Enweghi ike site na nchịkwa nke cocaine na-adịghị ala ala na-agbanwe usoro dopamine na-egbuke egbuke na rhesus enwe. (2009)

¹Ngalaba Physiology na Pharmacology, Center for Neurobiological Investigation of Drug Abuse, Wake Forest University School of Medicine, Winston-Salem, NC, USA

Nzakọrịta: Dr LJ Porrino, Ngalaba Physiology na Pharmacology, Center for Neurobiological Investigation of Drug Abuse, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1083, USA. Tel: +1 336 716 8575; Fax: +1 336 716 8501; Email: [email protected]

enwetara 29 Eprel 2008; Emegharịrị 25 Julaị 2008; nabatara 30 Julaị 2008; Ebipụtara ya na Septemba 3, 2008.

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nkịtị

Ọ bụ ezie na dysregulation n'ime usoro dopamine (DA) bụ njirimara mara mma nke ikpughe cocaine na-adịghị ala ala, ajụjụ nke ma mgbanwe ndị a na-adịgide na abstinence ka na-azabeghị nke ukwuu. Ndị primates na-abụghị mmadụ na-anọchite anya ezigbo ihe atụ nke iji nyochaa mmetụta nke abstinence na sistemụ DA na-eso mkpughe cocaine na-adịghị ala ala. N'ime ọmụmụ ihe a, ụmụ nwoke rhesus enwe na-elekọta cocaine (0.3 mg/n'arọ kwa ntụtụ, 30 ndị na-agba ume kwa nnọkọ) n'okpuru nkeji 3-nkeji schedule maka 100 ụbọchị sochiri ma ọ bụ 30 ma ọ bụ 90 ụbọchị abstinence. Egosiputara oge a nke nchịkwa onwe nke cocaine iji belata DA D2-dị ka njupụta nnabata na ịbawanye ọkwa nke ndị na-anabata D1-dị ka ndị na-ebugharị DA (DAT). A na-edozi nzaghachi site na enwe njikwa site na ngosi nri n'okpuru ụkpụrụ yiri nke ahụ na otu oge abstinence. [³H]SCH 23390 jikọtara ya Ndị na-anabata DA D1 na-eso ụbọchị 30 nke abstinence dị elu nke ukwuu na akụkụ niile nke striatum, ma e jiri ya tụnyere ụmụ anụmanụ na-achịkwa, ebe [³H]njikọ raclopride na ndị na-anabata DA D2 adịghị iche n'etiti otu. [³H]WIN 35 428 njikọ na DAT dịkwa elu nke ukwuu n'ihe fọrọ nke nta ka ọ bụrụ akụkụ niile nke azụ azụ na ventral striatum na-eso ụbọchị 30 nke abstinence. Na-eso ụbọchị 90 nke abstinence, agbanyeghị, ọkwa nke ndị na-anabata DA D1 na DAT adịghị iche na ụkpụrụ njikwa. Ọ bụ ezie na nsonaazụ ndị a na-egosi na enwere mgbake nke ihe dị iche iche nke sistemụ DA, ha na-egosipụtakwa ụdị ike nke akụrụngwa ndị a n'oge usoro izizi nke abstinence na nchịkwa cocaine na-adịghị ala ala.

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OKWU

Ejikọtala ojiji cocaine na-adịghị ala ala n'etiti ndị na-eri ahụ mmadụ na neuroadaptations na sistemụ dopamine (DA).Malison et al, 1998; Volkow et al, 1993, 1997). Ndị a gụnyere mmụba na njupụta nke ndị na-ebugharị DA (DAT) na mbelata na ntinye nke DA D2-dị ka ndị nnata (Little et al, 1999; Mash et al, 2002; Volkow et al, 1993). Na mgbakwunye, a hụkwara mgbanwe na ntọhapụ DA. Dịka ọmụmaatụ, ndị nyocha na-eji positron emission tomography (PET) ọmụmụ na [¹¹C]raclopride na methylphenidate egosila mbelata na ntọhapụ DA na striatum nke ndị ọrụ cocaine na-adịghị ala ala.Volkow et al, 1997; Wong et al, 2006). Otú ọ dị, otu nsogbu bụ na ọ na-esikarị ike iwepụ mmetụta nke ihe ndị ọzọ dị ka iji ọgwụ ndị ọzọ na-akwadoghị iwu na iwu kwadoro, ọdịiche dị na ịṅụ ọgwụ ọjọọ tupu oge na iji usoro, na ọdịiche dị n'ụdị ndụ. Ndịiche ndị a, yana ịdị adị nke ọnọdụ ndị nwere ike ịmalite iji ọgwụ ọjọọ eme ihe, nwere ike igbochi nkọwa nke ọmụmụ na ndị ọrịa mmadụ.

Ụdị primate ndị na-abụghị nke mmadụ, nke enwere ike ijikwa mgbanwe dị iche iche n'usoro, na-anọchite anya ụzọ ọzọ maka ọmụmụ ihe na-esi na nchịkwa cocaine na-adịghị ala ala na abstinence na-esote. Nnyocha ndị gara aga egosila na ikpughe cocaine na-adịghị ala ala na-esonyere ya na mbelata dị ukwuu na ntinye nke ndị na-anabata DA D2 yana ọkwa dị elu na ọkwa nke ndị na-anabata D1 na njupụta nke DAT.Letchworth et al, 2001; Moore et al, 1998a, 1998b; Nader et al, 2002, 2006). Mmetụta ndị a na-egosipụta nke a na-ahụ n'ime mmadụ, si otú a na-egosi uru nke ụdị ikpughe ọgwụ ndị a.

