin fata na kwakwalwa. Wannan shi ne ainihin abin da akin gwanin heroin ya yi wa VTA (Ba a lokaci daya amfani da heroin ba, amma aikin heroin na yau da kullum). Ka lura cewa wannan shrinkage na jikin VTA yana faruwa a cikin 'yan jaridan heroic addicts.

Jirgin da aka shigar da jima'i ya kasance na tsawon kwanaki 7. Canje-canje da aka samu ta hanyar jima'i sun koma al'ada a 30 kwanakin, amma masu bincike sun gwada kwanaki 1, 7, da 30.

Sharfafa jikin kwayar halitta a cikin jarabar heroin yana haifar da ƙananan dopamine a cikin ƙananan ƙwayoyin cuta - ko abin da muke kira lalatawa. Masu binciken sun gudanar da morphine ga berayen don tantance martaninsu (bayan jima'i), amma ba abin da ya faru. Yawancin lokaci berayen suna son morphine da yawa, amma a nan an daina amfani da su na ɗan lokaci. A takaice dai, sakamakon berayen da aka samu bayan kammalawa bai samu karbuwa ba ga matakin da ya rage na tabar heroin. Masu binciken sun yi hasashen cewa za a bukaci allurai masu yawa don haifar da halin bera na "al'ada".

Don taƙaitawa - Jima'i (na ɗan lokaci) yayi daidai daidai a cikin VTA kamar yadda jaraba ga heroin: ƙyamar dopamine ke haifar da jikin ƙwayoyin jijiyoyin. Wannan yana haifar da ƙananan dopamine a cikin cibiyar lada, da ƙasa da amsa ga narcotics - kuma yana ɗaukar aƙalla kwanaki 7 don ƙwaƙwalwar bera ta murmure.

 

J Neurosci. 2014 Jun 25;34(26):8825-36. Doi: 10.1523 / JNEUROSCI.0133-14.2014.

Pitchers KK1, Coppens CM2, Beloate LN3, Fuller J2, Van S2, Frohmader KS2, Laviolette SR2, Lehman MN4, Coolen LM5.

Abstract

Sakamakon halitta da magunguna na cin zarafi a kan hanya na mesolimbic kuma kunna hanyar da ake amfani da shi ta hanyoyi daban-daban na ƙananan filastik a cikin tsakiya. Gwanin lokacin da ake amfani da shi a cikin kwaskwarima yana haifar da filastik a cikin ƙananan ƙwayoyin maganin ƙwayoyin maganin ƙwayar jiki (VTA), wanda ke sarrafa rashin lafiyar morphine.

A nan, muna gwada tsinkayen da yakamata sakin ƙananan opioids a cikin VTA ke haifar da canjin morphological na VTA dopamine kwayoyin jikinsu a cikin ratsan namiji, wanda a cikin juyawa ke tsara mahimmancin maganganu na ƙarfafawar halayyar halayyar jima'i.

Na farko, halin jima'i ya rage VTA a matsayin girman 1 da 7 kwanakin baya, amma ba 30 kwanakin bayan da ta gabata ba.. An katange wannan sakamako tare da naloxone kafin kowane lokaci; Ta haka ne, VTA dopamine cell filastity ya dogara da aikin na opioids endogenous.

Hakanan kuma, haɗin gwiwar VTA yana hade da sakamakon sakamako na canzawa, kamar yadda mazajen da ba su da ɗaɗɗun jima'i ba su samar da zaɓi na musamman ba don 0.5 mg / kg morphine.

Bayan haka, an ƙaddara shi ko aiki na karshe na opioid yana ba da ladabi da kuma ƙwaƙwalwar ajiya a cikin ratsan namiji da aka yi da naloxone a yayin da ake samu mating, ko dai a cikin tsarin ko VRA. Naloxone bai hana gwaninta na farko ba - ya haifar da halayyar halayyar jima'i a kan lokuta na jima'i, ko sanya wuri mai kyau ga mating. Duk da haka, maganin naloxone ya ragu na tsawon lokacin da aka gabatar da labarun da ke tattare da halayyar jima'i da haɓakawa a cikin sassan mesolimbic da aka haifar da shafuka masu dangantaka.

Tare, waɗannan bayanan sun nuna cewa tsauraran kwayoyin halitta a lokacin da suke yin jima'i suna haifar da filastan ƙananan ƙwayoyin cuta a cikin VTA dopin neurons waɗanda ke da muhimmanci ga sakamakon morphine da kuma ƙwaƙwalwar ƙwaƙwalwar ajiya don yanayin ladabi.

 

Gabatarwa

Hanyoyin sakamako na ladabi sunyi ta hanyar sulhu ta tsarin mesocorticolimbic (Meisel da Mullins, 2006; Hoebel et al., 2009; Frohmader et al., 2010a; Pitchers et al., 2010a; Young et al., 2011; Blum et al., 2012). Magunguna na cin zarafi suna haifar da gyare-gyaren ƙwayoyin jiki a cikin wannan tsarin, wanda ke ba da gudummawa ga cigaba da kuma nuna ma'anar cin zarafi (Hyman et al., 2006; Nestler, 2012). Mun riga mun ƙaddara cewa kwarewa tare da ladabi na dabi'a, watau, jima'i a cikin ratsan namiji, kuma yana haifar da filastar ƙwayoyin jiki a cikin ƙwayar mahaifa (NAc), ciki har da ƙananan ɗigon ƙwayoyin dendritic (Pitchers et al., 2010a) da kuma deltaFosB (Pitchers et al., 2013). Sau da yawa, wannan jima'i da aka haifar da jima'i yana da mahimmanci ga ilimin jima'i a matakan jima'i, wanda aka nuna a matsayin jagorancin farawa da kuma yin halayyar jima'i (Pitchers et al., 2010b, 2012, 2013). Bugu da ƙari, jituwa ta jima'i yana musanya amsa ga psychostimulants, ciki har da fahimtar aikin aiki na locomotor da ingantaccen sakamako (Frohmader et al., 2010a; Pitchers et al., 2010a, 2013).

NAC yana ɗaya daga cikin ƙananan ƙananan ƙwayoyin cuta a cikin ƙananan ƙananan ƙananan hanyoyi (VTA). VTA dopin nema suna aiki a yayin da ake yin jima'i da kuma bayan daukan hotuna zuwa sanannun alamun ladabi na ladabi (Balfour et al., 2004; Frohmader et al., 2010a), ta hanyar peptide opioid (EOP) mai tsauri -binding a masu karɓa na μ-opioid (MORs; Matthews da Jamusanci, 1984; Johnson da Arewa, 1992; Klitenick et al., 1992; Ikemoto et al., 1997; Balfour et al., 2004). Saboda haka, bayyanar da bayanin da aka sani game da jima'i yana haifar da sakin EOP da VTA dopamine-cell activation, wanda ke taimakawa wajen halayyar jima'i (Mitchell da Stewart, 1990; van Furth et al., 1995; van Furth da van Ree, 1996) da kuma dopamine release a cikin NAc (Fiorino et al., 1997).

Maimaitawa mai fadi ga masu tsauraran motsi suna haifar da canji na morphological a cikin VTA (Mazei-Robison et al., 2011; Mazei-Robison da Nestler, 2012), rage soma girman VTA dopamine neurons (Sklair-Tavron et al., 1996; Spiga et al., 2003; Chu et al., 2007; Russo et al., 2007; Mazei-Robison et al., 2011), matakan rage yawan sunadaran neurofilament (Beitner-Johnson et al., 1992), ƙara yawan kwayoyin kwayoyin halitta na kwayoyin halitta, da kuma rage yawan sufuri da kuma bayanan dopamine zuwa NAc (Beitner-Johnson et al., 1992; Mazei-Robison et al., 2011). Wadannan canje-canje na VTA sunyi saurin safarar halayyar salphine kuma suna da tsauri yayin da suke suma a cikin wata guda da miyagun ƙwayoyi (abstinence)Russo et al., 2007). A halin yanzu babu tabbacin ko filastik a cikin VTA dopamine neurons ne na musamman ga ayyukan na opiates ko kuma idan an samar da su ta hanyar sakin EOP a yayin dabi'u masu ladabi.

A nan, muna gwada tsammanin cewa sakamakon ladabi na halitta yana haifar da ƙananan ƙwayoyin kama da abin da ya faru da opiates, kuma haka ne, cewa yana son haɗawa a kan wani tsari na filastik wanda yake da wuyar gaske ga yanayin ladabi da ladabi. Muna jarraba ko kwarewar jima'i a ratsan namiji yana rage girman girman VTA dopamine ne ta hanyar tsari wanda ke dogara akan aikin EOP a cikin VTA. Bugu da ƙari kuma, zamu binciki ko gyare-gyare na EOP a cikin VTA dopin ƙananan haɗin ke hade da ƙarfafa hali na ladabi da kuma sanya haɗin mai da hankali ga abubuwan da suke hade da ladabi, yayin da suke haifar da haɗin kai ga morphine sakamako.

Kaya da matakai

Animals

An samo ratsan daji na Sprague-Dawley (200-225 g) daga Charles River da kuma zama a cikin nau'i biyu a cikin ɗakunan da aka yi a kan wani haske a cikin 12 h haske / duhu a dukkan gwaje-gwaje (hasken wuta a 10: 00 AM sai dai don gwajin hawancin morphine , hasken wuta a 5: 00 PM). Abincin da ruwa suna samuwa ad libitum sai dai lokacin gwajin hali. Yawancin mata da aka sanya su a cikin jiki da kuma sanya su a ƙarƙashin hanyar tare da 5% 17-β-estradiol benzoate SILASTIC capsules (1.98 mm cikin ciki, 0.5 cm tsawon, Dow-Corning). Injections na progesterone (subcutaneous, 500 μg a 0.1 ml of sesame man) an gudanar da 3-6 h kafin gwaji don yin jima'i karɓa. Dukkan hanyoyin da Jami'ar Western Ontario da Jami'ar Michigan na Kula da Dabbobin Kiwon Lafiyar ta amince sun amince da su, kuma sun bi Kwamitin Kanada game da Dabbobin Kiwon Lafiya da Cibiyoyin Kula da Lafiya na sha'anin kiwon dabbobi a binciken.

Lokaci lokaci na VTA dopamine fara girma canje-canje

Taron jima'i na yau da kullum.

Don nazarin yanayin lokaci na canje-canje a cikin kwayar cutar dopamine a cikin VTA, an kashe dabbobin da suka shafi jima'i da marasa kyau a 1, 7, ko 31 d (n = 5-8 da ƙungiya) bayan rana ta ƙarshe ta mating (gogewa) ko sarrafawa (maciji). Ƙungiyoyin da suka shafi jima'i sun dace da halayen jima'i a lokacin taron jima'i na ƙarshe, da kuma yawan lambobin da aka yi a kan zaman biyar (ƙananan 5 na kowane rukuni), kuma ba su bambanta a kowane matsayi na halin jima'i ba.

Taron jima'i.

