Ukuququzelelwa kokuziphatha ngokwesondo kunye nokuphucula i-dopamine efflux kwi-nucleus accumbens yeempuku zamadoda emva kwe-D-amphetamine-induced behaviour sensitization (1999)

QAPHELA - iqulethe iigrafu ezininzi.

J Neurosci. 1999 Jan 1;19(1):456-63.

Fiorino DF1, Phillips AG.

ISICWANGCISO ESIPHELELEYO- IPDF

Abstract

Ukuqonda ukuziphatha okubangelwa kulawulo oluphindaphindiweyo kunye nolwethutyana lwee-psychostimulants, ezifana ne-cocaine kunye ne-D-amphetamine, ikhatshwa ngumsebenzi ophuculweyo kwi-limbic-motor circuitry ebandakanyekayo kwisizukulwana sokuziphatha okukhuthazwayo. Uphononongo lwangoku lwe-microdialysis luphande ifuthe le-D-amphetamine-induced sensitization kwi-dopamine (DA) efflux kwi-nucleus accumbens (NAC) yeempuku zamadoda ngexesha lokuziphatha ngokwesondo. Iigundane zamadoda zanikwa inaliti enye ye-D-amphetamine (1.5 mg / kg, ip) okanye i-saline yonke imihla nge-injection ye-10. Kwiiveki ezintathu emva kokuyeka unyango lweziyobisi, iigundane zavavanywa ukuziphatha ngokwesondo ngexesha lovavanyo apho i-microdialysis yenziwa. Kwakukho i-efflux eyandisiweyo ye-DA kwi-NAC ye-D-amphetamine-i-rats-sensitized rats xa kuthelekiswa ne-nonsensitized control rats xa umfazi owamkelayo ekho emva kwesikrini (35 vs 17%). Iigundane ezivuselelweyo zibonise ukuziphatha okuququzelelweyo ngokwesondo xa isikrini sisusiwe, njengoko kuboniswa yi-latency emfutshane kakhulu yokunyuka kunye nokwanda okupheleleyo kwisixa sokuziphatha kokukopa. Nangona kukho ukwanda okuphawulekayo kwi-NAC DA ekugxininiseni ukusuka kwisiseko kwiigundane zombini ezivezwayo kunye nezingabonakaliyo ngexesha lokudityaniswa, kukho ukwanda okukhulu kwe-DA efflux kwi-NAC yeegundane ezivakaliswayo ngexesha lokuqala le-10 min isampula yokuphindaphinda (60 vs 37%). Ezi ziphumo zibonisa ukuba ulwazelelelo lokuziphatha olubangelwa lulawulo oluphindaphindiweyo lwe-psychostimulant lunokuthi "ludlulise ubuthathaka" kwindlela yokuziphatha yendalo, efana nokwabelana ngesondo, kwaye ukukhutshwa kwe-NAC yeDA kunokuba negalelo ekuququzeleleni imiba ekhangayo kunye neyokugqibela yokuziphatha.

Ukuvezwa kwangaphambili kwi-psychostimulants, njenge-d-amphetamine, kunokukhokelela ekuphenduleni okuphuculweyo kokuziphatha kwichiza, into eyaziwa ngokuba yi-sensitization yokuziphatha. Uphuhliso kunye nokubonakaliswa kokuvuselela ukuziphatha kuhambelana notshintsho olusebenzayo kwi-limbic-motor circuitry (URobinson noBerridge, i-1993; I-self kunye ne-Nestler, 1995; Pierce kunye neKalivas, i-1997). Le sekethe idlala indima ebalulekileyo ekuboniseni ukuziphatha okukhuthazwayo okanye okuqhutywa ngumvuzo (Phillips et al., 1991; Kalivas et al., 1993; URobbins no-Everitt, i-1996). Kuye kwacingelwa ixesha elithile ukuba iindlela ezifanayo ze-neural ezilamla impendulo kwiziyobisi ezikhobokisayo, ukuziphatha ngokwesondo, kunye nokuziphatha kokutya, zihlobene ngokusebenzayo (URobinson noBerridge, i-1993; Pierce kunye neKalivas, i-1997).

Nangona ukubonakaliswa kovakaliso lokuziphatha kwii-psychostimulants kubonakala kusisiphumo sotshintsho oluntsonkothileyo olubandakanya uninzi lwee-neurotransmitters kunye ne-nuclei, izifundo ezininzi ziye zaxela ukongezwa komsebenzi ngaphakathi kwenkqubo ye-mesolimbic dopamine (DA) (URobinson noBerridge, i-1993; I-self kunye ne-Nestler, 1995; Pierce kunye neKalivas, i-1997). Ewe, ukukhutshwa okwandisiweyo kwe-DA kwi-nucleus accumbens (NAC), indawo yokugcina ye-mesolimbic dopaminergic neurons, yenye yezona zinto zifunyaniswayo zihambelana nokubonakaliswa kwexesha elide lokuziphatha.URobinson kunye no-Becker, 1986; UPaulson noRobinson, ngo-1995; Pierce kunye neKalivas, i-1997; kodwa yabona Kuczenski et al., 1997).

I-Mesolimbic DA idlala indima ebalulekileyo njengemodyuli yeenkqubo zomvuzo ezinzima eziququzelela ukuziphatha okukhuthazwayo, njengokusela, ukutyisa, kunye nokwabelana ngesondo, ngokuphononongwa kwezinto ezikhuthazayo zokusingqongileyo.Blackburn et al., 1992; Kalivas et al., 1993; Kiyatkin, ngo-1995; Salamone, 1996). Ithiyori yenkuthazo yenkuthazo yeziyobisi iphakamisa ukuba ulawulo oluphindaphindiweyo lweziyobisi zokusetyenziswa kakubi lwenza le ndlela ye-DA ibe ne-hypersensitive kwaye, ngokwenza njalo, yongeza umsebenzi wayo wokubala inkuthazo yenkuthazo kwiimpawu ezinxulumene nomvuzo (URobinson noBerridge, i-1993). Kutshanje, sibonise ukuba ukuvuselela isimilo kwii-psychostimulants nako kunokuphucula iimpawu zenkuthazo zomvuzo wendalo (UFiorino noPhillips, 1995).