Ọ bụ ezie na enwere nnukwu ihe akaebe maka dysregulation nke sistemụ DA, egosila na ọ siri ike karị ịtụle ma enwere ihe akaebe ọ bụla maka mgbake na-esochi ịkwụsị iji ọgwụ ọjọọ eme ihe (Malison et al, 1998; Jacobsen et al, 2000; Volkow et al, 1993) ma ọ bụ na mgbanwe ndị a na-aga n'ihu karịa oge nke ikpughe cocaine na-aga n'ihu. Ọzọkwa, ụdị primate ndị na-abụghị nke mmadụ nwere ike inye nghọta n'ime usoro ihe riri ahụ a. Farfel et al (1992) kọrọ mbelata mkpokọta DAT na D1-dị ka ndị na-anabata ya na striatum nke enwe na-esote abstinence na ikpughe na-adịghị ala ala na cocaine. Otú ọ dị, ọrụ a kapịrị ọnụ nke abstinence siri ike ịchọpụta n'ihi enweghị nha na otu na-enweghị oge nkwụsị. N'otu aka ahụ, Melega et al (2008) kọrọ na ọkwa DAT belatara nke ukwuu na striatum nke enwe vervet na-esochi izu atọ nke ịghara ịghara usoro methamphetamine na-arị elu. Nlekọta nke ihe na-akpali akpali na ọmụmụ abụọ, Otú ọ dị, adịghị adabere na ya. Ụzọ nchịkwa (continent vs egosila na ọ na-emetụta ụbụrụ dị iche iche gbasara ntọhapụ DA abụọ ahụ.Hemby et al, 1997na glucose metabolism (Graham na Porrino, 1995; Porrino et al, 2002). Ya mere, iji nchịkwa onwe onye n'ime ihe ọmụmụ a na-agbaso okwu a. Na mgbakwunye, a mụọla mmetụta nke nchịkwa cocaine ogologo oge na sistemụ ụbụrụ DA nke ọma site na iji ihe atụ nke nchịkwa onwe onye na enwe rhesus, si otú a na-enye usoro ndabere nke iji nyochaa neuroadaptations na-eme n'oge abstinence.

Ebumnuche nke ọmụmụ ihe ndị a, ya mere, bụ iji chọpụta ma mgbanwe ndị dị na DAT na DA D1 na D2 ndị na-anabata ihe ndị egosipụtara na mbụ n'ime anụmanụ ndị ekpughere na nchịkwa onwe ha cocaine (Letchworth et al, 2001; Moore et al, 1998a, 1998b; Nader et al, 2002) ga-atụgharị mgbe ogologo oge nke abstinence gasịrị. Na ndabere nke ọmụmụ n'ime ndị na-eji ọgwụ mmadụ eme ihe (cf Volkow et al, 1993), anyị chere na mgbanwe ndị a na usoro DA ga-adịgide ọbụna mgbe ọnwa 3 nke abstinence gasịrị. Iji mezuo nke a, enwe na-achịkwa cocaine n'onwe ya maka nnọkọ 100, yana ngụkọta nke 900. mg/n'arọ, nke na-esote ụbọchị 30 ma ọ bụ 90 nke ịghara ịṅụ ọgwụ ahụ. Ndị na-anabata DA D1 na D2, yana DAT, ka ejiri ọnụọgụ tụọ na vitro receptor autoradiography.

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METHODS

Ndị isi

Ngụkọta nke enwe rhesus 17 na-enweghị isi (nyocha)Macaca mulatta) dị n'etiti 7.7 na 13 kg (pụtara ± SD, 10.2 ± 1.32) na mmalite nke ọmụmụ jere ozi dị ka isiokwu. Emere usoro niile dabere na omume guzosiri ike dịka akọwara na Ụlọ akwụkwọ ntuziaka ahụike mba maka nlekọta na ojiji nke anụmanụ ụlọ nyocha. Na mgbakwunye, kọmitii na-ahụ maka anụmanụ na ojiji nke Mahadum Wake Forest tụlere wee kwado usoro niile. A na-etinye mmiri n'otu n'otu n'ime nnukwu igwe anaghị agba nchara ad libitum; ụmụ anụmanụ na-enwe mmekọrịta anụ ahụ na anya na ibe ha. A na-edobe ịdị arọ nke ahụ ha na ihe dịka 90–95% Nri nri nri n'efu site na pellet ndị nwere banana enwetara n'oge oge nnwale yana site na nri mgbakwunye nke Lab Diet Monkey Chow, enyere n'oge na-adịghị anya karịa 30 min post-nzukọ. Tụkwasị na nke ahụ, a na-enye ha mkpụrụ osisi ma ọ bụ ahụekere ọhụrụ ọ dịkarịa ala ugboro atọ kwa izu. A na-atụ enwe ọ bụla otu ugboro n'izu, ma ọ bụrụ na ọ dị mkpa, a na-edozi nri ha iji nọgide na-ebu ibu.