An sanya mazajen jima'i a cikin nau'i na gwaji guda biyu: jima'i na jima'i ko jima'i. An yarda da dabbobi masu jima'i suyi sau biyar a kwanakin jere tare da mata masu karɓa a ɗakunan gwaji na rectangular (60 × 45 × 50 cm) har sai nuna nauyin haɗi ko zuwa 1 h (duk wanda ya fara). An yi tsabtace cages tare da bayani na 70% ethanol kuma an saka kwanciyar safi a tsakanin zaman mating. An yi halayen jima'i a cikin duhu (2-6 h bayan an fara duhu). Dabbobi kawai wadanda aka yi amfani da ita a lokacin akalla hudu daga cikin lokuta biyar na jima'i an dauke su da jima'i da kuma hada su cikin gwaje-gwaje. An lura da dukkan lokuttan jima'i kuma an rubuta labarun jima'i. Yawan adadin (M) intromissions (IM), latency (ML, lokaci daga gabatarwar mace zuwa dutse na farko), latency intromission (IL, lokaci daga gabatarwa da mace zuwa farko intromission), da kuma latency naja (EL; lokaci daga farko intromission zuwa ciniki) an rubuta (Agmo, 1997). An saka dabbobi a Nairobi a cikin gidan gwaji mai tsabta don 1 tare da ma'aurata da suka yi jima'i a cikin ɗaki guda, kamar yadda aka nuna su ga ƙarancin ƙananan mata, da kuma matakan rikice-rikice da muhalli kamar maza.

Lambar lakabi ta immunofluorescence.

An yi amfani da dabbobi sosai ta hanyar amfani da pentobarbital sodium (270 mg / kg, ip) kuma sun hada da 50 ml na 0.9% saline, daga bisani 500 ml na 4% paraformaldehyde a 0.1 m sodium phosphate buffer (PB). An cire kwakwalwa kuma an ajiye su don 1 h a dakin da zazzabi (RT) a cikin wannan madaidaicin, sa'an nan kuma an cika su a cikin 20% sucrose da 0.01% sodium azide a 0.1 m PB don ajiya a 4 ° C. An yanke sassan coronal a 35 μm a kan microtome mai daskarewa (H400R, Microm) kuma an tattara su a cikin jigon hudu a cikin bayanin cryoprotectant (30% sucrose, 30% ethylene glycol a 0.1 m PB) sannan an adana a 20 ° C. Dukkanin da aka yi a RT tare da raɗaɗɗen hanzari da rinses tare da 0.1 m PBS, pH 7.35, tsakanin incubations. An bayyana sassan a cikin 1% H2O2 don 10 min don halakar da peroxidases, sannan an katange shi don 1 H a cikin bayani na shiryawa (PBS +: PBS dauke da 0.4% Triton X-100; Sigma-Aldrich) da kuma 0.1% kundin albumin bovine (Jackson Immuno Research Laboratories). Daga baya, an sanya sassan cikin dare a RT a cikin motsin tyrosine hydroxylase (TH) -antibody (1: 20 000; Millipore). Bayan na farko da aka yi amfani da cutar anti-incubation, an raba sassan a Alexa antibody-mouse antiphonic AlexaFluor 555 (1: 100; Invitrogen, Eugene, OR) na 30 min. A karshe, an wanke sashe tare da 0.1 m PB, an saka shi a kan gilashin Superfrost Plus, dried, kuma an rufe shi da gelvatol dauke da wakilin 1,4-diazabicyclo (2,2) octane (DABCO; 50 mg / ml, Sigma-Aldrich; Lennette, 1978).

Bayanin bayanan bayanai: ya fara girma.

An dauki hotuna ne na nauyin TH-immunoreactive (IR) a cikin VTA a 40 × magnification a cikin uku na rostral zuwa matakan caudal (Balfour et al., 2004). Babu bambance-bambance da aka gano a tsakanin sel a matakan daban. An yi la'akari da ƙananan samfurin TH-IR ne ta hanyar amfani da ImageJ (Cibiyoyin Lafiya na Ƙasar). An auna yanki, kewaye, da ƙaddara kamar yadda aka bayyana ta Sklair-Tavron et al. (1996). An kiyasta yawan kwayoyin 25 akan dabba (hada dukkan nau'ikan 3 VTA) kuma kawai kwayoyin halitta tare da siffar da aka gani a fili sun haɗa. Ga kowane dabba, yankin yanki, kewaye, da kuma ƙididdiga aka ƙidaya. Don nazarin ilimin lissafi an yi amfani da ANOVA guda biyu (dalilai: jima'i (jima'i ko jima'i) da kuma lokacin (1, 7, ko 31 d)]. bayan hoc kwatanta ta hanyar amfani da Holm-Sidak tare da matsayi mai muhimmanci na 0.05.

VTA wadanda ba dop dopin canje-canjen ba

Taron mating biweekly.

Don gwada ko kullin jima'i a lokacin jima'i na yau da kullum ana buƙata don ragewa a cikin nauyin ƙwayoyin cuta mai suna TH-IR, VTA dopin dabbobin dabbobin da suka haɗu a lokacin lokuta biyar na biyun suna nazari. Taron tarurruka kamar yadda aka bayyana a sama, amma a tsawon lokutan 2.5. An tattara 7 d bayan ƙwaƙwalwar bayan an gama tabarbare ko sarrafawa.

Imbinoperoxidase lakabi.

Bugu da ƙari, an gwada shi ko ta yin amfani da matakai masu mahimmanci tare da immunoperoxidase da kuma ganowar chromogen, zai kuma ba da izinin ganin yadda canje-canje masu girma na TH-IR suka fara. An yi amfani da sinadarin furotin da kuma nama kamar yadda aka bayyana a sama. Bayan magancewa tare da 1% H2O2 da kuma PBS +, an rarraba sassan na dare a RT a cikin nau'in polyclonal tyrosine hydroxylase (TH) -antibody (1: 20 000; Millipore). Bayan an riga an kafa suturar rigakafi, an raba sassan da kwayar cutar IgG-zubar da kwayar halitta (1 h, 1: 500 a PBS;; Laboratories Vector), avidin-biotin-horseradish peroxidase (1 h, ABC elite; 1: 1 000 a PBS ; Laboratories Vector), kuma 3,3'-diaminobenzidine tetrahydrochloride (10 min, 0.02%, DAB; Sigma-Aldrich) da aka inganta tare da sulfate nickel a (0.02% a 0.1 m PB) tare da hydrogen peroxide (0.015%). Ana wanke sassan a cikin 0.1 m PB don ƙare aikin kuma saka a kan Superfrost tare da gilashin gilashin (Fisher) tare da 0.3% gelatin a ddH2O. Bayan an warkar da su, dukkanin zane-zane sun kasance tare da dodon DPX (dibutyl phthalate xylene Sigma-Aldrich).

Bayanin bayanan bayanai: ya fara girma.

An bincika sel na TH-IR don yanki, kewaye, da kewaye kamar yadda aka bayyana a sama. Bugu da ƙari, an bincika sel sel-TH a cikin substantia nigra (SN), a cikin sassan guda ɗaya da aka yi amfani da su don nazarin ƙwayoyin VTA TH-IR. A ƙarshe, bayan bincike game da ƙwayoyin VTA da SN TH-IR, an bincika sassan ta amfani da violin cresyl kuma an bincika ƙwayoyin sel waɗanda ba su da TH-IR ta amfani da hanyoyin guda ɗaya kamar yadda aka bayyana a sama. An bambanta bambance-bambancen tsakanin ƙungiyoyi masu ilimi da masu ƙwarewa ta amfani da ɗalibin Studentan Taku biyu t gwaje-gwaje tare da matsayi na musamman na 0.05.

Hanyoyin naloxone a kan gwanin dopamine ya fara raguwa

Don sanin ko MOR ya taka muhimmiyar rawa a cikin jima'i-ya haifar da canje-canje a cikin girman kwayoyin halitta, MOR an katange a lokacin halayen jima'i. Rabin dabbobin da suka sami jima'i, yayin da sauran rabin ana kula da su amma sun kasance masu jima'i. An yarda da dabbobi masu fama da jima'i su haɗu a kan 5 a cikin jere. A cikin kungiyoyi masu tsaurin ra'ayi da masu banƙyama, ana kula da dabbobi tare da wanda aka ba da izinin MOR naloxone (10 mg / kg, sc; Sigma-Aldrich, wanda ya ragu a cikin 0.9% saline) ko sallar 30 min kafin gabatarwa da mace (ko a'a) ko kafin a daidaita shi (maciji); ta hanyar samar da ƙungiyoyi masu gwaji hudu: Saline na jima'i (Naive Sal), mailoxone mai jima'i (Naive NLX), Saline (Exp Sal), da kuma naloxone da aka yi da jima'i (Exp NLX; n = 5-8 da ƙungiya). Maganin Naloxone ba shi da tasiri mai mahimmanci akan kowane fasalin jima'i, a kan kowane 5 d, da naloxone- kuma kungiyoyin saline-treated sun kasance daidai a cikin jima'i. Dukkan dabbobi an kashe su ta hanyar zubar da ciki 7 d bayan ƙaddamarwa ta ƙarshe. Sashewa, immunohistochemistry, da kuma bayanan bayanai (hanyoyi guda biyu ANOVA; dalilai: jima'i da kuma maganin miyagun ƙwayoyi) domin girman tsarin dopamine da aka gudanar kamar yadda aka bayyana a sama.

Morphine yanayin sanya wuri

Zane gwaji.

A baya, Russo et al. (2007) ya nuna ciwon daji na yau da kullum yana haifar da haƙuri ga sakamakon morphine. Tun da kwarewar jima'i da ciwon daji na yau da kullum yakan haifar da raguwa kamar yadda ake amfani da kwayoyin dopamine a cikin VTA, an yi amfani da muhimmancin aikin sauyi na maye gurbin jigilar halittu don samfurin morphine. An raba dabbobin da suka shafi jima'i da jahilai zuwa ƙungiyoyi masu gwaji guda shida (n = 9-13 ta kowace ƙungiya) dangane da halayen jima'i (jima'i ko jima'i) da kuma morphine (0.5, 5.0, ko 10.0 mg / kg, ip) kuma an gwada su don neman gurbin da aka sanya a cikin gurbin jini (CPP).

Morphine-CPP.