Kufunyaniswe kakuhle ukuba iipropathi zenkuthazo zowesifazane owamkela ngokwesondo zibaluleke kakhulu ekuziphatheni ngokwesondo kwiimpuku zamadoda ezingenamava (Ulwandle, ngo-1941; UMadlafousek noHlinak, ngo-1983). I-Mesolimbic dopamine yaziwa ngokudlala indima ebalulekileyo yokuququzelela ukudibanisa (Everitt, 1990; Pfaus kunye nePhillips, i-1991; Mas, ngo-1995; UMelis noArgiolas, 1995), kunye nenani lezifundo ze-microdialysis ziye zanika ingxelo yokwanda kwe-NAC ye-DA efflux ehambelana nazo zombini izinto ezikhangayo / ezikhuthazayo kunye nezokuziphatha zokuziphatha ngokwesondo kwiimpuku zamadoda (Damsma et al., 1992;Wenkstern et al., 1993; Mas, ngo-1995; UFiorino et al., 1997a). Kuphononongo lwethu lokuqala, ukuvezwa kwangaphambili kwe-d-amphetamine kuququzelele indlela yokuziphatha ngokwesondo kwiigundane zamadoda ezingenalwazi ngokwesondo (UFiorino noPhillips, 1995). Kunikwe ingqikelelo yokuba oku kuququzelelwa kokuziphatha ngokwesondo kulamlwa ngokukhutshwa okuphuculweyo kwe-NAC DA, uphononongo lwangoku lusebenzise i-microdialysis ukufumanisa ukuba ukonyuka koxinzelelo lwe-NAC ye-DA yongezwa ngexesha lokuziphatha ngokwesondo kumagundane angamadoda angenamava ngokwesondo aziva i-tod-amphetamine. Emva koko, umceli mngeni we-d-amphetamine wanikezelwa ukunika isiqinisekiso esizimeleyo sokuba i-Augmented NAC DA efflux ibonakala kwiimpuku ze-d-amphetamine-sensitized.

IMPAHLA NENKQUBO

Olu vavanyo lulandelayo lwenziwe ngokuhambelana nemigangatho yeBhunga laseKhanada lokuNakekelwa kweZilwanyana.

I zifundo. Iimpuku ze-Sprague Dawley eziyindoda (i-225-250 gm) zafunyanwa kwiYunivesithi yaseBritish Columbia yeZiko lokuNakekelwa kweZilwanyana kwaye zahlaliswa ngabanye kwiikheji zeplastiki. Igumbi lekholoni lagcinwa kumjikelezo wokukhanya / omnyama (ukhanyisa ngo-7 AM ukuya kwi-7 PM). Iimpuku ze-Female Long-Evans (iCharles River Canada, iSt. Constant, iQuebec, eKhanada) zazihlaliswa kwigumbi lekholoni elahlukileyo kumjikelo ofanayo wokukhanya / omnyama. Ubushushu be-Ambient babungu-∼20°C, kwaye iimpuku bezinawo ad adum ukufikelela ekutyeni nasemanzini. Uvavanyo lwenzeka kwisiqingatha sesithathu somjikelo omnyama.

Ukuhlinzwa. Iigundane zabasetyhini zayenziwe i-ovariectomized bilaterally phantsi kwe-halothane gas anesthesia (i-Fluothane; i-Ayerst Laboratories) ubuncinane kwiiveki ze-4 ngaphambi kovavanyo. Ukwamkelwa ngokwesondo kwi-stimulus females kubangelwa ii-injection ezingaphantsi kwe-estradiol benzoate (10 μg) kunye neprogesterone (500 μg), i-48 kunye ne-4 hr, ngokulandelanayo, phambi kweseshoni yovavanyo ngalunye. Bonke abasetyhini babenamava ngokwesondo ngaphambi kokuba kuqaliswe iimvavanyo zokuziphatha ngokwesondo.

Iigundane zamadoda zovavanyo ngalunye zi-anesthetized nge-ketamine hydrochloride (100 mg / kg, ip) kunye ne-xylazine (10 mg / kg, ip) ngaphambi kokuhlinzwa kwe-stereotaxic. I-Microdialysis probe guide cannulae (igeyiji eyi-19) yafakelwa phezu kwe-NAC (ilungelelanisa ukusuka kwi-bregma: ngaphambili, +1.7 mm; i-medial, -1.1 mm; kunye ne-ventral, -1.0 mm ukusuka kwi-dura; ukakayi olucaba), kwaye lukhuselwe kukhakhayi ngamazinyo Izikrufu ze-acrylic kunye ne-jewelers. I-19 ye-gauge yocingo "isithuba soqeqesho" yayifakwe phezulu kwekhakhayi emva kwe-cannulae yesikhokelo.

Izixhobo. Uvavanyo lwenziwa kumagumbi (48 × 24 × 35 cm) acandeke kabini ngesahlulelo esicacileyo sePlexiglas esisusekayo (32 cm), ukudala iindlela ezimbini ezibanzi ezingama-12 cm ubude. Iimpuku zazihamba ngokukhululekileyo phakathi kwecala ngalinye kuzo zombini iziphelo zegumbi. I-antechamber (24 × 8 × 16 cm), eyayisetyenziselwa ukubamba i-estrous female, yayibekwe kwelinye icala le-apparatus kwaye yahlulwe kumzimba oyintloko wegumbi ngesikrini se-wire mesh. I-infrared photobeam emitters / detectors ivumele ukubala inani lemisebenzi (ukunyakaza ukusuka kwelinye icala lesahlulelo ukuya kwelinye) ukuba kubekwe iliso ngokuzenzekelayo ngekhompyutheni (i-2 Hz scan rate). Amagumbi acocwa ngesisombululo se-Windex esidityanisiweyo phakathi kovavanyo lokuziphatha ukuze kuncitshiswe impembelelo yevumba lempuku eseleyo.

Ukungeniswa kwemvakalelo yokuziphatha. Izitofu zazilawulwa kwigumbi elinye elalisetyenziselwa uvavanyo lokuziphatha ngokwesondo (jonga ngezantsi) kumfuniselo ngamnye. Kuvavanyo ngalunye, iimpuku zamadoda zabelwa ngokungakhethiyo nokuba kukuphindwaphindwa kwe-d-amphetamine (AMPH) okanye kulawulo lwe-saline (CONT) amaqela. Ekuqaleni kovavanyo lomsebenzi ngamnye, i-coil yensimbi, eyayifakwe kwi-swivel ye-liquid (Instech, i-375 sec) ifakwe phezulu kwegumbi lokuvavanya, igcinwe kwisithuba soqeqesho kusetyenziswa ikhola yesikhokelo sophando lwe-microdialysis (bona Fiorino et al., 1993 ngeenkcukacha). Ngale ndlela, iimpuku ziye zaqhelana nesixhobo esiyimfuneko kwi-microdialysis. Iimpuku zafakwa kumagumbi ovavanyo kwaye, emva kwemizuzu engama-30 yokuhlala, zanikwa inaliti ye-intraperitoneal nokuba yi-d-amphetamine sulfate (1.5 mg/kg; Smith-Kline Beecham, Oakville, ON) okanye isithuthi se-saline (1 ml/kg; Baxter Corporation); , Toronto, Ontario, Canada). Kwiiyure ezimbini emva kokutofwa, iimpuku zabuyiselwa kwizindlu zazo. Iinaliti zanikwa kanye ngeentsuku ezi-2 xa zizonke iinaliti ezili-10. Ubalo lomsebenzi luqokelelwe kwimigqomo ye-10 yemizuzu, kwaye ukunyuka okuphawulekayo ukusuka kuvavanyo lokuqala ukuya kweyeshumi kuthathwe njengobungqina bokuqonda ukuziphatha.