Ngwa omume

Emere oge nnwale n'ime ụlọ ndị na-ekuku ikuku na ụda dara ụda (1.5 × 0.74 × 0.76). m; Med Associates Inc., East Fairfield, VT) emebere iji nabata oche primate (Model R001; Ngwaahịa Primate, Redwood City, CA). Ụlọ ahụ nwere ogwe ọgụgụ isi (48 × 69 cm), nke nwere levers abụọ enwere ike iweghachi (5 cm n'obosara) na ọkụ mkpali atọ. A dobere levers n'ebe dị mfe nke enwe nọ ọdụ n'oche primate. Nri nri banana nwere ụtọ (1 g; Bio-Serv, Frenchtown, NJ) sitere na onye na-enye nri dị n'elu ụlọ ahụ. A na-eji mgbapụta infusion peristaltic (7531-10; Cole-Parmer Co., Chicago, IL) na-ebunye injections ọgwụ na ọnụ ọgụgụ dị ihe dịka 1. ml kwa 10 s na anụmanụ ndị ahụ na-ejide onwe ha cocaine. Ejiri sistemu kọmputa Power Macintosh nwere interface (Med Associates Inc.) rụzuo ọrụ nke ọnụ ụlọ na nnweta data.

Usoro ịwa ahụ

Enwekwara enwe niile, gụnyere njikwa, nke a kwadebere n'ịwa ahụ, n'okpuru ọnọdụ adịghị mma, nke nwere catheters intravenous na ọdụ ụgbọ mmiri vaskụla (Model GPV; Access Technologies, Skokie, IL). Eji otu ketamine were kpochapu enwe (15 mg/kg, im) na butorphanol (0.03 mg/n'arọ, im) wee mebe mbepụ n'akụkụ akwara femoral. Mgbe a gbasasịrị nke ọma na ikewapụ akwara, a na-etinye njedebe dị nso nke catheter n'ime akwara maka anya gbakọọ ka ọ kwụsị na cava vena dị ala. A na-adụnye eriri dị n'ebe dị anya nke catheter n'okpuru akpụkpọ ahụ na mbepụ nke emere ntakịrị n'etiti ahịrị azụ. A na-etinye ọdụ ụgbọ mmiri vaskụla n'ime akpa nke kpụrụ site na nhụsianya na-adịghị mma n'akụkụ mbepụ a. Enyere enwe 24–48 h oge mgbake tupu ịlaghachi na nzaghachi nkwado nri. Ihe dị ka ụbọchị 5 tupu usoro njedebe ahụ, a kụnyere enwe ọ bụla nwere catheter na-adịghị ala ala n'ime akwara femoral dị n'akụkụ maka nchịkọta ọbara akwara nke oge. Usoro ịwa ahụ yiri nke a kọwara maka catheters venous. N'ụbọchị ikpeazụ nke nnọkọ ahụ, a na-eme ọmụmụ ihe ọmụmụ glukos nke cerebral nke ụbụrụ, ebe a na-agbanye enwe 2-[¹⁴C]deoxyglucose (2-DG) ihe dịka 2 min mgbe njedebe nke nnọkọ ahụ gasịrị, a na-enweta ihe nlele ọbara site na catheter arterial n'elu 45 nkeji oge (lee Beveridge et al, 2006 maka nkọwa). A naghị ewepụta data metabolism sitere na ọmụmụ ihe ndị a ebe a.

Usoro nchịkwa onwe onye

A zụrụ enwe na mbụ ịzaghachi n'otu n'ime levers abụọ site na iji pellet nri kwalite nzaghachi nke ọ bụla na lever ziri ezi. N'ime ihe dị ka izu 3, etiti dị n'etiti nnweta pellet nri ji nke nta nke nta mụbaa ruo mgbe enwetara nkeji nkeji 3 (ya bụ nhazi oge 3 nkeji oge nke nkwado; FI 3-min). N'okpuru ọnọdụ nhazi oge ikpeazụ, nzaghachi mbụ na lever mgbe 3 gasịrị min rụpụtara na nnyefe nke pellet nri; nnọkọ agwụla mgbe ihe ngosi nri iri atọ gachara. Na ngwụcha nnọkọ nke ọ bụla, eweghachite levers nzaghachi, gbanyụọ ọkụ ụlọ na ọkụ na-akpali akpali, anụmanụ nọkwa n'ime ụlọ gbara ọchịchịrị ihe dịka 30. min tupu eweghachite ha n'ụlọ ha. Enwe niile zara n'okpuru usoro FI 3-min nke ngosi nri maka opekata mpe 20 yana ruo mgbe enwetara arụmọrụ kwụsiri ike (± 20).% nke pụtara maka nnọkọ atọ n'usoro, na-enweghị usoro na ọnụego nzaghachi). Mgbe nzaghachi nri na-edozi ahụ kwụsiri ike, onye na-enye nri ewepụghị ya na mmetụta nke mkpochapụ na ịzaghachi a na-enyocha maka nnọkọ ise na-esochi, mgbe nke ahụ gasịrị, a na-edozighachi ma na-edozi ya site na ngosi nri.