Yanayin ya faru 1 d bayan an gama taron karshe kuma kungiyoyi sun dace da yin jima'i a lokacin zaman ta ƙarshe. Tsarin CPP wanda aka yi amfani da shi ya ƙunshi pretest, kwanakin kwangila, da kuma gwajin bayan gwaji, kuma na'urar ta dogara Tenk et al. (2009). A takaice, na'urar CPP (MED Associates) ta ƙunshi ɗakuna daban-daban guda uku. Tsakanin kowane zama, kayan an tsabtace kayan sosai tare da maganin ethanol 70% don rage alamun olsa. Don ƙayyade abubuwan da mutum ya so, an gudanar da pretest yayin da aka ba dabbobi damar shiga cikin dukkan kayan aikin na mintina 15. A zaman ƙungiya, dabbobi ba su nuna fifiko mai mahimmanci ga takamaiman ɗaki ba, amma kowane dabba yana da ɗan zaɓi na farko. Berayen da suka nuna fifikon fifiko ga ɗayan ɗakunan (> bambancin 200 s tsakanin lokacin da aka yi a kowace ɗakin; A lokacin kwaskwarima, an haɗa miyagun ƙwayoyi zuwa ɗayan da aka fi so da farko ko ɗakin da ba a ba shi izini ba ta amfani da yanayin ba da son zuciya (Tzschentke, 2007) da dabbobi an tsare su a ɗakunan 30 min. An kwantar da dabbobi da saline (ip) da safe (9: 00 AM zuwa 12: 00 PM) kuma an tsare su a cikin ɗakin da aka haɗa da salin. Da rana (1: 00-4: 00 PM), an kwantar da dabbobi tare da morphine (ip, 0.5 mg / kg, 5.0 mg / kg ko 10.0 mg / kg, morphine sulfate da aka narkar da 0.9% saline, Johnson Matthey) da kuma tsare zuwa ga jam'iyar morphine. An shafe dabbobi da kwana biyu na kwanciya. Kashegari (3 d bayan rana ta ƙarshe na jima'i) an gudanar da jarrabawar jarrabawa, kamar yadda aka yi da pretest. Don nazarin ilimin lissafi, lokacin da aka yi amfani da ita a cikin jima'i na morphine a lokacin jarrabawar aka kwatanta da lokacin da aka yi a cikin ɗakin salin saline a lokacin gwajin bayan jarrabawar jima'i ko jima'i a cikin kowace sashi ta amfani da alaƙa t gwajin. p <0.05 an yi la'akari da kimar lissafi. Groupsarin ƙungiyoyi masu kula da lalata na dabbobi da gogaggen dabbobi sun sami saline a ɗakunan haɗe-haɗe da waɗanda ba a daidaita su ba don kasancewa matsayin mummunan iko. Babu wani bambance-bambance a lokacin da aka ɓata tsakanin ɗakunan da aka gano don ɗayan ƙungiya.

Hanyoyin naloxone na yau da kullum game da halayyar halayyar jima'i

Zane gwaji.

Harkokin jima'i yana haifar da yunkurin yin jima'i da aka kiyaye don akalla 1 watan (Pitchers et al., 2012). Don bincika sakamakon hanawa MOR a kan yadda ake gudanar da halayyar halayyar jima'i, dabbobin da suka shafi jima'i da aka samu ko naloxone ko saline a gaban lokuta biyar na jima'i na jere (n = 12 kowane) kamar yadda aka bayyana a sama. Bayan mako daya bayan taron karshe, an gudanar da gwajin gwaji ta karshe a lokacin da aka yarda da dukkan dabbobi har sai an haɗu da juna ko har zuwa 1 h. Ba a yi amfani da maganin naloxone ko saline ba kafin yin jima'i a ranar gwajin karshe. An kwatanta sigogi na mating don tantance ko naloxone ya shafi tasirin jima'i-haɓakar mating (ranar 1 vs rana 5) ko kiyaye wannan gudanarwa (ranar 5 vs gwajin) ta hanyar amfani da hanyoyi guda biyu na ANOVA [dalilai: magani (saline da naloxone ) da rana (ranar 1, ranar 5, ko gwaji)] da kuma hanyar Holm-Sidak bayan hoc kwatanta. Ga dukan gwaje-gwaje na lissafi, p <Anyi la'akari da 0.05 a matsayin kimar lissafi.

Ƙarin kulawar gwajin

Naloxone na yau da kullum a ranar gwajin.

Don nuna cewa rikice-rikice a cikin jima'i a ranar jarabawar jima'i ta ƙarshe bai kasance ba saboda rashin nau'in naloxone, muna gudanar da kologixone ko saline a ranar jima'i na karshe na jima'i zuwa dabbobin da suka sami jima'i tare da naloxone yayin da suka sami kwarewa. Musamman ma, duk dabbobi sun karu da allurar naloxone (10 mg / kg, sc) 30 min kafin farawa zuwa haɗuwa guda daya a lokacin 5 kwanakin jere. A ranar gwajin 7 daga baya, kimanin rabin dabbobi sun sami allura naloxone (10 mg / kg, n = 7) ko saline (n = 6) 30 min kafin gabatar da mace mai karɓa. An lura da dabi'un jima'i da rubuce-rubuce. An kwatanta sigogi na mating don tantance ko naloxone ya shafi tasirin jima'i-haɓakar mating (ranar 1 vs rana 5) ko kiyaye wannan gudanarwa (ranar 5 vs gwajin) ta hanyar amfani da hanyoyi guda biyu na ANOVA [dalilai: magani (saline da naloxone ) da rana (ranar 1, ranar 5, ko gwaji)] da kuma hanyar Holm-Sidak bayan hoc kwatanta. Ga dukan gwaje-gwaje na lissafi, p <5% an yi la'akari da matsayin ƙididdigar lissafi.

Hanyoyin naloxone a kan ɗan gajeren lokaci na nuna halayyar halayyar jima'i.

An gwada tasirin naloxone (10 mg / kg, sc) a lokacin jima'i a kan halin jima'i na ƙarshe a lokacin gwajin gwaji ta ƙarshe, wanda aka gudanar kawai 1 d bayan bayanan karshe (saline, n = 5; naloxone, n = 4).

Hanyar naloxone na tsari.

Don sanin ko yin maimaita jiyya na naloxone kadai yana haifar da rashin haɗin 7 d bayan jiyya na karshe, dabbobi masu lalata ta hanyar karuwanci sun karbi naloxone biyar (10 mg / kg, sc) ko salin injections a cikin kwanaki masu jituwa kafin gwajin gwaji ta 7 d bayan naloxone na karshe ko infin salin. A wannan gwaji na karshe, dabbobi ba su sami allura ba. An lura da halayen jima'i da kuma rubuce kamar yadda aka bayyana a sama. An kwatanta sigogi na mating tsakanin kungiyoyi ta yin amfani da rashin kyauta t gwaje-gwaje. Ga dukan gwaje-gwaje na lissafi, p <5% an yi la'akari da matsayin ƙididdigar lissafi.

Naloxone na jima'i da jima'i.

Possibilityaya daga cikin yiwuwar tasirin sakamako naloxone akan bayyanar da kula da halayen jima'i da aka sauƙaƙa shine naloxone yana toshe sakamakon sakamako na halayen jima'i. Don gwada wannan yiwuwar, an gudanar da misalin CPP don halayen jima'i nan da nan biyo bayan allurar naloxone ko allurar saline a cikin maza ba tare da jima'i da jima'i ba. Hanyar CPP ya yi kama da wanda aka bayyana a sama don morphine-CPP, gami da mafi tsayi, ranakun yanayi, da gwajin gwaji.

Halin halayen jima'i ya haɗu tare da ɗakin da ba a yi ba. A cikin hanyar da ba daidai ba, kowace dabba ta sami allura daga naloxone (n = 12) ko saline (n = 11) 30 min kafin samun damar shiga mace mai karɓa. Yawan lokaci na lokacin jima'i shine ~13 min. Ɗaya daga cikin haɗuwa guda guda daya, an sanya dabba a cikin ɗakin da aka haɗa don 30 min. A wasu kwanakin kwandon, dabbobi sun sami allurar ko dai naloxone ko saline (duk da sun samu kafin su yi jima'i), an kuma sanya su cikin ɗakin da ba a biya ba don 30 min. Na gaba, an gudanar da gwajin bayan gwagwarmaya, kamar yadda ake nunawa. Don ƙayyade zaɓi na ɗakin gida, lokacin da aka shafe a cikin ɗakin da aka haɗa a lokacin da aka gabatar da gwajin bayan gwajin. Don nazarin ilimin lissafi, haɗin kai t an yi amfani da gwaje-gwaje don kwatanta fifiko da bambancin bambanci, da kuma lokaci a cikin jam'iyyun da aka haifa a lokacin bayyanar da kuma bayan gwaji don tantance ko an samu CPP mai muhimmanci don halayyar jima'i. p <0.05 an yi la'akari da mahimmanci.

Hanyoyin da ke ciki na VTA naloxone akan halayyar halayyar jima'i

Zane gwaji.

Don sanin ko aikin EOP musamman a cikin VTA, yana da alhakin abubuwan da ke tattare da jima'i-ya haifar da canje-canje a kan halayen jima'i, dabbobi suna shan jigilar naloxone ko saline a cikin VTA kafin zaman aure guda biyar. Misalin nau'i mai kama da tsarin gwajin naloxone. An yarda da dabbobi masu jima'i da juna a lokacin 5 a cikin kwanaki masu zuwa har zuwa tara guda ɗaya ko zuwa 1 h. Mintina goma sha biyar kafin gabatar da mace mai karɓa, ratsan namiji sun karbi jigilar su na biyu ko dai naloxone (10 μg / μl by hemisphere; 0.5 μl girma, sun rushe a cikin 0.9% saline) ko saline (0.5 μl da kowane ɗan adam). An yi amfani da microinjections na biyu a cikin wani nau'i na 0.5 μl / min a kan wani lokaci na 1 min wanda ya biyo bayan karin 1 min tare da canal injection da aka bari a wurin don watsawa. Ana maye gurbin cannula mai inuwa tare da cannula mota da ƙura. Kwana guda bayan rana ta ƙarshe na jima'i (ranar gwaji), duk dabbobi sunyi jima'i sau da yawa zuwa haɗuwa ba tare da jigilar naloxone ko saline ba. Figure 3A Ya tsara zane-zane. An gudanar da nazarin bayanai kamar yadda aka bayyana a gwaji naloxone.

Yin aikin tiyata.

An yi amfani da berayen aneshetized tare da allurar kwayar cutar (0.1 ml / kg) na ketamine (0.87 mg / ml) da kuma xylazine (0.13 mg / ml), kuma an sanya shi a cikin na'ura mai kwakwalwa (Kopf Instruments). An saukar da cannulas mai shiryarwa na 21 na biyu (Plastics One) a cikin ƙananan ramuka a cikin kwanyar cikin kwakwalwa zuwa ga VTA a -4.8 mm AP, ± 0.75 mm ML daga bregma da -7.8 mm DV daga saman kwanyar bisa ga Paxinos da Watson (2013). An yi amfani da gwangwani tare da ƙananan kwalliya wanda ya kasance a cikin ɓoye uku da aka sanya a cikin kwanyar. An ba dabbobi kyauta na mako-mako na 2, kuma ana kula da su yau da kullum don haɓakawa don yin amfani da hanyoyin da ake amfani da shi a lokacin gwajin hali.

Cannula sakawa tabbatarwa.

An saka jigon katako ta hanyar amfani da TH-immunostaining don tabbatar da cewa an ƙaddara VTA. Dabbobi kawai da wuraren da aka dace sun haɗa su a cikin nazarin (ragamar ƙungiya ta ƙarshe: saline n = 8; dandana naloxone n = 6). Sauran dabbobi guda uku da suka karbi rassa na VTA naloxone da aka kai a waje da VTA sun hada kansu a cikin ƙungiyar inji "rasa". Ƙungiyar da aka rasa ta bincika daban don aiki a matsayin mai sarrafa manufar Mann-Whitney U an yi amfani da gwaji don kwatanta hali a ranar gwaji na ƙarshe tare da naloxone da maza da suka ji dadin saline.

Abubuwan da aka haɗu da abubuwan da ke haɗuwa da juna sun hada da kalma

Zane gwaji.