Uvavanyo lokuziphatha ngokwesondo. Ngaphambi kokuqhuba isifundo se-microdialysis, uvavanyo lokuziphatha (uvavanyo loku-1) lwenziwa kumaqela ahlukeneyo eempuku (n = 10, amaqela omabini) ukuqinisekisa ukuququzelelwa kokuziphatha ngokwesondo emva kwe-amphetamine, ngaphakathi kwemiqobo yenkqubo ye-microdialysis. Njengoko kuphawuliwe ngasentla, zonke iigundane zazihlala kwikhoyili edibanisa indibano yentloko kwi-swivel ye-liquid, ngexesha lovavanyo lwe-10 lomsebenzi we-locomotor. Kwiintsuku ezingamashumi amabini ananye emva kwesitofu sokugqibela se-d-amphetamine okanye i-saline, iigundane ezingenangqondo ngokwesondo kumaqela e-AMPH kunye ne-CONT avavanyelwe ukuziphatha ngokwesondo. Uvavanyo belubandakanya i-60 min yesiseko sexesha kwigumbi le-unilevel, emva koko impuku yasetyhini e-estrous yafakwa kwi-antechamber eyahlulwe kwigumbi lovavanyo eliphambili ngesikrini socingo. Emva kwemizuzu eyi-10, isikrini sisusiwe, sivumela ukukopishwa ukuba kuqhubeke i-30 min. Imazi yasuswa emva koko, kwaye inkunzi yendoda yahlala egumbini ixesha elongezelelweyo le-60 min postcopulation. Ukuziphatha ngokwesondo kwathathwa ngevidiyo kwaye, emva koko, ikhompyuter kunye nesoftware efanelekileyo (ngenkxaso kaSonoko Ogawa, iYunivesithi yaseRockefeller) yayisetyenziselwa ukurekhoda imilinganiselo esemgangathweni yokuziphatha ngokwesondo: (1) i-mount frequency (MF), (2) intromission frequency (IF), (3) i-ejaculation frequency (EF), (4) intaba kunye (5) i-intromission latencies [ML kunye ne-IL; ixesha (i-sec) ukusuka ekunikezelweni kwesetyhini ukuya kwintaba yokuqala okanye i-intromission], (6) i-ejaculation latency [EL; ixesha (isekhondi) ukusuka kwi-intromission yokuqala ukuya kwi-ejaculation yokuqala], (7) inani le-intromissions ukuya kwi-ejaculation yokuqala (IE1), (8) isithuba sexesha lokuzala [i-PEI; ixesha (i-sec) ukusuka kwi-ejaculation yokuqala ukuya kwi-intromission elandelayo], (9) i-interintromission interval (III; EL/IE1), kunye (10) ne-intromission ratio (IR; IF / (MF + IF)). Iikhrayitheriya zokukhwela kunye ne-intromissions zichazwe kwiUSachs kunye noBarfield (1976).

Unyango. Iigundane (n = 10, omabini amaqela) afakwe kwi-microdialysis probes 12-18 hr phambi kovavanyo lwe-2 kwaye abekwe kwigumbi lovavanyo kunye ad adumukufikelela ekutyeni nasemanzini. Ngentsasa yovavanyo, iisampulu ze-microdialysis zaqokelelwa rhoqo ngemizuzu eyi-10. Uvavanyo lwalubandakanya izigaba ezihlanu: (1) isiseko (ubuncinci i-60 min); (2) i-estrous female emva kwesikrini (imizuzu eyi-10); (3) ukukopa kunye ne-estrous female (30 min); (4) i-postcopulation interval (i-60 min) emva kokuba iigundane zifakwe nge-d-amphetamine (1.5 mg / kg, ip); kunye (5) ixesha lokujova (i-120 min). Ukuziphatha ngokwesondo kwathathwa ngevidiyo kwaye kwahlalutywa njengoko kuchaziwe kuvavanyo loku-1.

Iinkqubo zeMicrodialysis kunye neempawu zophando ziye zaxelwa ngaphambili (UFiorino et al., 1997a). Ugxininiso lwe-microdialysate analytes, ebandakanya i-DA kunye ne-metabolites yayo i-dihyroxyphenylacetic acid (DOPAC) kunye ne-homovanillic acid (HVA), yavavanywa ngeendlela ze-HPLC zokufumanisa i-electrochemical.UFiorino et al., 1997a). Uphononongo oluqhelekileyo lophando, lwenziwe in vitro nakwiqondo lobushushu begumbi, bezi: kwiDA, 20.0 ± 0.9%; I-DOPAC, 15.2 ± 0.9%; kunye ne-HVA, 14.2 ± 0.6%.

Emva kovavanyo lwe-microdialysis, izilwanyana zanikwa i-overdose ye-chloral hydrate kwaye i-perfused intracardially nge-saline kunye ne-formalin (4%). Ubuchopho obukhenkcezisiweyo banqunyulwa, kwaye amacandelo e-coronal angcoliswa nge-cresyl violet ukumisela ukubekwa kwe-microdialysis probes. Iigundane ezinokubekwa kwe-probe ngaphakathi kwe-NAC kuvavanyo lwe-2 zazisetyenziselwa uhlalutyo lokuziphatha kunye ne-neurochemical.

Izibalo.Ubalo lwemisebenzi kunye nemilinganiselo yokuziphatha ngokwesondo yavavanywa kusetyenziswa ii-ANOVAs. Xa isiphumo esibalulekileyo sifunyenwe, ukuthelekiswa kwamaqela phakathi kwamaqela kwenziwa ngokusebenzisa uhlalutyo olulula lweziphumo eziphambili. Ngaphakathi-amaqela iposi uthelekiso lwenani elipheleleyo lemisebenzi esetyenzisiweyo kuvavanyo lweNewman–Keuls. Idatha ye-Neurochemical yahlalutywa ngendlela efanayo ngaphandle kokuba uvavanyo lukaDunnett lwalusetyenziselwa ukwenza uthelekiso lwangaphakathi lweqela kwiindlela zokulawula.

Uhlalutyo lweenkcukacha-manani olwahlukileyo lwedatha yokuziphatha ngokwesondo esetyenzisiweyo i-Kaplan-Meier yezicwangciso ze-ML kunye ne-IL, eziye zavavanywa luhlalutyo lokusinda (Bloch et al., 1993; Liu et al., 1997). I-latencies yokunyuka kunye ne-intromit kunye nepesenti yezifundo ezibonisa ezi ndlela zokuziphatha yimilinganiselo yamacandelo akhuthazayo okuziphatha ngokwesondo. Omabini la manyathelo asetyenziswa kwiiploti ze-Kaplan-Meier, eziveliswa ngokucwangcisa ixesha lokulinda ngokuchasene nepesenti yeempuku ezibonise ukuziphatha ngaphakathi kovavanyo. Le nkqubo inenzuzo eyongeziweyo yokuba idatha evela kwizifundo ezingaphumeleliyo ukunyuswa okanye i-intromit ayishiywanga okanye inikwe ixabiso elingenasizathu.