Mgbe emechara arụmọrụ ntọala, a na-eji ọgwụ venous catheter kwadebe enwe niile n'ịwa ahụ, dịka akọwara n'elu, wee kenye ya na otu n'ime otu atọ. Otu otu enwe jere ozi dị ka njikwa wee gaa n'ihu na-azaghachi n'okpuru nhazi oge FI 3 nkeji nke ngosi nri maka ngụkọta nke oge 100 (N=6). Enyere enwe 11 fọdụrụnụ na ndị otu na-ahụ maka onwe ha cocaine (0.3 mg/n'arọ kwa injection). N'ihi na 0.3 mg/A na-ahụta cocaine kilogram kwa injection dị ka nnukwu dose maka enwe mbụ cocaine-naive enwe, maka ọtụtụ anụmanụ, a na-enweta ọgwụ a n'ime oge abụọ site na ikwe ka enwe nwee onwe ya 0.1. mg/n'arọ nke cocaine. E kwere ka arụ ọrụ nke nri na-edozi ka ọ kwụsie ike mgbe a wachara ya ahụ (ihe dị ka ụbọchị 4-6) tupu a malite usoro nchịkwa onwe onye cocaine. Tupu nnọkọ nnwale ọ bụla, a na-eji 95 sachaa azụ anụ ahụ% ethanol na betadine scrub na 22 nlele Huber Point Needle (Model PG20-125) ka etinyere n'ọdụ ụgbọ mmiri na-eduga na catheter venous, na-ejikọta mgbapụta infusion nke nwere ngwọta cocaine na catheter. Tupu mmalite nke nnọkọ ahụ, a na-arụ ọrụ mgbapụta ahụ ihe dịka 3 s, na-ejuputa n'ọdụ ụgbọ mmiri na dose nke cocaine dị n'oge nnọkọ nnwale. Oge kwụsịrị mgbe 30 injections; dị ka a na-achịkwa ọnọdụ, enwe nọrọ n'ime ụlọ gbara ọchịchịrị ihe dịka 30 min. Na ngwụcha nke nnọkọ ọ bụla, ọdụ ụgbọ mmiri ahụ jupụtara na saline heparinized (100 U/ml) iji nyere aka gbochie mkpụkọ.

Emere oge nnwale n'ihe dịka otu oge kwa ụbọchị wee gaa n'ihu maka ngụkọta oge 100. Mgbe emechara nnọkọ 100 ahụ, ewepụtara oge abstinence nke ụbọchị 30 ma ọ bụ 90 n'oge a na-eji saline heparinized na-awụsa catheters kwa ụbọchị, mana enweghị cocaine ma ọ bụ nnọkọ nchịkwa onwe onye. Maka ndị otu na-achịkwa, a na-etinye oge nkwụsị nke ụbọchị 30 n'ime anụmanụ anọ na ụbọchị 90 n'ime abụọ ndị ọzọ. Maka otu cocaine, amachibidoro oge abstinence nke ụbọchị 30 n'anụmanụ asatọ na ụbọchị 90 n'ahụ anụmanụ atọ. Na njedebe nke oge abstinence, a na-eduzi nnọkọ nchịkwa ikpeazụ nke onwe (nchịkwa nri ma ọ bụ cocaine) na usoro 2-DG malitere ozugbo na nnọkọ ahụ. Na njikwa abụọ na anụmanụ anọ na-achịkwa onwe ha cocaine na otu ụbọchị abstinence nke ụbọchị 30, ọ dịghị cocaine natara na nnọkọ ikpeazụ. Egburu ụmụ anụmanụ site n'ịfefe pentobarbital (100 mg/kg, iv) na njedebe nke 45 min tracer mbanye oge.

Nhazi anụ ahụ

Mgbe e gbuchara, e wepụrụ ụbụrụ ozugbo, kpọchie, na oyi kpọnwụrụ na isopentane na -35 ruo -55 Celsius wee chekwaa ya na -80 Celsius. A na-egbutu ihe mgbochi anụ ahụ nwere striatum na cryostat na -20 Celsius C n'ime ụgbọ elu coronal n'ime 20. μm ngalaba, anakọtara na slides eletrọtically chaja, kpọsara n'okpuru oghere n'abali na 4°C, wee chekwaa ya na -80°C ruo mgbe edoziri ya maka autoradiography. A na-anakọta akụkụ ụbụrụ site na akụkụ nke caudate nucleus, putamen, na nucleus accumbens nke na-adaba n'ihu commissure. A na-akpọ mpaghara a dị ka precommissural striatum. Ọzọkwa, a họpụtara ọkwa rostral na caudal nke precommissural striatum na ntụnyere nucleus accumbens. Rostral precommissural striatum bụ mpaghara ebe nucleus accumbens adịghị ekewa n'ime shei dị iche iche na akụkụ nke isi. The caudal precommissural striatum bụ mpaghara dakọtara na mpụta nke shea na isi nke nucleus accumbens, bụ nke dị n'azụ ka mpụta nke tubercle olfactory. Maka ọmụmụ ihe nke ọ bụla, a na-ewere akụkụ abụọ dị n'akụkụ na ọkwa ise ọ bụla (abụọ rostral na atọ caudal) site na precommissural striatum maka ngụkọta nke ngalaba 10 maka anụmanụ ọ bụla.