Bayyanawa ga ɗakin da maza suka samu jimillar mating an nuna su haifar da haɓaka MOR a cikin VTA da kuma aikin neural a VTA da NAc (Balfour et al., 2004). Sabili da haka, yanayi na jima'i yana aiki ne a matsayin abin ƙayyadadden yanayin jima'i. Nazarin na yanzu yayi jarraba ko an kunna MOR a lokacin jima'i da ake buƙata don farawa da ƙwayar ƙwayoyin yanayi. An yi amfani da Naloxone ko saline a cikin tsari (ip) 30 min kafin sakawa a cikin fagen wasan mating da kuma gabatar da mace mai karɓa don mating (ko gogewa), ko kuma a gaban magudi wanda ya ƙunshi sanyawa a cikin caji mai cinyewa ba tare da gabatar da mace (tsaka tsaki ba yanayi; ƙwaƙwalwa). Saboda haka, an halicci kungiyoyin gwaji hudu: Naive Sal, Naive NLX, Exp Sal, da Exp NLX. Kwana guda bayan an gama jima'i, rabin dabbobi a kowane rukuni an nuna su a gidan caji (Mazaji maza: jinsi masu haɗuwa da jima'i) ko kulawa da caji (mazan maza: jahilci / tsaka tsaki), yayin da rabin rabi ba a fallasa su ba. duk wani ra'ayi kuma a maimakon haka ya kasance a cikin gida gida (don sanin ƙayyadaddun kalma). Wannan tsari na gwaji ya samar da ƙungiyoyi 8: Naive Sal-No Cue, Naive Sal + Cue, Naive NLX-No Cue, Naive NLX + Cue, Exp Sal-No Cue, Exp Sal ​​+ Cue, Exp NLX-No Cue, Exp NLX + Cue (n = 4 kowane sai Naive NLX-No Cue, n = 3). An shafe dabbobi da 10-15 min bayan da aka bayyana. An cire dabbobi masu iko daga gidajensu na gida kuma sun yi amfani da su a lokaci guda.

Immunohistochemistry.

An gudanar da sashe da immunohistochemistry kamar yadda aka bayyana a sama. A nan, mun yi amfani da kwayar cutar polyclonal ta rabbit akan p42 da P44 MAP Kinases ERK1 da ERK2 (PERK; 1: 4 000; An riga an ba da mahimmanci a cikin wallafe-wallafe na farko (antibody)Roux da Blenis, 2004; Murphy da Blenis, 2006; Frohmader et al., 2010b). Bugu da ƙari, cirewa na farko na antibody ya hana dukkanin rashin daidaito da kuma yaduwar kwakwalwa na yammacin kwakwalwa ta hanyar kwakwalwa da aka yi amfani da su a cikin ma'aunin kwayoyin da suka dace.

Bayanin bayanai.

SAN-immunoreactive (-IR) an kidaya kwayoyin halitta a cikin wasu ƙwayoyin kwakwalwa ta amfani da kyamara lucida da ke zana tubali a haɗe zuwa Leica DDD microscope: NAc [core (C) da harsashi (S); 400 × 600 μm; matsala na farko na tsakiya; mPFC; Yankin yanki na baya (ACA); prelimbic bawo (PL); infravenbic cortex (IL); 600 × 800 μm kowanne], caudate-putamen (CP; 800 × 800 μm), da amygdala masu bastoral (BLA; 900 × 1200 μm; Balfour et al., 2004; Frohmader et al., 2010b; Pitchers et al., 2010b). An ƙidaya sassan biyu a yankin ƙwaƙwalwar ajiya kuma ana yawan ƙididdigar kwayoyin halitta a cikin yankunan da aka ƙaddara a cikin ƙididdigar su a matsayin lambobi na sel da mm2. Kwararrun lambobi biyu sun kasance daidai da dabba don ƙididdigar ƙungiyar. Ƙididdigar rukuni a cikin kungiyoyi masu jima'i ko ƙananan kungiyoyi an kwatanta su ta hanyar amfani da hanyoyi guda biyu na ANOVA [dalilai: magani na miyagun ƙwayoyi (NLX ko Sal) da kuma cue (cue ko babu)] bayan hoc kwatanta ta amfani da Holm-Sidak ko Mann-Whitney gwaje-gwaje idan ya kamata tare da matukar muhimmanci p <0.05. A cikin kwasfa na NAc na dabbobin da suka kware a cikin jima'i, akwai ci gaba mai ƙarfi game da mahimmancin abubuwan kuma don haka, ana yin kwatancen biyun don kwatanta gishirin (Sal-No Cue) da ƙungiyar saline (Sal + Cue) kawai.

Hotuna.

An kama hotunan hotuna ta amfani da kyamarar CCD (Macrofire, Optronics) a haɗe zuwa a Leica microscope (DM5000B) tare da saitunan kamara mai gyara. An shigar da hotuna a cikin software na 9.0 Photoshop na Photoshop. Ba'a canza hotuna a kowane hanya sai dai daidaitawar haske da bambanci.

results

Jima'i kwarewa-haifar da canje-canje a VTA dopamine Kwayoyin

Jima'i kwarewa sa a rage a VTA dopamine fara size (Siffa 1A-C). Jima'i kwarewa rage yawan yanki da kuma kewaye da farkon VTA TH-IR sel (yankin: F(1,31) = 23.068, p <0.001; kewaye, F(1,31) = 18.225, p <0.001). Hakanan akwai babban tasirin tasirin lokaci (yanki: F(2,31) = 6.377, p = 0.005; kewaye, F(2,31) = 4.389, p = 0.021) da kuma muhimmiyar hulɗa tsakanin kwarewa da lokaci (yanki: F(2,31) = 5.284, p = 0.011; kewaye, F(2,31) = 4.347, p = 0.022). Bayanan kwatancen da aka kwatanta sun nuna cewa yanki da kuma kewaye da kwayoyin TH-IR sun rage rage 1 da 7 d bayan kwanakin ƙarshe na jima'i a cikin dabbobin da suka shafi jima'i idan aka kwatanta da jigilar jima'i na jima'i [Siffa 1B, yanki: p = 0.002 (1 d), p <0.001 (7 d); C, kewaye: p = 0.009 (1 d), p <0.001 (7 d)]. Tasirin halayen jima'i ya watse yayin da aka biyo bayan lokacin sakamako na abstinence kamar yadda girman girma na TH-IR neurons ya koma zuwa asalin 31 d bayan ƙarshen zaman mating na ƙarshe (Siffa 1B, yanki: p = 0.798; C, kewaye: p = 0.785). An gano nauyin jima'i-an haifar da canje-canje a cikin wani wuri a kowane lokaci (Siffa 1D). VTA dopamine fara girman ƙananan ba ya dogara ne a kan zaman yau da kullum, kamar yadda matsala ta hanyar mating a lokacin lokuta biyar matukar biweekly kuma ya haifar da rage girman VTA a cikin size (Siffa 2A,B, E-H, yanki: p = 0.004; kewaye: p <0.001). Sabanin haka, kwarewar jima'i bai shafi girman girman TH-IR ba a cikin mahimmin nigra (Siffa 2C, I-J, yanki: p = 0.13; kewaye: p = 0.16) kuma ba a canza girman farawa ba a kusa da VTA non-TH-IR neurons (Siffa 2D, E-H, yanki: p = 0.46; kewaye: p = 0.45).

Hoto 1. 

Abubuwan da suka faru a ciki sune canje-canje masu yawa na VTA dopamine neurons. A, Wakilan hotunan VTA dopin samfurori daga nauyin jima'i da dabbobin da suka shahara suna nuna ragewa a cikin girma 7 d bayan an gama jima'i na ƙarshe. Bar ma'auni, 5 μm. Bayanai masu yawa da suka nuna cewa jima'i (Exp, ƙananan sanduna) ya haifar da raguwa a yankin (B; a μm2) da kuma kewaye (C; a μm) na VTA dopamine Kwayoyin, 1 d (Naive, Exp; n = 6) da 7 d (Naive, n = 5; Exp, n = 6), amma ba 31 d (Naive ba, n = 6; Exp, n = 8) bayan ƙaddarar jima'i, idan aka kwatanta da kullun jima'i (Naive, sanduna). An rage yanki zuwa 84% a cikin ƙwararrun maza da aka kwatanta da nauyin sarrafawa a 1 ko 7 d. An rage iyakar zuwa 91.6 da 90% a cikin kungiyoyi masu gogaggen idan aka kwatanta da iko a 1 da 7 d resp. Babu wani tasiri a kan rabuwa (D). Wannan sanadin kwayoyin halitta na dopamine a yanki (E) da kuma kewaye (F) an hana shi ta naloxone (NLX, n = 8), amma ba salin (Sal, n = 7) magani a lokacin da yake yin jima'i, 7 d bayan ƙayyadaddun lokaci na ƙarshe idan aka kwatanta da halayen jima'i (Sal, n = 5; NLX, n = 6). Bayanan bayanan bayanai yana nufin ± SEM; * yana nuna bambanci mai banbanci idan aka kwatanta da nauyin jima'i na yau (B, C) ko kuma idan aka kwatanta da nauyin da aka yi wa salin da aka yi wa salin da ake yi wa mata da kuma wadanda aka haifa da maza da ke da magunguna (E, F).

Hoto 2. 

Halin jima'i bai rage yawan girman soma a cikin kwayoyi na dopamine ko na VTA nondopamine ba. VTA TH-IR neuron soma yankin (A; a μm2) da kuma kewaye (B; a cikin μm) a cikin jima'i na fari (fararen fata) da dabbobin da suka sani (baƙar fata) da suka sami kwarewa ta hanyar jima'i sau biyu a kowane mako maimakon lokutan jere. Substantia nigra Sashen yankin Yammacin Yamma (C) da kuma VTA wadanda ba TH-IR soma yankin (D) a cikin jinsin jima'i (fararen fata) da dabbobin da suka sani (baƙi). Bayanan bayanan bayanai yana nufin ± SEM; * nuna muhimmiyar banbanci idan aka kwatanta da jigilar jima'i. Wakilin zane na nuna TH-IR (launin ruwan kasa) neurons a VTA na jima'i yaudara (E), da kuma gogaggen (F) maza. G, H, Hoton ɗaukar hoto mafi girma na neuron da aka nuna ta kibiyar E da kuma F bi da bi. Ana nuna nau'in igiya na Nissl a cikin blue a wadannan hotunan. Hotunan da ke nuna wakilci na TH-IR a SN na yaudarar jima'i (I) da kuma gogaggen (J) maza. Siffofin zane: E-J, 20 μm.