Uhlalutyo lwenziwa kusetyenziswa iSPSS kunye neStatistica iipakethe zesoftware yezibalo.

IINKCUKACHA

Uvavanyo loku-1: isiphumo se-d-amphetamine sensitization kukuziphatha kwempuku yendoda

Umsebenzi we-locomotor

Iigundane kwiqela le-AMPH zibonise uphuculo oluqhubela phambili lwe-ind-amphetamine-induced umsebenzi kwixesha le-injection ye-10 (Fig. 1 A). Kukho ukwanda okubonakalayo kwinani lilonke lezibalo zemisebenzi kuzo zonke iinaliti kwiqela le-AMPH (Newman-Keuls; p<0.01), ebonisa ukubethelela ukuziphatha kwe-tod-amphetamine.

Umzobo 1. 

A, B, Impembelelo ye-d-amphetamine ephindaphindiweyo okanye iinaliti ze-saline kumanani omsebenzi aqokelelwe ngaphezu kwe-2 hr emva kwesitofu kwisilingo se-1 (A) kunye nomfuniselo 2 (B). Idatha imelwe njengenani eliqhelekileyo (± SEM) lomsebenzi. Kwakukho intsebenziswano ebalulekileyo phakathi kweqela kunye nenombolo yesitofu kuzo zombini iimvavanyo: uvavanyo 1, F(1,16) = 5.60,p < 0.05; umfuniselo 2,F(1,18) = 12.44, p < 0.01. Uthelekiso phakathi kweqela, ***p <0.001, usebenzisa uhlalutyo olulula lweziphumo eziphambili. Uthelekiso phakathi kweqela, †p < 0.01, ‡p < 0.001, usebenzisa iNewman–Keuls iposi vavanyo.

Ukuziphatha ngokwesondo

itafile 1 ishwankathela imilinganiselo yokuziphatha ngokwesondo kuvavanyo 1. Kwakukho ukuququzelelwa kokuziphatha ngokwesondo kwi-AMPH (n = 10) iqela elinxulumene neCONT (n = 10) iqela, njengoko kubonisiwe ziindlela zokubuya ezimfutshane kakhulu zokunyuswa (F (1,14) = 4.80;p <0.05) kunye ne-intromit (F (1,14)= 5.92; p <0.05). Uphononongo lokusinda kweKaplan-Meier curves ye-mount latency (Fig.2 A, Iphaneli yasekhohlo) kunye ne-intromission latency (Fig.2 A, Iphaneli yasekunene) ukuqinisekisile ukuququzelelwa kokuziphatha kwiigundane eziphathwe nge-AMPH (i-Log rank statistic = 9.43, p = 0.0021; Uluhlu lweenkcukacha manani = 10.48,p = 0.0012, ngokulandelelana).

Ithebula 1. 

Imilinganiselo yokuziphatha ngokwesondo evela kumfuniselo 1 kunye no-2

Umzobo 2. 

Isiphumo se-d-amphetamine okanye i-saline pretreatment kwi-latencies yokunyuka kunye ne-intromit. A, iKaplan–Meier ijika le-mount latency (Iphaneli yasekhohlo) kunye ne-intromission latency (Iphaneli yasekunene) kuvavanyo lwe-1. Uhlalutyo oluzimeleyo lokusinda lubonise umehluko omkhulu phakathi kwe-sensitized (AMPH) kunye ne-nonnsensitized (CONT) iigundane ngokubhekiselele kwi-mount latency (i-Log rank statistic = 9.43; p = 0.0021) kunye ne-intromission latency (i-Log rank statistic = 10.48; p = 0.0012). B, iKaplan–Meier ijika le-mount latency (Iphaneli yasekhohlo) kunye ne-intromission latency (Iphaneli yasekunene) kuvavanyo lwe-2. Uhlalutyo oluzimeleyo lokusinda lubonise umehluko omkhulu phakathi kwe-sensitized (AMPH) kunye ne-nonnsensitized (CONT) iigundane ngokubhekiselele kwi-mount latency (i-Log rank statistic = 6.12; p = 0.0134) kunye ne-intromission latency (i-Log rank statistic = 4.38;p = 0.0364).

Kukho ukwanda ngokubanzi kwisixa sokuziphatha ngokwesondo okubangelwa kukuvezwa kwangaphambili kwe-d-amphetamine, njengoko kubonisiwe linani elikhulu kakhulu le-intromissions (F (1,16) = 5.89; p <0.05) kunye nokukhutshwa kwe-ejaculations (F (1,16) = 6.37; p<0.05) kwisithuba semizuzu engama-30 yokukopa xa kuthelekiswa neqela leCONT. Nangona kunjalo, amanye amanyathelo avela kuthotho lokuqala lwe-ejaculatory emva kokuba i-copulation iqalisiwe, njenge-EL, PEI, IE.1, III, kunye ne-IR, zazingahlukanga phakathi kwamaqela.

Uvavanyo lwe-2: i-dopamine efflux kwi-NAC kunye nokuziphatha ngokwesondo emva kwe-amphetamine-induced sensitization

Umsebenzi we-locomotor

Ulawulo oluphindaphindiweyo lwe-d-amphetamine luphinde lwabangela uvakalelo lokuziphatha kwiimpuku ze-AMPH (Fig.1 B). Iigundane kwiqela le-AMPH libonise impendulo yokuziphatha ekhuthazayo kwi-d-amphetamine, njengoko kuboniswe ngokunyuka okuphawulekayo kwinani elipheleleyo lezibalo zemisebenzi ukusuka kwi-injection 1 ukuya kwi-injection 10 (i-Newman-Keuls; p <0.05).

Ukuziphatha ngokwesondo

Imilinganiselo yokuziphatha ngokwesondo kumfuniselo wesi-2 (n = 8, omabini amaqela) abonisiwe kwiTheyibhile 1. Nangona iqela le-AMPH libonise ixesha elifutshane lokunyuka kunye nokungena, le milinganiselo ayizange ihluke kakhulu kwiqela le-CONT. Nangona kunjalo, uphononongo lokusinda lweKaplan-Meier curves yeML kunye ne-IL (bona iFig. 4 A) uye wabonisa ukuphuculwa okubalulekileyo kokuziphatha ngokwesondo kwiigundane ze-AMPH (i-Log rank statistics = 6.12,p = 0.0134; Iinkcukacha-manani zokuLokha = 4.38,p = 0.0364, ngokulandelanayo). Iqela le-AMPH liphinde lafumana i-ejaculations engaphezulu kwi-30 min copulatory period kuneqela le-CONT (F (1,14) = 5.56; p < 0.03). Ngokubanzi, iigundane kuvavanyo lwe-2 zibonise inqanaba elinobuchule ngakumbi lokuziphatha ngokwesondo kuneempuku zokulinga 1, ngokubhekiselele kwi-latencies ukunyuka, intromit, kunye ne-ejaculate, kunye nenani elipheleleyo lokukopa.