D1 nnabata nnabata

Achọpụtara njupụta saịtị nnabata DA D1 na [³H]SCH 23390 (ọrụ a kapịrị ọnụ—85 Ci/mmol; PerkinElmer, Boston, MA) site quantitative na vitro receptor autoradiography dị ka usoro emegharị si Idgha et al (1991) na Nader et al (2002). Ebubere akụkụ ahụ maka nkeji iri abụọ min na nchekwa (50 mM Tris, 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 1 mMgCl₂, pH 7.4, 25 ° C) iji wepụ DA endogenous, cocaine na [¹⁴C] site na usoro 2-DG. A na-etinye akụkụ ahụ maka nkeji iri atọ min n'otu nchekwa ahụ, pH 7.4, 25°C, nwere 1 mM ascorbic acid, 40 nM ketanserin, na 1 nM [³H]SCH 23390. Mgbe incubation gasịrị, a na-asacha akụkụ ugboro abụọ maka 20 s na nchekwa nwere 1 mM ascorbic acid na pH 7.4, 4°C, wee tinye ya na mmiri distilled na 4°C, wee kpoo n'okpuru iyi nke ikuku dị jụụ. Akọwapụtara njide na-abụghị nke akọwapụtara site na ntinye nke akụkụ ndị dị n'akụkụ n'ime ngwọta nnabata n'ihu 5. μM (+- butaclamol. Akụkụ, yana ahazigharịrị [³H] ụkpụrụ autoradiographic (Amersham, Piscataway, NJ), ka akwadoro na ihe nkiri Kodak Biomax MR (Fisher Scientific, Pittsburgh, PA) maka izu isii.

D2 nnabata nnabata

Achọpụtara njupụta na nkesa saịtị njikọ nnabata DA D2 [³H]raclopride (ọrụ a kapịrị ọnụ, 87 Ci/mmol; PerkinElmer) dị ka usoro sitere na Idgha et al (1991) na Nader et al (2002). Ebubere akụkụ ahụ maka nkeji iri abụọ min na nchekwa (50 mM Tris, 120 mM NaCl, 5 mM KCl, pH 7.4, 25°C) iji wepu DA, cocaine, na endogenous. [¹⁴C] site na usoro 2-DG. A na-etinyezi ihe mmịfe maka iri atọ min n'otu nchekwa ahụ, nwere 5 mM ascorbic acid na 2 nM [³H]raclopride. A kpochapụrụ akụkụ 3 × 2 min na nchekwa na pH 7.4, 4°C, wee tinye ya n'ime mmiri distilled na 4°C, wee kpoo n'okpuru iyi nke ikuku dị jụụ. Akọwapụtara njide na-abụghị nke akọwapụtara site na ntinye nke akụkụ ndị dị n'akụkụ na ngwọta nnabata n'ihu 1. μM (+- butaclamol. Akụkụ, yana ahazigharịrị [³H] ụkpụrụ autoradiographic, ka etinyere na ihe nkiri Kodak Biomax MR maka izu asatọ.

Njikọ nke Transportgbọ njem Dopamine

Achọpụtara njupụta nke saịtị njikọ DAT site na iji [³H]Mmeri 35,428 (ọrụ a kapịrị ọnụ, 87 Ci/mmol; PerkinElmer) autoradiography dị ka usoro ewepụtara site na Canfield et al (1990) na Letchworth et al (2001). Ebubere akụkụ anụ ahụ na nchekwa (50 mM Tris, 100 mM NaCl, pH 7.4, 4°C) maka 20 min iji wepụ DA ọ bụla fọdụrụnụ, cocaine, na [¹⁴C] site na usoro 2-DG. A na-etinye akụkụ ahụ maka nkeji iri atọ h na 4°C n'otu ebe nchekwa nwere 5 nM [³H]Mmeri 35 428. A na-asacha akụkụ maka ngụkọta nke 2 min na nchekwa na 4ºC, wee tinye ya na mmiri a na-ekpo ọkụ na 4 Celsius C, wee kpoo n'okpuru iyi nke ikuku oyi. Akọwapụtara njide na-abụghị nke akọwapụtara site na ntinye nke akụkụ ndị dị n'akụkụ na ngwọta nnabata n'ihu 30. μM cocaine. Akụkụ, yana ahazigharịrị [³H] ụkpụrụ autoradiographic, ka etinyere na ihe nkiri Kodak Biomax MR maka izu asatọ.