Jima'i kwarewa-ya haifar da raguwa mai yawa na VTA dopamine neurons yana dogara ne a kan kunnawa mai karɓar sakonni na opioid

Ragewar VTA dopamine neuron girma girman da aka lalacewa ta hanyar jima'i kwarewa an katange ta nonselective MOR antagonist naloxone, da aka gudanar a gaban kowane taron jima'i. Maganin naloxone kafin jima'i yana da muhimmiyar tasiri akan yanki (F(1,22) = 4.738, p = 0.041) kuma yana fuskantar gagarumar tasiri a kewaye (F(1,22) = 2.892, p = 0.052). Wani muhimmin hulɗa tsakanin kwarewa da maganin naloxone aka samu don yanki (F(1,22) = 5.578, p = 0.027) da kuma kewaye (F(1,22) = 8.167, p = 0.009). Ƙwararrun kwatancen juna ya nuna cewa jima'i a cikin dabbobin da aka yi da saline ya rage yankin da kewaye da VTA dopin samfurin 7 d bayan ƙaddarar ƙarshe idan aka kwatanta da wadanda aka yi wa sallar da aka yi wa sallah (Siffa 1E, yanki: p = 0.018; F, kewaye: p = 0.007). Ya bambanta, dabbobin da aka kula da cutar taloxone da ke fama da jima'i ba su bambanta da mazaunin da ke fama da naloxone (Siffa 1E, yanki: p = 0.483; F, kewaye: p = 0.330). Bugu da ƙari, yawancin fararan dabbobi masu narkar da aka yi daidai lokacin da aka kwatanta da gogaggen naloxone na dabbobi (Siffa 1E, yanki: p = 0.002; F, kewaye: p = 0.002). Wannan tasirin naloxone ya ƙayyade ne don sanin jima'i, kamar yadda maganin naloxone kadai bai shafe yawancin suturar TH-IR ba a cikin mutanen da ke ɗauke da nau'in naloxone mai jima'i idan aka kwatanta da kula da saline (Siffa 1E,F). Bugu da ƙari, wannan tasirin naloxone a kan ƙananan haɓakaccen gwaninta bai haifar da sakamakon naloxone a kan halayen jima'i ba, kamar yadda halin jima'i ba ya bambanta tsakanin naloxone da maza masu saline ba, sai dai don lokaci mai tsawo don fara jima'i bayan tarawa (bayan ragowar haɗuwa) a cikin mazaunin da aka yi da naloxone a lokacin farko da biyar na jima'i (p = 0.03 da kuma p = 0.004, bi da bi). Dukansu saline- da naloxone wadanda aka bi da su sun hada da juna a yayin kowane lokaci na biyar.

Harkokin jima'i-haifar da haɓakar morphine sakamakon haƙuri

A sakamakon ilimin jima'i a kan VTA dopamine fara girman da mataki na EOP a VTA ne kama da waɗanda aka ruwaito domin exogenous opiates (Sklair-Tavron et al., 1996; Russo et al., 2007). Saboda haka, an gwada shi ko sakamakon dabi'a na VTA dopamine cell filastik yana rinjayar sakamako ga morphine. Hakika, abubuwan jima'i sun haifar da haɗin gwiwar morphine, wanda ya kasance daidai da illa mai tsauri (Russo et al., 2007). Mazan da suka shafi jima'i sun kasa samar da CPP don 0.5 mg / kg morphine kashi; Duk da haka, maza ma'aurata sun hada da CPP don wannan kashi, kamar yadda aka nuna ta ciyar da mafi yawan lokuta a cikin jam'iyar morphine idan aka kwatanta da ɗakin saline a cikin gwajin bayan gwaji (Siffa 3; p = 0.039). Dukkanin jinsin jima'i da kungiyoyi masu gogaggun sunyi amfani da wani lokaci mafi yawa a cikin jam'iyya na morphine idan aka kwatanta da ɗakunan saline wanda ke da nauyin morphine: 5.0 mg / kg (Siffa 3; Naïve: p = 0.029; Exp: p = 0.012) da 10.0 mg / kg (Siffa 3; Naïve: p <0.001; Kashe: p = 0.002).

Hoto 3. 

Hanyoyin ilimin jima'i akan sakamako na morphine. Lokaci ya yi amfani da saline- (Sal) ko 'ya'yan morphine- (Mor, 0.5, 5 ko 10 mg / kg jikiweight) a lokacin gwajin bayan jarrabawar jima'i (Naive, n = 10-13) ko gogaggen (Exp, n = 9-13) maza. Bayanan da aka gabatar kamar yadda ake nufi ± SEM; * yana nuna bambanci mai mahimmanci idan aka kwatanta da ɗakin da aka haɗa Sal guda a cikin waɗannan dabbobi. NS, Ba mahimmanci ba.

Harkokin jima'i-haɓaka aikin haɓaka ta hanyar jima'i yana dogara ne akan kunnawa mai karɓar mai karɓa na opioid

Abubuwan da aka gano a yanzu sun nuna cewa EOP da ke aiki a cikin VTA a lokacin 5 na yau da kullum na yin jima'i yana haifar da nauyin VTA dopin ne wanda yake kama da illa na ciwon daji ko gwanin heroin.Russo et al., 2007; Mazei-Robison et al., 2011). Mun yi tsammanin cewa VTA ya fara rage girman ƙaddamarwa don ƙwarewar ilmantarwa kuma musamman ga jima'i-kwarewa game da jima'i cikin hali game da dalili da kuma aikin. An gwada wannan jaddada ta hanyar hana MOR ta amfani da naloxone a lokacin da ake yin jima'i da kuma nazarin abubuwan da zasu haifar da haɓaka halayyar jima'i da ta haifar da jima'i a lokacin zaman jima'i biyar. An gabatar da bayanai a cikin Figure 4 don zama na farko da na biyar kawai, kamar yadda waɗannan su ne bayanan da suka fi dacewa da misalin irin abubuwan da ake gudanarwa ta hanyar jima'i. Bugu da ƙari kuma, ana yin gwajin maganin naloxone a lokacin da ake jima'i ta hanyar jima'i don tabbatar da haɓaka aikin halayen mating, a yayin gwajin gwaji na karshe na 1. Figure 4A yana nuna gwajin gwaji. Akwai muhimmiyar mahimmancin tasiri na jima'i a kan dukkan sigogi na halayyar jima'i (tsaunin tsage: F(2,55) = 11.286, p <0.001; jinkirin intromission: F(2,55) = 8.767, p <0.001; Fitar da maniyyi: F(2,55) = 10.368, p <0.001) da kuma maganin naloxone akan jinkiri zuwa hawa (F(1,55) = 6.585, p = 0.013) da kuma intromission (F(1,55) = 7.863, p = 0.007). Kwararrun kamfanoni guda biyu sun nuna cewa maganin naloxone ya shafi halin jima'i a lokacin da aka fara yin jima'i saboda dabbobin da ke da ƙwayar dabbobi sun fi tsayi da yawa zuwa tsawan farko (p = 0.002) da kuma intromission (p = 0.002) idan aka kwatanta da saline controls a ranar farko ta mating. Wannan mummunan sakamako akan halayen jima'i na farko ya ɓata ta hanyar jima'i da kuma ba a kiyaye shi a lokacin kowane lokuta na gamuwa (Table 1). Bugu da ƙari, mulkin naloxone a gaban kowane lokaci na jima'i biyar bai hana haɓaka ta farko da ta shafi jima'i da jima'i ba. Dangane da ƙarfafawar illa ga jima'i, mutanen da aka bi da saline sun nuna ƙananan latencies don hawa (Siffa 4B; p = 0.032) intromission (Siffa 4C; p = 0.033) da kuma haɓaka (Siffa 4D; p <0.001) yayin zaman jima'i na biyar idan aka kwatanta da farkon lokacin saduwa, wanda ya nuna sauƙin halayyar jima'i. Hakanan, mazan da aka yiwa magani naloxone sun nuna jinkiri mafi jinkiri don hawa (Siffa 4B; p <0.001), intromission (Siffa 4C; p <0.001), da fitar maniyyi (Siffa 4D; p = 0.017) a kan biyar idan aka kwatanta da ranar farko. Bugu da ƙari, nau'in naloxone-treated basu bambanta da sarrafa saline a cikin dukkanin latencies ba a lokacin da aka gama ta biyar.

Hoto 4. 

Abubuwan da ke ciki sunyi taka muhimmiyar rawa wajen tafiyar da halin jima'i. A, Zane gwaji. B-D, Yanayin halayen jima'i maza da namiji da saline (Sal, farin sanduna, n = 11) ko naloxone (NLX, sanduna baƙi, n = 12) tare da tsarin gudanarwa. Bayanan da aka nuna suna da lalata don hawa (B; seconds), intromission (C; seconds), da kuma ejaculation (D; seconds) a kwanakin 1 da 5 na kwana biyar na jima'i na mating. Bugu da ƙari, an nuna bayanai don gwajin gwaji ta ƙarshe, 7 d bayan bayanan ta biyar. Ana gabatar da bayanai a matsayin ma'ana ± SEM; + yana nuna bambanci tsakanin kwanaki 1 da 5 cikin magani; * yana nuna bambanci tsakanin gwaji da rana 5 cikin magani; # nuna muhimmancin bambanci tsakanin naloxone da saline kungiyoyi a cikin rana.

Table 1. 

Gwamnatin Naloxone kafin mating ƙara yawan latencies don hawa da ƙaddamarwa kawai a ranar farko ta mating

Sabanin haka, maganin naloxone a yayin zaman jima'i ya rushe kulawa da gwaninta ta hanyar yin jima'i a ranar gwaji ta ƙarshe. An gudanar da ranar gwajin 7 d bayan an gama jima'i na karshe idan babu injin naloxone. Ma'aikatan saline-kulawa sun nuna abin da ake sa ran zata iya haifar da halayyar jima'i. Musamman, latencies zuwa dutsen, intromission, da kuma ejaculation ba su bambanta tsakanin na biyar da jima'i da kuma gwaji na ƙarshe (Siffa 4B-D). Ganin cewa, mutanen da aka haifa naloxone sun nuna karuwa a cikin latencies don hawa (Siffa 4B; p = 0.033), intromission (Siffa 4C; p = 0.036) da kuma haɓaka (Siffa 4D; p = 0.049) a ranar gwajin idan aka kwatanta da na biyar na jima'i. Har ila yau, a gwajin gwajin naloxone a lokacin gwajin an gano cewa yana da hankali a hankali fiye da mutanen da aka ji daɗin salin kamar yadda aka nuna su ta wurin wanzuwa da tsayi.Siffa 4B; p = 0.017) da kuma intromission (Siffa 4C; p = 0.043). Saboda haka, maganin naloxone ya hana kariya, amma ba farko ba, haɓaka aikin haɓakawa na ilmantarwa. Wadannan binciken sun nuna muhimmancin rawar da VTA dopamine ke haifar da filayen ƙwayoyin cuta a kan dogon lokaci na nuna ƙarfin hali na dabi'a.