I-Neurochemistry yokuziphatha ngokwesondo

Ukuvezwa kwangaphambili kwe-d-amphetamine akuzange kutshintshe ukugxilwa kwe-basal ye-DA, i-DOPAC, okanye i-HVA (Itheyibhile2). Kwakukho utshintsho olupheleleyo kwi-NAC DA efflux ehambelana nokuziphatha ngokwesondo (Fig.3). Ngokukodwa, ukugxininiswa kwe-DA kwiigundane ze-AMPH kunyuswe kakhulu ngokumalunga nesiseko kuzo zonke izigaba zeseshoni yovavanyo, kubandakanywa nexesha apho ibhinqa lalikhona emva kwesikrini, ngexesha lokukopa, kunye nemizuzu engama-20 emva kokususwa kwayo. Ngokwahlukileyo, ukonyuka okubalulekileyo kokugxilwa kwe-DA kwiimpuku ze-CONT bekuthintelwe kwiisampulu ezinxulumene nokukopa. Ngokumalunga nezigaba ezahlukeneyo zovavanyo, ukunikezelwa kowesifazane owamkelayo emva kwesikrini (Scr; ixesha = i-20 min) kubangele ukwanda okubonakalayo kwi-NAC ye-DA yogxininiso ukusuka kumaxabiso asisiseko kwiqela le-AMPH (+ 35%; p <0.01) kodwa hayi kwiqela leCONT (+17%). Kubekho ukonyuka okungaphezulu kwe-DA efflux ngexesha lokudityaniswa kwawo omabini amaqela. Kwiigundane ze-AMPH, i-DA ifikelele ekugxininiseni okuphezulu ngexesha lesampula yokuqala yokukopisha (ixesha = i-30 min; + 60%), kunye ne-NAC DA yahlala iphakanyisiwe kwi-20 min emva kokususwa kwebhinqa. Ubuninzi bemilinganiselo ye-DA kwiqela le-CONT lenzekile kwi-10 min yesibini yesampula ye-copulatory (ixesha = 40 min; + 47%).

Ithebula 2. 

I-Basal concentrations ye-analytes ehambelana ne-100% yesiseko

Umzobo 3. 

Utshintsho kwi-nucleus accumbens dopamine efflux (igrafu yomgca) ngexesha lokuqala (Bas), ngelixa umfazi owamkelayo wayekho emva kwesikrini (Scr), ngexesha lokukopa, kwaye emva kokubambisana kweegundane ze-CONT kunye ne-AMPH. Iigrafu zebar bonisa inani lokunyuswa kunye namangeniso (igrafu yebha ephezulu) kunye nokukhupha (ibrafu yezantsi) eboniswe kwiqela ngalinye ngexesha leesampuli ezintathu ze-10 min. *p <0.05; **p <0.01 usebenzisa uhlalutyo olulula lweziphumo eziphambili. Ngaphakathi kweqela iNewman–Keuls iposi iimvavanyo zibonise ukubaluleka (p <0.05) ukwanda kwi-nucleus accumbens i-DA igxininise ukusuka kwisiseko kwi-AMPH (ixesha = 20-50 min) kunye ne-CONT (ixesha = 30-50 min) iirathi.

Ukunyuka kwe-NAC DA kwiqela le-AMPH kwakukhulu kakhulu kunokunyuka okufunyenwe kwiqela le-CONT, zombini xa ibhinqa lisemva kwesikrini (ixesha = 20 min) (F (1,182)= 4.76; p <0.05) kwaye ngexesha lokuqala le-10 min yokukopisha (ixesha = 30 min) (F (1,182) = 6.32; p <0.05). Ukongezwa okubalulekileyo kwe-NAC DA efflux kwiqela le-AMPH (ixesha = 30 min) lihambelana nenani elongezelelweyo lokunyuka kunye ne-intromissions (F (1,28) = 18.56; p <0.01) kunye nokukhutshwa kwe-ejaculations (F (1,18) = 5.09; p<0.05) ngokunxulumene neqela leCONT.

Ukugxininiswa kwe-Extracellular ye-DOPAC kunye ne-HVA kuye kwanda emva kokubambisana (Umfanekiso. 4). Ukunyuka okuphawulekayo kwi-DOPAC ekugxininiseni ngokumalunga nesiseko senzeke ngexesha lokuqala lokubambisana kumaqela omabini kwaye yahlala iphakanyisiwe kakhulu kwi-70 min emva kwe-injection kwiigundane ze-CONT (ubuninzi, ixesha = i-40 min; + 40%) kunye ne-60 min emva kwe-injection kwiirats ze-AMPH. (ubuninzi, ixesha = 40 min; + 55%). Ukonyuka kwe-HVA ekugxininiseni ukusuka kwisiseko esiphunyeziweyo ukubaluleka kwezibalo kwixesha lokuqala le-10 lexesha lokudityaniswa kweqela le-AMPH (ubuninzi, ixesha = i-60 min; + 50%) kwaye yahlala iphakanyisiwe kakhulu kwi-30 min emva kokubambisana. Nangona kunjalo, ugxininiso lwe-HVA kwiimpuku ze-AMPH lwalusenyukile ngaphambi nje komngeni we-d-amphetamine (+28%). Ukugxininiswa kwe-HVA kwiigundane ze-CONT ziphakanyiswe kakhulu ukusuka kwixesha elidlulileyo le-10 min copulatory period (ixesha = i-50 min) de kube i-injection ye-d-amphetamine (ixesha = i-110 min), kwaye ifikelele ekunyukeni okuphezulu kwe-49% (ixesha = i-70 min). Kwakungekho mmahluko wamanani ekugxininiseni kwe-metabolite phakathi kwamaqela nakweyiphi na indawo kuvavanyo.

Umzobo 4. 

Utshintsho kwi-DOPAC (iphaneli ephezulu) kunye neHVA (iphaneli esezantsiUgxininiso kwi-nucleus accumbens ngexesha lesiseko (Bas), ngelixa umfazi owamkelayo wayekho emva kwesikrini (Scr), ngexesha lokukopa, nasemva kokukopela. Ngaphakathi kweqela iNewman–Keulsiposi iimvavanyo zibonise ukubaluleka (p <0.05) ukwanda kwi-nucleus accumbens i-metabolite concentrations ukusuka kwisiseko kwi-AMPH (DOPAC, ixesha = 30-80 min; HVA, ixesha = 30-90 min) kunye ne-CONT (DOPAC, ixesha = 30-90 min; HVA, ixesha = 50- 100 min) iimpuku.