Densitometry na nyocha data

Emepụtara ihe nkiri site na onye nrụpụta Kodak GBX, stopbath na Rapid Fixer (VWR, West Chester, PA), wee sachaa ya. A na-eduzi nyocha nke autoradiogram site na densitometry quantitative nwere usoro nhazi onyonyo kọmputa (MCID, Nnyocha onyonyo; InterFocus Imaging Ltd, Cambridge, UK). Atụgharịrị ụkpụrụ njupụta anya ka ọ bụrụ fmol/mg (nke anụ ahụ dị arọ) site na ntụnye aka na calibrated [³H] ụkpụrụ. Ekpebiri njide a kapịrị ọnụ site na iji dijitalụ wepụrụ onyonyo nke njide na-abụghị nke akọwapụtara n'elu onyonyo dị n'akụkụ nke mkpokọta njikọ. Achọpụtara ihe owuwu site na Nissl ntụpọ nke akụkụ ndị dị n'akụkụ ndị nyochara maka njide nnabata. A tụlere data sitere na nyocha nke ọ bụla n'onwe ya site na nyocha otu ụzọ nke iche iche na-esote ndịiche pere mpe. post hoc ule maka otutu ntụnyere. Mpaghara ọ bụla nwere nyocha dị iche. N'ihi na njide data enwetara site na ụmụ anụmanụ na-achịkwa abstinent maka ụbọchị 30 na 90 adịchaghị iche na ibe ha, dị ka ọmụmụ gara aga.Nader et al, 2002), data sitere na ndị otu njikwa jikọtara ọnụ. Tụkwasị na nke ahụ, enweghi ọdịiche dị ịrịba ama n'etiti data sitere na anụmanụ ndị ahụ natara cocaine na ndị na-adịghị na nnọkọ ikpeazụ ha, ya mere, a na-ejikọtakwa data sitere na otu ndị a.

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IHE

Mmetụta ọgbaghara na nchịkwa onwe nke Cocaine na-adịghị ala ala ruo ụbọchị 30

Ntinye uche nke [³H]SCH 23390 na-ejikọ ndị na-anabata DA D1 na precommissural striatum ka egosiri na Isiokwu 1. Nke a kapịrị ọnụ nke [³H]SCH 23390 ruru ihe karịrị 90% nke mkpokọta njikọ. Nkwekọ na akụkọ ndị gara aga (Moore et al, 1998a; Nader et al, 2002), njide nke [³H]Ndị na-anabata SCH 23390 ruo D1 na ụmụ anụmanụ na-anaghị ekpughe ọgwụ ọgwụ bụ ihe dị iche iche nwere nnukwu ọdịiche dị na ogo njikọ dị n'etiti mpaghara nke striatum. Ịkpọ aha dị oke n'akụkụ akụkụ rostral na etiti n'ofe striatum.

Mgbe ụbọchị 30 nke abstinence na ikpughe cocaine gasịrị, njide na ndị na-anabata D1 bụ ihe e ji mara ọkwa dị elu n'ofe oke rostral-caudal nke precommissural striatum, ma e jiri ya tụnyere njide njupụta na anụmanụ na-adịghị ekpughe ọgwụ.Isiokwu 1; Nyocha 1). Na rostral striatum karịa, ntinye uche dị elu karịa na caudate nucleus gụnyere dorsolateral (+27%), etiti (+27%dorsomedial (+27%, na ventromedial (+23%) akụkụ, yana na azụ (+17%), etiti (+22%), na ventral (+23%) akụkụ nke putamen, ma e jiri ya tụnyere njupụta nke anụmanụ na-adịghị ekpughe ọgwụ. Elu elu pụtara ìhè pụtakwara na nucleus accumens (+23%) n'ọkwa a. N'ọkwa nke striatum ebe isi na shei nke nucleus accumbens kacha dị iche, njupụta nke ndị na-anabata D1-dị ka ndị na-anabata ya dịkwa elu nke ukwuu na mpaghara dorsolateral (+31%), etiti (+29%dorsomedial (+30%, na ventromedial (+18%) caudate nucleus, yana azụ azụ (+23%), etiti (+29%), na ventral (+28%) putamen, ma e jiri ya tụnyere njupụta nke njikwa anaghị ekpughe ọgwụ. N'ime ventral striatum na ọkwa a, ntinye uche nke D₁ saịtị njikọ nnabata dị elu na isi nucleus accumbens (+45%) na shei (+20%), nakwa na tubercle na-esi ísì ụtọ (+26%), dị ka atụnyere njupụta na njikwa.

Ntinye uche nke [³H]egosipụtara raclopride na-ejikọ ndị na-anabata DA D2 na precommissural striatum Isiokwu 2. Ejikọ kpọmkwem na [³H]raclopride ruru ihe karịrị 90% nke mkpokọta njikọ. Nkesa nke [³H]raclopride na-ejikọta na ndị na-anabata D2 bụkwa ihe dị iche iche n'ofe mpaghara azụ na ventral striatum dị ka ọ dị na akụkọ ndị gara aga.Moore et al, 1998b; Nader et al, 2002). N'ime njikwa na-abụghị ọgwụ ekpughere, ọnụọgụ dị elu nke saịtị njikọ D2 dị na azụ azụ ma e jiri ya tụnyere ventral striatum. Tụkwasị na nke ahụ, e nwere ihe àmà na-egosi gradient dị n'etiti ruo n'akụkụ ya na njupụta dị elu nke saịtị njikọ dị n'akụkụ akụkụ nke striatum.

Mgbe ụbọchị 30 nke abstinence gasịrị, ọkwa nke ndị na-anabata D2 na-ejikọta na cocaine-ekpughere na anụmanụ na-akwado nri adịghị iche na ibe ha n'ọtụtụ mpaghara nke striatum. A na-ahụ ọkwa dị elu nke saịtị njikọ na ventral putamen (+10%) na nucleus accumbens (+12%) n'ime anụ ahụ sitere na enwe ndị na-ekpuchi cocaine tụnyere njikwa. Ọnweghị ndịiche dị ịrịba ama ndị ọzọ achọpụtara.