An gudanar da wasu gwaje-gwaje masu sarrafawa don sanin cewa sakamakon sakamako mai karɓar mai karɓar mai kwakwalwa a kan asarar ƙarfafa tsawon lokaci na halayen jima'i ya kasance mai zaman kanta daga rashin kulawar naloxone a ranar gwaji na karshe (Siffa 5A,B), sun danganta ne ga hasara na dogon lokaci, amma ba taƙaitaccen lokacin kiyaye gyaran matakan ba.Siffa 5E,F), ba a haifar dasu ba ne a yau da kullum zuwa naloxone kadai (Siffa 5C,D), kuma ba a lalacewa ta hanyar hasarar cinikin jima'i a cikin mazaunin da aka yi da naloxone (Siffa 5G,H). Na farko, don nuna cewa canza yanayin jima'i a gwajin gwaji na karshe bai kasance ba saboda rashin naloxone, ko dai naloxone ko saline da aka gudanar a ranar gwaji ta karshe ta dabbobi don dabbobi da suka karbi jima'i tare da naloxone yayin da suka sami kwarewa (Siffa 5A). Akwai muhimmiyar mahimman sakamako na ranar jima'i akan latencies don hawa (Siffa 5B; F(2,27) = 30.031, p = 0.038) da kuma intromission (Table 2; F(2,27) = 10.686, p = 0.048). Babu wani babban sakamako na ranar jima'i a kan latency ga ejaculation (Table 2; F(2,27) = 2.388, p = 0.109) Kamar dai yadda aka bayyana a sama, maganin naloxone a lokacin da ake yin jima'i bai shafi rinjayar halayyar jima'i ba a lokacin zaman farko na jima'i. Dukansu kungiyoyin (saline- da naloxone-treated groups kamar yadda aka samu ta hanyar karuwar da aka samu a lokacin gwajin gwaji ta ƙarshe) dukansu biyu sun karu a lokacin jima'i) ya nuna cewa halayyar jima'i ne a ranar 5 idan aka kwatanta da ranar 1 kuma ya nuna raguwa da raguwa zuwa saman farko (Siffa 5B; saline: p = 0.033; Naloxone: p = 0.014) da kuma intromission (Table 2; saline: p = 0.034; Naloxone: p = 0.026). Dabbobi da suka karɓa ko dai naloxone ko saline a ranar gwaji ta ƙarshe sun daina tsayi da yawa don a hau (Siffa 5B; saline: p = 0.018; Naloxone: p = 0.029) da kuma intromission (Table 2; saline: p = 0.019; Naloxone: p = 0.020) idan aka kwatanta da rana ta biyar na kwarewar mating. Saboda haka, gudanar da aikin naloxone ko saline a ranar gwajin nan da nan kafin jima'i bai rinjayar tasiri na maganin naloxone ba a yayin zaman jima'i da kuma ci gaba da yin gyare-gyare na tsawon lokaci ya kasance daidai da abin da aka nuna a dabbobin da ba su sami allura ba. a gwajin gwaji ta ƙarshe (Siffa 4).

Hoto 5. 

Abubuwan da ke tattare da halayen su na da muhimmanci a cikin dogon lokacin da aka nuna irin yadda ake yin halayyar jima'i. A, Gwajin gwaji don gwaji don sakamakon NLX magani a ranar gwaji. B, Dutsen latency a kwanakin 1 da 5 na kwana biyar na jima'i da gwajin gwaji ta ƙarshe (Test) bayan saline (launin toka) ko injin naloxone (baki). Bayanai na bayanan yana nufin ± SEM. * nuna muhimmiyar bambanci a tsakanin ranar 1 da ranar 5 a cikin magani. # yana nuna muhimmiyar bambanci tsakanin gwaji da ranar 5 a cikin magani. C, Gwajin gwaji don gwaji don gwada tasiri na maganin naloxone ne kawai ba tare da jin dadin jima'i akan halayyar mating ba. D, Latency na lalata a ranar gwaji ta ƙarshe, kwanakin 7 bayan kwanaki 5 na ko dai saline ko injection naloxone ba tare da mating ba. Bayanai na bayanan yana nufin ± SEM. E, Gwajin gwaji don gwaji don gwada ko maganin naloxone ya shafi abin da ke faruwa na gajeren lokaci na halayyar jima'i a cikin dabbobin jin dadi. F, Dutsen latency a ranar 1 da rana 5 na kwana biyar na jima'i da rana ta ƙarshe, gwajin 1 kowace rana 5 a gaban saline (launin toka) ko injin naloxone (baki). Bayanai na bayanan yana nufin ± SEM. * nuna muhimmiyar bambanci a tsakanin ranar 1 da ranar 5 a cikin magani. G, Gwajin gwaji don gwaji don gwada ko maganin naloxone ya katange sakamakon sakamako na jima'i. H, Lokaci da aka yi amfani da shi a cikin jima'i na biyu (a cikin seconds) a lokacin pretest (fararen fata) da kuma bayan gwaji (baƙar fata) don dabbobi masu karɓar kolo ko ƙarancin salin kafin aron. Bayanan bayanan bayanai yana nufin ± SEM; * nuna muhimmancin bambanci idan aka kwatanta da pretest.

Table 2. 

Bayanai da aka nuna sun kasance marasa ƙarfi ga intromission da ejaculation (seconds) daga gwaje-gwajen gwaje-gwajen da aka gudanar domin sanin cewa sakamakon MOR na hana hasara ta tsawon lokaci na halayen jima'i ya kasance mai zaman kansa daga rashin kulawar naloxone a ranar gwajin ƙarshe

Don sanin ko yayi maganin naloxone lokacin da aka haɗu tare da jima'i da kuma ba a maimaita zuwa naloxone ba saboda abin da ya haifar da lalata tsarin 7 d bayan jiyya na karshe, dabbobi masu kamuwa da jima'i sun karbi kofuna biyar na inganci na naloxone ko saline injections kafin gwajin gwaji ta ƙarshe 7 daga baya (Siffa 5C). Babu wani bambanci mai banbanci da aka gano don kowane matsala tsakanin matin tsakanin saline da naloxone wadanda aka kirkiro su (Siffa 5D; Ƙarfin lalata; latency intromission: saline 139.7 ± 40.3 da naloxone 121.83 ± 42.55; latency naja: salin 887.9 ± 70.0 da naloxone 1050.8 ± 327.31). Wadannan sakamakon sun nuna cewa kawai naloxone bai isa ya canza halin halayen jima'i ba, kama da rashin tasirin naloxone kadai a kan VTA dopamine neuron plastics.

Muna tsammanin cewa maganin naloxone a lokacin sayen jima'i ya rushe maganganun jima'i da aka haifar da shi-ya haifar da yunkurin yin jima'i. Don gwada wannan karar, an gwada tasirin maganin naloxone a lokacin jima'i akan halin jima'i na ƙarshe yayin gwaji ta karshe, wadda aka gudanar kawai 1 d bayan ƙayyadewa na ƙarshe (gwajin gwaji; Siffa 5E). Akwai muhimmiyar mahimman sakamako na ranar jima'i a Dutsen (Siffa 5F; F(2,20) = 19.780, p <0.001) da jinkirin jinkiri (Table 2; F(2,20) = 19.041, p <0.001). Babu wani muhimmin tasirin tasiri na yini akan latency ejaculation (Table 2; F(2,20) = 3.042, p = 0.070). Kamar misalin da aka bayyana a sama, duk maza (duk da jinin saline ko naloxone) ya nuna matakan halayyar jima'i a lokacin lokuta biyar na jima'i da aka nuna ta wurin raguwa da raguwa don hawa (Siffa 5F; saline: p = 0.002; Naloxone: p = 0.018) da kuma intromission (Table 2; saline: p = 0.006; Naloxone: p = 0.009) a ranar 5 idan aka kwatanta da ranar 1. Hakazalika, an nuna halin jima'i a ranar gwajin idan aka kwatanta da ranar 1 da aka nuna ta wurin raguwa da raguwa don hawa (Siffa 5F; saline: p = 0.001; Naloxone: p = 0.020) da kuma intromission (Table 2; saline: p = 0.004; Naloxone: p = 0.009). Abu mafi mahimmanci, maganin naloxone a yayin da ake yin jima'i bai shafi tasirin jima'i-yadda ake yin jima'i ba idan aka jarraba 1 d bayan jima'i, kwarewa daga lafiyar naloxone a wannan gwaji ta gwaji.

A ƙarshe, mun gwada yiwuwar tasirin sakamako naloxone akan bayyanar jima'i na sauƙaƙan halayen jima'i ya faru ne sakamakon toshewar ƙirar naloxone akan ƙimar halayen halayen jima'i. Koyaya, naloxone an gudanar dashi nan da nan kafin canjin canjin bai canza tsarin CPP don mating ba (Siffa 5G), suna nuna cewa maganin naloxone bai canza juyin jima'i ba. Dukansu kungiyoyin saline- da naloxone sun kirkiro CPP mai kyau don yin jima'i kamar yadda aka nuna ta hanyar ƙara yawan lokacin da aka yi amfani da su a cikin ɗakin jima'i (Siffa 5H; saline: p = 0.038; Naloxone: p = 0.002) a lokacin gwaji idan aka kwatanta da pretest. Saboda haka, naloxone ba zaiyi tasiri akan tasiri na halayyar halayyar jima'i ta hanyar hana haɗin da ke hade da halayyar jima'i.

Gudanar da halayen jima'i yana dogara da aikin EOP a cikin VTA

Don tabbatar da cewa EOP yayi aiki musamman a cikin VTA don haifar da halayyar jima'i na tsawon lokaci, gwajin gwaji da aka tsara a cikin Figure 3A aka maimaita tare da Intra-VTA naloxone infusions maimakon tsarin injections. Sakamakon sun kasance daidai da tsarin tsarin da aka bayyana a sama. Akwai muhimmiyar mahimman sakamako na ranar jima'i akan duk sigogi na jima'i hali (Siffa 6A, alamar layi: F(2,33) = 4.494, p = 0.019; B, lalata na intromission: F(2,33) = 4.042, p = 0.027; C, latency naja: F(2,33) = 5.309, p = 0.010) da kuma VTA naloxone magani a kan latencies zuwa hawa (F(1,33) = 7.345, p = 0.011) da kuma intromission (F(1,33) = 6.126, p = 0.019). Intra-VTA naloxone bai hana gwaninta na farko da ya haifar da halayyar jima'i a lokacin 5 d na mating ba, yayin da mazaunin da aka haifa sun nuna cewa sun rage latencies don hawa (Siffa 6A; p = 0.001), intromission (Siffa 6B; p <0.001), da fitar maniyyi (Siffa 6C; p = 0.001) a ranar 5 idan aka kwatanta da ranar 1. Mazan da aka bi da ɗabaran sunyi banbanta daga mazajen saline a rana ta biyar na mating a cikin kowane latencies. Magungunan naloxone na Intra-VTA, kamar tsarin kulawa, ya haifar da karuwa sosai (Siffa 6A; p <0.001) da jinkirin jinkiri (Siffa 6B; p <0.001) a ranar farko ta saduwa idan aka kwatanta da mazan da aka kula da su, wanda ba a lura da su ba yayin zaman da suka biyo baya (lokacin da naloxone- da majin da aka kula da salin ba su da bambanci). Wani abin lura da ba zato ba tsammani shi ne a cikin wannan gwajin, maza da aka kula da su cikin saline ba su nuna mahimmin sauƙin aiki na hauhawa ba ko lalatattun lamuran (kamar yadda aka nuna a duk gwaje-gwajen da aka bayyana a sama), kuma lalataciyar ɓarkewar maniyyi ne kawai ya ragu a rana ta biyar idan aka kwatanta da ranar farko (saline: p = 0.001).

Hoto 6. 