Ukuziphatha kunye ne-neurochemistry emva komngeni we-ad-amphetamine

Ukulawulwa kwenkqubo ye-d-amphetamine (i-1.5 mg / kg) kubangele impendulo yokuziphatha kunye ne-neurochemical ekhuthazayo liqela le-AMPH ngokumalunga neqela le-CONT (Umfanekiso.5). Amanyathelo aphindaphindiweyo i-ANOVA kumanani omsebenzi abonise umphumo obalulekileyo weqela (F (14,196) = 28.50; p <0.01). Ukonyuka kwamanani omsebenzi emva kokuba ulawulo lwe-d-amphetamine luqhubekile kwi-2 hr emva kokutofa kumaqela omabini ngokumalunga nesiseko, njengoko kuhlolwe nguNewman-Keuls. iposiiimvavanyo. Iqela le-AMPH libonise inani elikhulu kakhulu lezibalo zemisebenzi kuneqela le-CONT kwi-30 min yokuqala emva kwe-injection yeziyobisi kunye ngokubhekiselele kwinani elipheleleyo lomsebenzi emva kwe-injection (413.5 ± 37.7 vs 303.6 ± 37.8) (F (1,14) = 4.84; p <0.05).

Umzobo 5. 

Utshintsho kwi-nucleus accumbens dopamine efflux ekuphenduleni umngeni we-d-amphetamine (1.5 mg/kg, ip). *p <0.05; **p <0.01 usebenzisa uhlalutyo olulula lweziphumo eziphambili. Ukugxininiswa kwe-Dopamine kunye nokubalwa komsebenzi kuhlala kuphakanyisiwe kulo lonke ixesha le-2 hr postinjection ngokumalunga nesiseko (Bas) kuwo omabini amaqela.

Kwakukho ukonyuka okuhambelanayo kwi-extracellular NAC DA emva kwenaliti kumaqela e-CONT kunye ne-AMPH (F (14,196)= 39.16; p <0.01), kunye nokunyuka okubonwe kwiqela le-AMPH kwakukhulu kakhulu kuneqela le-CONT kwimizuzu yokuqala ye-40 emva kwe-injection (Fig. 5, iphaneli ephezulu). Zombini i-metabolites ye-DA yehla emva kokutofa kumaqela e-CONT kunye ne-AMPH. Ukulawulwa kwenkqubo ye-d-amphetamine kubangele ukuhla okuphawulekayo kwi-DOPAC efflux 10 min emva kwe-injection, ukufikelela kwi-concentration encinci ye-48% kwiqela le-CONT kunye ne-44% kwiqela le-AMPH (ixesha = i-50 min, amaqela omabini). Ukunciphisa okuphezulu kwi-HVA ekugxininiseni kwabambezeleka ngakumbi, ukufikelela kwiimpawu ezixinzelelekileyo ze-40 kunye ne-50 min emva kwe-injection kwi-CONT (ubuncinci, ixesha = i-80 min; 82%) kunye ne-AMPH (ubuncinci, ixesha = 100 min; 83%) iirathi, ngokulandelanayo. Kwakungekho mahluko phakathi kwamaqela kwi-DA yokugxilwa kwe-metabolite nakweyiphi na indawo emva kolawulo lwe-d-amphetamine.

Utshintsho olwahlukileyo kwi-extracellular NAC DA ye-metabolite concentrations ekuphenduleni izikhuthazo zesini kunye nolawulo lwe-amphetamine (okt, ukwanda kunye nokunciphisa, ngokulandelanayo) ngexesha apho i-DA efflux yanda ngokuqhubekayo, iphinda igxininise iingxaki ezihambelana nokugqithiswa kwe-DA ngotshintsho I-DA metabolite efflux (UFiorino et al., 1997a;O'Neill et al., 1998).

Histology

Amaphecana e-Microdialysis probes afunyenwe kuzo zombini igobolondo kunye nemimandla engundoqo ye-NAC kuluhlu olusuka kwi-+1.60 ukuya kwi-2.20 mm ukusuka kwi-bregma (Fig. 6).

Umzobo 6. 

Indawo ye-microdialysis probes ngaphakathi kwe-nucleus accumbens yeempuku ezisetyenziswe kuvavanyo lwe-2. Imigca emnyama emi nkqo ihambelana nendawo yefiber esebenzayo ye-microdialysis probes. Ngezizathu zokucaca, ukubekwa kophando lweempuku ze-CONT kubonisiwe kwi khohlo, kunye neempuku ze-AMPH ziboniswa kwi kunene. Amacandelo engqondo yeCoronal athathwe kwakhona ukusuka I-Paxinos ne-Watson (1997).

UKUQALA

Ukuboniswa okuphindaphindiweyo kunye nokungena kwi-d-amphetamine, okwaneleyo ukukhuthaza ukuziphatha, ukuququzelela ukuziphatha ngokwesondo kwiigundane zesini ezingenamava ngokwesondo, ngaloo ndlela siqinisekisa oko sikuqwalasele ngaphambili (UFiorino noPhillips, 1995). Esi siphumo saphindwa kwakhona kuvavanyo lwe-microdialysis, olubonise ngokucacileyo ukuba ukuziphatha okuphuculweyo kwezesondo kwanxulunyaniswa ne-Augmented NAC DA efflux. Iziphumo zovavanyo lwangoku aziboneleli kuphela ngenkxaso yendima ye-mesolimbic ye-DA ekuziphatheni okukhuthazwayo, kodwa igxininisa i-hypothesis eguqukayo kwi-limbic-motor circuitry, ngokukodwa kwiindlela ze-mesolimbic dopaminergic, igalelo ekuziphatheni okubonakalayo ekuphenduleni zombini ulawulo lwe-psychostimulant kunye nendalo. inkuthazo.