Ntinye uche nke [³H]WIN 35428 jikọtara DAT na precommissural striatum ka egosiri na Isiokwu 3. Nkwekọ na akụkọ ndị gara aga (Letchworth et al, 2001), njide na saịtị DAT n'ime anụmanụ ndị na-adịghị ekpughe ọgwụ dị elu na azụ azụ ma e jiri ya tụnyere ventral striatum. N'ime nucleus accumbens, a hụrụ njupụta dị elu na isi ma e jiri ya tụnyere nkewa shei. N'ikpeazụ, njikọ na-enweghị nkọwa erughị 10% nke ngụkọta.

Mgbe ụbọchị 30 nke abstinence na ikpughe cocaine gasịrị, ijikọ na DAT dị elu nke ukwuu n'ọtụtụ mpaghara nke striatum rostral ruo n'ihu commissure ma e jiri ya tụnyere njide na anụmanụ na-adịghị ekpughe ọgwụ.Nyocha 1). Kpọmkwem, mkpokọta saịtị njikọ DAT na ọkwa rostral dị elu nke ukwuu na etiti (+22%dorsomedial (+25%, na ventromedial (+28%) caudate nucleus, na n'azụ (+16%) na Central (+23%) putamen, ma e jiri ya tụnyere njikwa ihe oriri. Na mgbakwunye, enwekwara njikọ dị elu nke ukwuu na DAT na nucleus accumbens.+37%) na cocaine- ma e jiri ya tụnyere enwe na-eme ka nri sie ike. N'ime akụkụ caudal karịa nke precommissural striatum, njupụta nke saịtị njikọ DAT dị elu nke ukwuu na etiti caudate nucleus (+21%), na putamen, Central (+20%) na ventral (+19%; Nyocha 1). N'ime ventral striatum na ọkwa a, ijikọ na DAT dị elu nke ukwuu na nucleus accumbens core (+20%) na akpịrị tubercle (+24%) na anụ ahụ sitere na cocaine- vs enwe ike nri.

Mmetụta ọgbaghara na nchịkwa onwe nke Cocaine na-adịghị ala ala ruo ụbọchị 90

N'adịghị ka ọdịiche zuru ebe niile na njupụta nke saịtị njikọ nnabata D1 hụrụ na anụmanụ ndị ekpughere cocaine na-esote ụbọchị 30 nke abstinence, mgbe ụbọchị 90 nke abstinence gasịrị, enweghị nnukwu ọdịiche dị ma e jiri ya tụnyere njikwa nkwado nri na akụkụ ọ bụla nke precommissural. striatum (Isiokwu 1; Nyocha 1). N'otu aka ahụ, ịta nke [³H]raclopride na-ejikọta ndị na-anabata DA D2 na precommissural striatum mgbe ụbọchị 90 nke abstinence adịghịkwa dị iche na nke anụ ọhịa na-adịghị ekpughe ọgwụ.Isiokwu 2).

The ịta nke [³H]WIN 35428 na-ejikọta ya na DAT gosipụtara ụkpụrụ yiri nke ahụ na ndị nnata D1 na D2. Enweghị ọdịiche dị ịrịba ama na njupụta nke DAT n'etiti enwe na-ekpuchi cocaine na-esote ụbọchị 90 nke abstinence ma e jiri ya tụnyere ọkwa dị na njikwa na-adịghị ekpughe ọgwụ (ọgwụ).Isiokwu 3; Nyocha 1), ọ bụ ezie na ekwesịrị iburu n'uche na e nwere usoro na-aga n'ihu n'ọkwa dị elu nke njikọ dị n'ihu nucleus accumens.

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NKWASỊTA

Nnyocha ndị gara aga sitere na otu anyị egosila na ikpughe na-adịghị ala ala na nchịkwa onwe onye cocaine na-esonyere nnukwu dysregulation nke usoro DA nke primates na-abụghị mmadụ.Letchworth et al, 2001; Moore et al, 1998a, 1998b; Nader et al, 2002, 2006). Nsonaazụ nke ọmụmụ a na-egosi na dysregulation a na-apụta ìhè mgbe ọ kwụsịrị ikpughe cocaine. Na-esote ụbọchị 30 nke abstinence, mkpokọta nke ndị na-anabata DA D1 na DAT buliri elu nke ukwuu n'oge niile nke enwe nwere akụkọ ihe mere eme nke nchịkwa cocaine na-adịghị ala ala ma e jiri ya tụnyere njikwa ike nri. Otú ọ dị, ọmụmụ ihe dị ugbu a na-enyekwa ihe àmà doro anya maka mgbake n'ime usoro DA mgbe ogologo oge nke abstinence (ụbọchị 90) gasịrị, dị ka ihe àmà na-egosi na enweghị nnukwu ọdịiche dị n'etiti cocaine-ekpughere ma na-achịkwa ụmụ anụmanụ n'oge a. Data ndị a na-egosi na ikpughe cocaine nwere ike ọ gaghị emepụta mgbanwe na-adịgide adịgide na sistemụ DA, mana mgbake ahụ nwere ike ime na nkwụsị ogologo oge site na iji ọgwụ ọjọọ eme ihe.