Magoya bayan sunyi aiki a cikin kwarewa na VTA - sunyi jagorancin halayyar jima'i da kiyayewa na tsawon lokaci. Hanyoyin sifofin jima'i maza da namiji da saline (Sal, farin sanduna, n = 8) ko NLX (sanduna na baki, n = 6) tare da gwamnatin VTA. Bayanan da aka nuna suna da lalata don hawa (A), intromission (B), da kuma haɓaka (C) a kwanakin 1 da 5 na kwana biyar na jima'i na mating. Bugu da ƙari, ana nuna bayanai don jimlar gwajin ƙarshe, 7 d kwanan nan na 5 a cikin babu saline ko injection naloxone. Bayanan bayanan bayanai yana nufin ± SEM; + yana nuna bambanci tsakanin kwanaki 1 da 5 cikin magani; * yana nuna bambanci tsakanin gwaji da rana 5 cikin magani; # nuna muhimmancin bambanci tsakanin naloxone da ƙungiyoyin Sal a cikin rana. Hoto na zane-zane na VTA sassan (H, -4.60; I, -5.00; J, -5.25 daga bregma) na nuna wuraren intra-VTA ga dukan dabbobi a cikin gwaji 5 (saline, fari; naloxone, black; Missed, gray), ta amfani da zanen samfuri daga Swanson Brain Maps (Swanson, 2004). Kayan gine-gine sun kasance haɗin gwiwar, amma shafukan da aka yi amfani da allurar suna nuna ba tare da wata hanya ba don sauƙin gabatarwa. fr, Fasciculus retroflexus; ML, Mediya lemniscus; SN, substantia nigra.

Maganin naxolone na Intra-VTA ya hana kariya ta hanyar yin jima'i da aka lura da shi a cikin mazajen jima'i, kamar maganganun naloxone. Musamman, a ranar gwajin gwaji na ƙarshe wadanda maza da aka haifa nalo sun kasance sun fi tsayi da yawa a kan dutse (Siffa 6A; p = 0.011), intromission (Siffa 6B; p = 0.010), da kuma haɓaka (Siffa 6C; p = 0.015) idan aka kwatanta da haɗuwarsu ta biyar kuma idan aka kwatanta da mutanen da aka kula da salin a ranar gwajin karshe (Siffa 6A, p = 0.006; B, p = 0.008). Ya bambanta, dabbobin da aka kula da saline ba su bambanta a cikin latencies don hawa da ƙaddamarwa tsakanin gwajin karshe da rana ta 5 na mating. Wadannan sakamakon sune musamman ga bayarwa naloxone zuwa VTA, a matsayin maza da wuraren shafewa a kusa amma ba da niyyar VTA ba (Siffa 6D; n = 3) ya nuna alamar tsawon lokaci na halayyar jima'i da kama da maganin sallah (ML, IL = 53 ± 6.245, EL = 389 ± 299.5 da mahimmanci idan aka kwatanta da dabbobi na VTA naloxone a ranar gwaji na karshe (ML, IL: p = 0.029; EL: p = 0.0395).

Ana buƙatar aikin EOP don haɗuwa da ƙwayoyin mu'amala ta hanyar jima'i

Bisa ga binciken da ake ciki har yanzu, muna tsammanin cewa an shigar da ETA a VTA a yayin da ake yin jima'i da kuma saurin VTA na ƙaddamar da ƙananan raguwa yana da mahimmanci ga haɓakar mai da hankali ga haɓaka ga haɓakar jingina ta hanyar jingina tare da sakamakon haka, tabbatar da saurin halayyar jima'i. Don gwada wannan tsinkaya, sakamakon tasirin masu karɓa na opioid a yayin da ake ganewa ta hanyar jigilar matsala a kan ayyukan da ke tattare da ƙananan halayyar ta hanyar haɗakarwa ga wasu abubuwan da aka sani game da jima'i. Kodayake dabbobi mazhabar jima'i suna nunawa ga abubuwan da ke cikin muhalli, amma waɗannan ba su da dangantaka da abubuwan da suka faru a baya, saboda haka sune ra'ayoyin da basu dace ba. A karshe, tushen ƙaddarar matakan da aka ƙaddara a ƙauyuka masu kula da jima'i da marasa rinjaye da suka kasance a cikin gidaje kuma ba a nuna su ba a cikin wani layi (-No Cue). Tabbatawa da kuma fadada binciken da suka gabata (Balfour et al., 2004), yadawa zuwa abubuwan da suka shafi mahallin da suka shafi dangantaka da jima'i da suka wuce a yayin da aka haɓaka ya ƙãra ƙara ƙaddamar da magana a cikin jima'i maza da mata a cikin NAc (Siffa 7) da kuma mPFC (Siffa 8A-C), amma bai haifar da kunnawa neuronal a BLA (Siffa 8D) ko CPu (bayanai ba a nuna su) ba. Akwai tasiri mai yawa na nuna hotuna a cikin NAc (F(1,12) = 12.1941, p = 0.004), ACA (F(1,12) = 5.541, p = 0.038), da kuma PL (F(1,12) = 5.241, p = 0.041), da kuma maganin naloxone a cikin NAc core (F(1,12) = 6.511, p = 0.025), ACA (F(1,12) = 15.242, p = 0.002), da kuma PL (F(1,12) = 7.336, p = 0.019). Akwai muhimmiyar hulɗa a cikin NAc (F(1,12) = 10.107, p = 0.008), ACA (F(1,12) = 16.060, p = 0.002), PL (F(1,12) = 8.235, p = 0.014), da IL ((F(1,12) = 6.965, p = 0.022). Na farko, halayen Cue da aka haɗu da haɗuwar haɗari sun kara ƙaruwa a cikin kwayoyin da suka ji daɗin jin dadin jiki (Exp Sal ​​+ Cue) idan aka kwatanta da masu sarrafawa wanda ba a bayyana su ba a duk wani bayani kuma an cire su daga ɗakin gida (Exp Sal-No Cue) a cikin NAc (Siffa 7A; p <0.001), da kuma mPFC subregions ACA (Siffa 8A; p = 0.001), PL (Siffa 8B; p = 0.003), da IL (Siffa 8C; p = 0.029). Ya bambanta, a cikin dabbobin da aka yi wa salin da za su yi saline, suna nunawa ga abubuwan da ke cikin al'amuran da ba su da alaƙa da ladabi, ba su jawo hankalinsu a kowane bangare na kwakwalwa ba (Naive Sal + Cue idan aka kwatanta da naive Sal-No Cue; Fig. 7, 8), nuna cewa ƙaddamar da PERK ya danganci daukan hotuna game da halayen jima'i. Bugu da ƙari, jima'i kawai ba ya canza tushen bayani a cikin kowane yankuna na kwakwalwa, saboda babu bambancin tsakanin kungiyoyin da aka karɓa daga gidajensu, ko kuma jima'i ko jima'i, kuma sun bi da saline ko naloxone.

Hoto 7. 

Ana buƙatar aikin aiki na ƙaƙƙarfan ƙarancin aiki don yin aiki na jiki a cikin NAc da aka haifa ta hanyar jima'i. Lissafi na kwayoyin halitta-kwayoyin halitta a cikin mm2 a cikin nucleus accumbens core (A) da harsashi (B) a cikin jima'i (fararen fata) da kuma gogaggen (ƙananan baƙin ciki) dabbobin da aka sanya su tare da NLX ko saline (Sal) a lokacin lokacin jima'i (Maza maza) ko tarurruka (mazajen Naira). Ƙungiyoyi sun kasance suna nunawa a cikin abubuwan da ke ciki (Cue), wadanda suke da alaƙa da juna a cikin mazajen Exp da maza a cikin dabbobi Naive, ko kuma daga ɗakin gida (No Cue; Ana gabatar da bayanai a matsayin ma'ana ± SEM; * yana nuna bambanci mai banbanci idan aka kwatanta da saline-pretreated babu wani nau'i mai kwance-kwance (Naive Sal-No Cue da Exp Sal-No Cue); # nuna muhimmancin banbanci idan aka kwatanta da ƙungiyar Ƙungiyar C mai-fallasa ta Gida (Exp Sal ​​+ Cue). Wakilin zane-zane na RU-IR kwayoyin halitta ta mm2 a cikin NAc mahimmancin jima'i da maza da Sal (C, D) ko NLX (E, F) wanda aka ɗauka daga ɗakin gida (No Cue, C, E), ko kuma an nuna su ga abubuwan da aka haɗu da juna ta hanyar jima'i (Cue; D, F). N = 4 kowace ƙungiya sai Naive NLX (No Cue), n = 3. ac, Anterior commissure. Bar ma'auni, 100 μm.

Hoto 8. 

Hanyoyin naloxone a kan abubuwan da aka samu a cikin mating suna nuna cewa a cikin sauran yankuna na VTA. Lissafi na kwayoyin halitta-kwayoyin halitta a cikin mm2 a cikin jima'i na fari (fararen fata) da kuma kwarewa (Bayyana baƙin ciki) dabbobin da aka sanya su tare da NLX ko Saline (Sal) a lokacin lokutan jima'i kuma aka nuna su a Cue (Cue) ko gidan gida (no cues) a ACA (A), PL (B), IL (C), da BLA (D). Bayanan bayanan suna nufin ± SEM; * yana nuna bambanci mai banbanci idan aka kwatanta da saline-pretreated babu wani nau'i mai kwance-kwance (Naive Sal-No Cue da Exp Sal-No Cue); # yana nuna muhimmiyar banbanci idan aka kwatanta da Sallar da aka yi wa Sal-Cue.

Don tallafawa tunaninmu, maganin naloxone a lokacin kwarewa ta hanyar jima'i wanda aka haɓaka a hankali yana mai da hankali ta hanyar haɓaka ta hanyar jima'i da aka hade. KARIN kalma a cikin waɗannan mazajen da aka yi wa kwakwalwa (Exp NLX + Cue) ba su bambanta ba daga bambance-bambance a cikin kowane ɗayan jima'i ko masu kula da kwarewar da aka karɓa daga ɗakin gida (Naive Sal-No Cue ko Naive NLX- Babu Cue). Bugu da ƙari, GABATAR kalma a cikin mazan da aka yi wa kwakwalwa naloxone (Exp NLX + Cue) ya fi muhimmanci idan aka kwatanta da dabbobin da aka ji daɗin saline (Exp Sal ​​+ Cue) a cikin NAc babban (Siffa 7A; p = 0.002) da kuma subregions na mPFC (Siffa 8A, ACA: p <0.001; B, PL: p = 0.002; C, IL: p = 0.015).

A cikin nauyin NAC, hanyar binciken ANOVA guda biyu ba ta samar da tasiri mai mahimmanci daga abubuwan da ke haifar da farfadowa da kuma maganin naloxone. Duk da haka, kwatancen da aka kwatanta ta biyu ya nuna cewa tasirin da aka yi amfani da shi ya haifar da kwarewa a cikin ƙungiyar da aka yi wa saline (Exp SAL + Cue) idan aka kwatanta da wani rukuni na saline wanda ba a bayyana shi ba (Siffa 7B; Naive SAL-No Cue: p = 0.0163).

tattaunawa

Binciken na yanzu ya nuna cewa EOP ke aiki a cikin VTA a lokacin halayen jima'i, dabi'a ta dabi'a, ya haifar da raguwa mai zurfi amma ragewa a cikin girman tsarin VTA dopamine. Raguwa a yawancin soma ba a lura da shi a VTA wadanda ba kwayoyin dopamine ba, kuma ba a cikin kwayoyin dopamine a kusa da kwayar cutar ta kusa, cewa wannan canji ya kasance musamman ga kwayoyin VTA dopamine. Wannan VTA dopamine filastik ya bayyana kama da cewa induced by na kullum opiate daukan hotuna (Sklair-Tavron et al., 1996; Russo et al., 2007; Mazei-Robison et al., 2011) kuma ya haifar da haƙuri irin wannan ga sakamakon sakamako na morpine (morphine). Mun nuna cewa VTA dopamin filastik yana da mahimmanci ga tsawon lokaci (goyon baya) amma ba gajeren lokaci (ci gaba), ƙarfafa hali na jima'i da aikin haɗin gine-gine na haɗin gwiwar (pERK) a cikin yankunan VTA: NAc da mPFC. Wadannan binciken sun nuna muhimmancin ga VTA dopamine filastity a cikin lokaci mai tsawo na nuna jin daɗin haɓaka na ladabi na ladabi ko ladaran ƙwarewa.