Uphononongo lwangaphambili lufumene ukuba ukuziphatha ngokwesondo kwaququzelelwa kwiigundane zamadoda xa zivavanywa kwindawo edityaniswe ngokuphindaphindiweyo ngenaliti ye-systemic morphine.UMitchell noStewart, i-1990). Ngokukodwa, bekukho ukongezwa okukhethekileyo kumanyathelo enkuthazo, anje ngenani lokuphononongwa kwe-anogenital, ipesenti yezilwanyana ezidibanayo, kunye ne-latency yokunyuka, kunokuba i-indices of copulation ngokwayo. Nangona injongo yolo phononongo yayikukuphanda ukuba ngaba ukuziphatha ngokwesondo kunokuphuculwa ngomanyano olumiselweyo phakathi kweempawu zokusingqongileyo kunye nomvuzo we-opiate, irejimeni yokutofa esetyenzisiweyo kuye kwabikwa ukuba ikhuthaze uvakalelo lokuziphatha kwiziphumo ze-locomotor-activating of morphine.UKalivas noStewart, i-1991). Uvavanyo lwangoku luvavanye ngokuthe ngqo ifuthe lokuziphatha ngendlela yokuziphatha ngokwesondo kwiimpuku zamadoda kwaye yafumana uququzelelo olufanayo lwezinto ezikhuthazayo zokuziphatha ngokwesondo, kubandakanya intaba kunye ne-intromission latencies. Nangona inani elipheleleyo lokubambisana liye lanyuswa kwiigundane ezithuthukisiweyo, njengoko kuboniswe yi-EF enkulu kunye ne-IF kwi-30 min yokulinganisa ixesha (uvavanyo lwe-1) kunye nenani le-intromissions kunye ne-mounts kunye ne-ejaculations ngexesha lokuqala le-10 min yokukopisha (uvavanyo lwe-2), Amanyathelo okugqibela ngaphakathi kwemida yokukopa, efana ne-IE1, III, IR, kunye ne-EL azizange zitshintshwe kakhulu. Impembelelo ekhethiweyo yokwazisa kwimiba ekhangayo yokuziphatha ngokwesondo iqinisekisa ukuqwalaselwa kwangaphambili (UFiorino noPhillips, 1995). Ngokuchaseneyo nesifundo ngo UMitchell noStewart (1990), sifumene le mpembelelo izimeleyo kumxholo apho iigundane zifumana iinaliti zeziyobisi (imibono yethu engapapashwa). Kufuneka kuqatshelwe ukuba, nangona zonke iigundane kwiqela le-AMPH zihlanganiswe kwiimvavanyo zangoku, i-d-amphetamine sensitization, ebangelwa yi-injection regimen, ayiqinisekisi ukuba iigundane ezingenazo ngokwesondo ziya kuhambelana (UFiorino noPhillips, 1995). Nangona kunjalo, siye saqaphela ukuba ipesenti ephezulu kakhulu yeegundane ezichazwe ngaphambili kwi-d-amphetamine ziya kuhambelana ngexesha lovavanyo lwabo lokuqala lokuziphatha ngokwesondo (okt,> 85%).

Iingxelo zangaphambili ziye zaphawula ukuba ukonyuka kwendawo ye-medial preoptic (mPOA) okanye i-NAC DA efflux ekuphenduleni umntu obhinqileyo owamkelayo emva kwesikrini kwabonwa kuphela kwiigundane zamadoda eziye zadityaniswa emva kokuba isikrini sisusiwe.Hull et al., 1995; Wang et al., 1995; UFiorino et al., 1997a). Ubudlelwane obufanayo bubonwe kwisifundo esikhoyo; kwimeko yempuku yomntu ngamnye, ukunyuka kwangaphambili kwe-NAC DA efflux kwakuqikelelwa ngokuziphatha okulandelanayo okulandelayo. Kwakungekho ukwanda okubonakalayo kokutya kwi-NAC DA efflux kwiqela leCONT. Nangona kunjalo, iigundane ezimbini ze-CONT (25%) azizange zidibanise, kwaye utshintsho oluhambelanayo kwi-NAC ye-DA yokugxila ekuphenduleni umfazi owamkelayo kwiqela le-CONT lancitshiswa. Uqwalaselo lwethu lokuba ukwanda kwe-mesolimbic ye-DA yosulelo kwanxulunyaniswa nokudityaniswa kweempuku ezingenangqondo kuvumelana neziphumo zovavanyo lwangaphambili lwe-microdialysis (Wenkstern et al., 1993). Iziphumo zangoku zibonisa ukuba ukonyuka kokugxilwa kwe-NAC DA ekuphenduleni inkuthazo yezesondo kwenzeka kwiimpuku zamadoda ezingamadoda.

Kwakukho ulwandiso olubalulekileyo lwe-NAC DA efflux kwiqela le-AMPH ngokunxulumene neqela le-CONT ngexesha lokuziphatha ngokwesondo, kwaye oku kwabonakala ngexesha lokuziphatha kwesondo (oko kukuthi, ibhinqa emva kwesikrini) kunye nesampuli yokuqala yokukopisha. Njengoko kukhankanyiwe ngasentla, iimpuku ze-CONT ezingahlanganisiyo azizange zibe negalelo ekuthandeni okanye ekunyukeni kokuphindaphinda kokugxilwa kwe-NAC DA. Ke ngoko, inani elongezelelweyo lokukopa okubonwayo ngexesha lesampulu yokuqala yokudibanisa kwiigundane ze-AMPH ngokubhekiselele kwiigundane ze-CONT, kwaye ngokukodwa inani elikhulu le-ejaculations, linokuthi lichaze i-augmented efflux ye-NAC DA kwiqela le-AMPH. Uvavanyo lweChronoamperometry olwenziwa kwilabhoratri yethu lubonise ukuba imisinga ye-oxidation ephezulu ehambelana ne-DA inxulunyaniswe ne-ejaculations (Phillips et al., 1991; UFiorino et al., 1997b), nangona kunzima ukugqiba ukuba i-ejaculation okanye umsebenzi wokufuna ngamandla okhokelela kwi-ejaculation uhambelana nobuninzi be-NAC DA efflux. Kule nkalo, kubalulekile ukuqaphela ukuba isigaba "sokugqitywa" sokuziphatha ngokwesondo kwendoda (okt, ukudibanisa) iqulethe izinto ezininzi ezinomdla (UFiorino et al., 1997a), kwaye akunakwenzeka, kuphononongo lwangoku, ukulungelelanisa i-NAC DA efflux ngokukhethekileyo kunye necandelo elinye okanye elinye. Nangona kunjalo, ukuziphatha okunzulu kweegundane ezivuselelweyo ngexesha lesampulu yokuqala yokukopisha, ngokumalunga neegundane ze-CONT, zinokuthi ziphendule umahluko kwiiprofayili ze-neurochemical phakathi kwamaqela.

Ubukho bokudluliselwa kwe-dopaminergic eyandisiweyo kwi-NAC enyanzelwa lulawulo oluphindaphindiweyo lwe-d-amphetamine inika inkxaso ekuqwalaseleni ukuba umsebenzi ophuculweyo we-dopaminergic unokuququzelela ukuqaliswa kokuziphatha ngokwesondo kwiimpuku zamadoda ezingenangqondo (I-Agmo kunye nePicker, 1990). I-Dopamine kwi-mPOA ibandakanyeka kuyo yomibini imiba ekhangayo kunye neyokugqibela yokuziphatha ngokwesondo kweempuku zamadoda (Pfaus kunye nePhillips, i-1991; Hull et al., 1993, 1995; Shimura et al., 1994; Mas et al., 1995;Sato et al., 1995), kunye nokosulelo lwe-mPOA oluphuculweyo lweDA lunokuba negalelo ekuququzeleleni indlela yokuziphatha ngokwesondo ebonwe kolu phando.