An riga an rubuce cewa jimlar jima'i ta haifar da haɓaka halin halayen jima'i, wanda ya haɗa da saurin farawa zuwa farawa na mating da kuma karuwa (Balfour et al., 2004; Pitchers et al., 2010a,b, 2012). Wannan haɓakawa ko ƙarfafa hali na jima'i an kiyaye shi don akalla 28 d bayan an yi mata (Pitchers et al., 2012). Bugu da ƙari, an nuna cewa hali na jima'i da sanannun labarun jima'i suna haifar da ƙwaƙwalwa ta MOR a cikin VTA da kuma yin amfani da neuronal a cikin tsarin mesolimbic, ciki har da VTA (dopamine da nondopamine neurons), NAc, PFC, da BLA (Balfour et al., 2004, 2006). An kafa VTA dopin ƙananan ƙwayoyin ƙafafun kwaikwayo na taka muhimmiyar gudummawa a cikin ilmantarwa da kuma haɓakar mai da hankali na haɓaka da haɗin gwiwa (sakamakon haɗin gwiwa)Berridge da Robinson, 1998; Berridge et al., 2009; Flagel et al., 2011) kuma suna da mahimmanci ga farfadowar sakamako (Schultz, 2010). Binciken da aka samu a yanzu yana fadada iliminmu na yanzu ta hanyar nuna cewa neuroplasticity mai amfani da wannan sakamako yana da mahimmanci ga waɗannan ayyuka, kuma yana dogara ne akan kunnawa MOR ta EOP a cikin VTA. A halin yanzu ba'a sani ba wanda EOP shine MOR ligand da ke aiki a cikin VTA a lokacin halayyar jinsi. Kodayake biyu ƴon endorphin da kuma enkephalin sun kasance suna cikin motsa jiki na karfafawa ga masu taimakawa abinci (Hayward et al., 2002), wannan ya kasance a kafa don halaye na namiji. Mun nuna a baya cewa ba'a kunna ƴ-endorphin neurons ba a yayin da ake yin jima'i, kuma babu karuwa a cikin mRNA POMC; saboda haka, yana nuna cewa maganin β na iya zama mai mahimmanci na EOP da yake aiki a cikin VTA a yayin da yake da mating (Davis et al., 2007). Wannan Vista ta filayen lantarki yana da mahimmanci ga ayyukan da ke cikin jiki a cikin mPFC, NAc, da kuma VTA bayan an nuna su ga aikin jima'i-tsinkayar abubuwan da ke cikin muhalli. Bugu da ƙari, VTA dopin filastik abu ne mai mahimmanci ga maƙasudin lokaci na ƙaddamar da ƙaddamarwa da kuma yin jima'i. Ya bambanta, ƙananan ƙwayoyin VTA da aka haifar da jima'i ba a buƙata don amsawar da aka ba shi ba kamar yadda jima'i (sakamakon ƙaddarar da CPP ya tsara) da kuma karfafawa na dan lokaci na jima'i da kuma aikin (a lokacin jima'i ko 1 daga bisani)Mehrara da Baum, 1990). Maimakon haka, bayanan sun bada shawara cewa VTA dopin neuroplasticity yana jaddada lokacin da ya fi tsayi (7 d bayan bayanan jima'i; Pitchers et al., 2012) furta "son" na jima'i da ladabi da kuma ƙarfafa ra'ayoyin da aka yi a cikin layi (Miller da Baum, 1987; Berridge da Robinson, 1998).

Dabbobin da suka shafi jima'i sun nuna nuna haɗin kai zuwa sakamakon kyautar morphine, kamar kamannin motar da ke gudana a cikin mice, wani yanayi mai ladabi, wani sakamako da aka katange tare da maganin naloxone (Lett et al., 2001, 2002) kuma an ƙaddara su dogara ga VTA dopamine cell filastity (binciken yanzu). Hakazalika da ladabi na al'ada, maimaitawa ta nunawa ga magungunan morphine ko sakamakon heroin a cikin ragowar ƙwayar VTA ta atomatik girma (Sklair-Tavron et al., 1996; Spiga et al., 2003; Russo et al., 2007; Mazei-Robison et al., 2011). Bugu da ƙari, ɗaukar samuwa mai tsauri tare da ragowar lokacin ƙetare yana haifar da haɗin haƙuri, kamar yadda ake buƙata ta hanyar ƙwayar miyagun ƙwayoyi da ake buƙata ta zama ƙungiyoyi masu ladabi (Shippenberg et al., 1987; Russo et al., 2007), kuma yana sa dabbobi masu kula da kansu su ci gaba da yin amfani da miyagun ƙwayoyi (Ahmed et al., 2000; Walker et al., 2003). Saboda haka, EOP da opiates sunyi aiki a kan hanyoyin da za'a iya amfani da ita don su sami juriya a lokacin da ake janyewa daga baya, wanda zai iya kwatanta hanyar da za a iya amfani da su don taimakawa wajen ƙwace motsin jiki ta hanyar sake bayyanawa (Koob da Le Moal, 2005). Ya bambanta, a lokacin da ake amfani da maganin miyagun ƙwayoyi na tsawon lokaci, haƙuri ya juya zuwa hankali zuwa ga dukiyar da aka ba da ita ga miyagun ƙwayoyi (Harris da Aston-Jones, 2003; Aston-Jones da Harris, 2004; Harris da Gewirtz, 2004). Abin sha'awa shine, irin jima'i da aka bi bayan jima'i na 7-28 d an samo shi don haifar da gicciye-gizon haɓaka ga psychostimulant sakamako (Pitchers et al., 2010a), wanda ya dogara ne akan maganganun deltaFosB da aka samu a cikin mahaifa da kuma maye gurbin 1 mai karɓa na dopamine a cikin NAc (Pitchers et al., 2013). Saboda haka, sakamakon kwarewa na jima'i yana haifar da ƙwarewar samun haƙuri da kuma haɓakar ƙwararrun asiri, kodayake tsawon lokacin jima'i akan rashin lafiyar morphine ya kasance da za a jarraba shi. Muna tsammanin cewa wadannan sakamako na daban a kan sakamako na miyagun ƙwayoyi za su iya yin sulhu da nau'o'i daban-daban na filastik neural a sassa daban-daban na tsarin mesolimbic: Ayyukan VTA EOP da dopamine filasti sunyi tsayayya da haƙuri (nazarin na yanzu), yayin da bayanin NAC deltaFosB yake jagorancin ganewa na psychostimulant (Pitchers et al., 2013). Duk waɗannan abubuwa zasu iya taimakawa wajen bunkasa magungunan ƙwayoyi (Ahmed da Koob, 1998, 1999; Ahmed et al., 2000, 2002, 2003; Walker et al., 2003).

Ka'idodin kwayoyin halitta wanda EOP ke tasiri na amfani da VTA dopamine a yayin halin ladabi na dabi'a ba a sani ba. Hanyar IRS2-Akt-mTORC2 babbar maƙilaci ne na rage girman soma a cikin VTA da aka lalata ta hanyar morphine (Jaworski et al., 2005; Russo et al., 2007; Mazei-Robison et al., 2011). Maimaitawar tsarin morphine wanda aka haifar da canje-canje a cikin girman kwayoyin dopamine a cikin VTA za a iya hana shi ta hanyar VIR infusions na ƙwayar neurotrophic na kwakwalwa (BDNF; Sklair-Tavron da Nestler, 1995). BDNF tana kunna wannan hanyar ta hanyar alamar TrkB (Russo et al., 2007), haɗin mai karɓa tare da dangantaka mai zurfi ga BDNF da kuma ɓangare na hanyar IRS2-Akt (Seroogy da Gall, 1993; Numan da Seroogy, 1999), kuma ya bayyana a kan kwayoyin dopamine da GABA a cikin VTA. Rage layi na sassa daban-daban na hanyar IRS2-Akt ta yin amfani da fasaha ta hanyar canza fasaha ta hanyar kyamara ta hanyar kyamara yana iya haifar da tasirin tasiri mai tsada. Bugu da ƙari, za a iya ceton sakamakon ƙwaƙwalwar tilasta ta hanyar mayar da wannan hanya ta sigina (Russo et al., 2007) da kuma maganganun wani sashi na mTORC2 ya hana VTA dopin gurguntaccen kwayar cutar morphine ta ragewa (Mazei-Robison et al., 2011). Sabili da haka, aikin da aka yi a baya na bincike akan tasirin da ake samu a kan VTA dopamine ya fara nuna cewa maye gurbi na morphine na hanyar IRS2-Akt-mTOR ya cancanci ya zama dole don wannan sakamako (Mazei-Robison da Nestler, 2012). Saboda haka, yana da jaraba don tantance cewa sakamakon ilimin jima'i akan VTA dopin neuroplasticity ana daidaita su ta hanyar BDNF da hanyar IRS2-Akt-mTORC2.

A ƙarshe, binciken nan na yanzu ya nuna cewa neuroplasticity na VTA ya haifar da kwarewa tare da dabi'a mai ladabi, musamman ma ta hanyar zinawa ta maza. Musamman, EOP yayi aiki a cikin VTA don rage girman tsarin dopamine, wanda ake zaton cewa za'a hade shi da haɓaka ƙananan ƙananan hanyoyi da ƙasa da sakamako na dopamine wanda ya haifar da tsarin hypodopaminergic, kuma yana canza tsarin aiki na mesolimbic don mayar da martani game da alamun da ake bayarwa game da ladabi. Bugu da ƙari, ƙananan ƙarancin VTA yana da mahimmanci ga motsawar motsawa da ƙwarewar ƙwaƙwalwar ajiya, amma ba don tasiri na halayen jima'i ba. A ƙarshe, ƙananan ƙwayar VTA da lalacewa ta hanyar dabi'ar dabi'a ta biyo bayan wani ɗan gajeren lokaci na sakamako abstinence rinjayar sakamako na opiate kuma yana iya haifar da rashin lafiyar zuwa ci gaban ƙwayar maganin miyagun ƙwayoyi.

Bayanan kalmomi

  • An samu Janairu 12, 2014.
  • An sake dawowa daga Mayu 17, 2014.
  • An karɓa Mayu 20, 2014.

  • Wannan bincike ya goyi bayan tallafi daga Cibiyar Nazarin Lafiya ta Kanada zuwa LMC da Kimiyyar Kimiyya da Kimiyya kan Kwalejin Kwalejin KKP.

  • Masu marubuta sun bayyana ba abin da ya shafi kudade.

  • Dole ne a ba da labari ga Dr Lique M. Coolen, Jami'ar Mississippi Medical Center, Ma'aikatar Jiki da Lafiya, 2500 North State Street, Jackson, MS 39216-4505. [email kariya]

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