Umceli mngeni we-systemic d-amphetamine uphinde wakhokelela ekuziphatheni kwe-locomotor eyandisiweyo kunye ne-NAC DA efflux kwiqela le-AMPH ngokunxulumene neqela le-CONT. Oku kufunyanisiweyo kunegalelo ekukhuleni koncwadi olubonisa ukuba ukonyuka kosulelo lwe-DA lokubulala lukhapha uvakalelo lokuziphatha kwi-psychostimulants, xa luvavanywa emva kwexesha elongeziweyo (> 14 d) emva kokuyekiswa konyango lweziyobisi (uphononongo, bona. Pierce kunye neKalivas, i-1997; kodwa yabona Kuczenski et al., 1997). Ulumkiso kufuneka lusetyenziswe, nangona kunjalo, xa kuthelekiswa ezi ziphumo kunye neengxelo zangaphambili ngenxa yokuba umngeni weziyobisi okhoyo ulawulwa emva kwexesha lomsebenzi wesondo, kwaye i-residi ye-sex-related scents ingaba negalelo, mhlawumbi ngokwahlukileyo, kwiimpendulo ze-neurochemical kumaqela omabini. Umandlalo ovela kwiikheji zabasetyhini abakwi-estrous kuye kwabikwa ukuba yonyusa i-NAC ye-DA engaphandle kwiimpuku zamadoda (UMitchell noGraton, i-1992).

Iziphumo zethu ziyangqinelana nethiyori yenkuthazo-yokukhuthaza ukuba likhoboka leziyobisi (URobinson noBerridge, i-1993), ephakamisa ukuba ixabiso lenkuthazo leengcebiso ezinxulumene nomvuzo liphuculwe ngenxa yolawulo oluphindaphindiweyo lwee-psychostimulants ngokwandisa umsebenzi we-DA we-mesotelencephalic; Ukosulelwa kwe-mesotelecephalic ye-DA eyomeleziweyo ekugqibeleni kunegalelo ekufuneni iziyobisi okunyanzelekileyo nasekuthatheni iziyobisi, ezichaza iimpawu zokukhotyokiswa ziziyobisi. Imifuniselo yangaphambili yomvuzo weziyobisi yafumanisa ukuba ukuvezwa kwangaphambili kwezilwanyana kwi-psychostimulants kuququzelele imilinganiselo eyahlukeneyo yokuzilawula kweziyobisi zokuxhatshazwa (Woolverton et al., 1984; Horger et al., 1990, 1992;I-piazza et al., 1990; UMendrek et al., 1998; kodwa yabona Li et al., 1994). Kuphononongo lwakutshanje, UMendrek et al. (1998) ubonise iimpuku ezivuselelweyo ze-thad-amphetamine ezibonise inkuthazo eyongeziweyo yokuzilawula ngokwakho i-d-amphetamine, njengoko kubonisiwe yindawo yokuphumla ephezulu kakhulu phantsi kweshedyuli yomlinganiselo oqhubekayo wokuqiniswa. Uphononongo lwangoku lwandisa ukongezwa kweendlela zokuziphatha ezikhuthazayo ezibangelwa lulawulo oluphindaphindiweyo lwe-psychostimulant kwabo bakhuthazwa yinkuthazo yendalo. Kule meko, unyango lwangaphambili lwe-amphetamine lunokuthi lwandisile ukubaluleka kwezinto ezikhuthazayo ezingenamiqathango ze-estrous female, ezibandakanya i-pheromones, i-vocalizations ye-ultrasonic, i-ear wiggling, kunye ne-darting, kwaye ikhokelele ekuququzeleleni ukuziphatha ngokwesondo. Ubukho bosasazo olwandisiweyo lwe-NAC ye-DA ekuphenduleni ibhinqa eline-estrous elibekwe emva kwesikrini liqinisa ingxoxo yokuba inkqubo ye-DA ye-mesolimbic inegalelo koku.

Ukuqondana phakathi kweebhloko zokuthatha i-DA kunye nokuziphatha ngokwesondo kukwaxhaswa luqwalaselo lweklinikhi. I-Bupropion, ichiza elichasayo elinokuthintela ukuthatha i-DA (Cooper et al., 1980; Nomikos et al., 1989), ukuphuculwa komsebenzi wesondo kwizigulana zamadoda nabasetyhini abaphathwa ukungasebenzi kakuhle ngokwesondo (ICrenshaw kunye neGoldberg, ngo-1995) kunye nokuphazamiseka kwengqondo (Imodeli et al., 1997). Kuyathakazelisa ukuba izifundo ze-preclinical zibonise ukuba ixesha elide (10 mg / kg, ibhidi × 21 d), kodwa kungekhona (10 mg / kg, ibhidi × 2 d), ulawulo lwe-bupropion luphumela kwi-Augmented NAC DA efflux ekuphenduleni. kumngeni we-bupropion (Nomikos et al., 1989, 1992). Ngokwahlukileyo, akukho kwandiswa okubalulekileyo kokudluliselwa kwe-DA okubonwe kwi-striatum emva konyango olungapheliyo lwe-bupropion (Nomikos et al., 1992). Ukuphuhliswa kwemiphumo ye-prosexual ye-bupropion inokuba sisiphumo sotshintsho lwe-neural olufana nalawo abandakanyekayo ekuqaliseni nasekuboniseni i-sensitization yokuziphatha kwii-psychostimulants. Ke ngoko, ukukwazi kwekhompawundi ukukhuthaza ukuphuculwa kokusebenza kwexesha elide kwinkqubo ye-mesolimbic ye-DA kunokubonelela ngolwazi oluxabisekileyo malunga nokubanakho ukunyanga ukungasebenzi kakuhle ngokwesondo.

Imihlathi

  • Ifunyenwe ngo-Agasti 3, 1998.
  • Uhlaziyo lufunyenwe ngo-Oktobha 16, 1998.
  • Yamkelwe ngo-Oktobha 21, 1998.

  • Lo msebenzi uxhaswe yiGroup Grant PG-12808 evela kwiBhunga loPhando lwezoNyango laseCanada. Siyabulela uDavid Mutch ngoncedo lwakhe ekwenzeni olu vavanyo kunye noFred LePiane kunye noKeith Waldron ngoncedo lwabo ekwakhiweni kwamagumbi okuvavanya. Kwakhona, ndiyabulela kakhulu ku-Ariane Coury kunye noJim Pfaus ngeenkcazo zabo ezincedo kunye noLiz McCririck ngeenkonzo zakhe zonobhala.

    Imbalelwano kufuneka ithunyelwe kuGqr AG Phillips, kwiYunivesithi yaseBritish Columbia, kwiSebe lezeNgqondo, 2136 West Mall, Vancouver, British Columbia, Canada, V6T 1Z4.

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