Dysregulation nke mkpokọta DAT egosiri ebe a na-eso abstinence kwekọrọ na akụkọ ndị gara aga na primates na-abụghị mmadụ (Letchworth et al, 2001), nke gosipụtara elu dị ịrịba ama na njupụta nke saịtị njikọ DAT na ventral na dorsal striatum. Ọ bụ ezie na anwaleghị ya nke ọma, ọ dị ka mgbe nkwụsị nke ikpughe ọgwụ na-adị elu na njupụta saịtị DAT na-ejikọta ma ọ dịkarịa ala ka ọ dị ukwuu ma na-agbasawanye n'ofe mpaghara nke striatum karịa ndị a kọrọ na-enweghị oge nkwụsị ọ bụla (Letchworth et al, 2001). N'otu aka ahụ, ọkwa dị elu nke saịtị njikọ nnabata D1 hụrụ ebe a na-eso ụbọchị 30 nke abstinence kwekọrọ na ọmụmụ gara aga nke gosipụtara mmụba D1 dị ka nnabata nnabata na striatum nke primates na-abụghị mmadụ ekpughere n'otu usoro nchịkwa nke cocaine.Nader et al, 2002). N'ụzọ dị iche, ọ nweghị nnukwu ọdịiche dị n'etiti ọkwa nke D2-dị ka ndị na-anabata ihe na-ejikọta densities na striatum nke cocaine-ekpughere na anụmanụ na-achịkwa. Enweghị dysregulation a dị, n'agbanyeghị nnukwu mbelata na mkpokọta nke ndị na-anabata D2 nke akọpụtala na ndị riri ahụ mmadụ abụọ.Volkow et al, 1993) na ụdị anụmanụ nke nchịkwa onwe onye cocaine (Moore et al, 1998a, 1998b; Nader et al, 2002, 2006). Ihe data dị ugbu a, yabụ, na-atụ aro nhazi ngwa ngwa karịa ijikwa ọkwa dị na sistemụ a ma e jiri ya tụnyere ndị nnabata D1 na DAT. Ejikọtara ọnụ, mgbanwe na ndị na-anabata DA na DAT na-egosi n'ụzọ doro anya na oge ozugbo nkwụsị nke nchịkwa onwe onye cocaine bụ nke ukwuu na mgbanwe dị ukwuu na nhazi nke usoro DA na-eme, ma na nke a na-esote usoro nhazi nke Sistemu na-abịaru nso nkesa nke ndị nnata DA na nke DAT ka ọ gafechara abstinence ogologo oge.

Mgbanwe Nnabata D1

Ngosi elu zuru ebe niile na njupụta nke ndị na-anabata D1 hụrụ ebe a ka nkwụsị nke iji cocaine kwekọrọ na akụkọ na-egosi mmụba nke ndị na-anabata D1 n'oge mwepụ. Emere nleba anya nke D1 na nyocha site na Henry na White (1991), nke otu ihe ndekọ nke neurons dị na nucleus accumens ka achọpụtara na ọ na-enwe mmetụta nke ọma na onye na-anabata D1 agonist SKF 38393 na-agbaso ọgwụ cocaine na-adịghị ala ala kwa ụbọchị ma e jiri ya tụnyere njikwa saline. Mmetụta a na-adịgide adịgide, na mmụba uche na-apụta ìhè ruo otu ọnwa n'ime nkwụsị. Ndị ode akwụkwọ chere na nnabata nnabata D1 bụ n'ihi nnabata D2 autoreceptor subsensitivity na mpaghara somatodendritic A10, si otú a na-ebelata mkpali mmechi na-agafe na sistemụ mesoaccumbens DA niile.Henry na White, 1991). Ihe omuma a sitere na ihe omumu a gosiputara otutu ebe ndi nnabata D1 na abstinence, nke nwere ike akowa onu ogugu nke neurons dopaminergic na agonist D1 na-eme ihe ozugbo. Ọzọkwa, mmetụta nkwalite nke SKF 38393 na nucleus accumbens neurons apụtaghị ọnwa abụọ ka ewepụrụ ya, na-atụ aro na enwere mgbake nke uche nnabata D1.Henry na White, 1991); Nsonaazụ kwekọrọ na mgbake nke njupụta nke nnabata D1 kwuru na ọmụmụ ihe ugbu a mgbe ụbọchị 90 nke abstinence gasịrị. Akụkọ ndị ọzọ na-akwadokwa ọrụ dị mkpa maka ndị na-anabata D1 na nlọghachi azụ. Mkpali kpọmkwem nke ndị na-anabata D1 na shea nke nucleus accumens nwere ike iweghachite cocaine na-achọ ndị na-adịghị ike (Schmidt et al, 2006). Otú ọ dị, akwụkwọ ndị ahụ adabaghị n'ihi na ma ndị D1 agonists na ndị na-emegide ya nwere ike ibelata ọgwụ na-achọ site na cocaine primes ma ọ bụ ihe mkpali metụtara cocaine.Alleweireldt et al, 2002; De Vries et al, 1999; Khroyan et al, 2000; Self et al, 1996; Weiss et al, 2001). Na nso nso a, Khroyan et al (2003) kọrọ na D1 agonists na ndị na-emegide ya na-ebelata nlọghachi azụ n'ụdị primate nke ịchọ cocaine. Ndị ode akwụkwọ a tụrụ aro na enwere ike ịnwe oke ọrụ nnabata D1 dị mkpa maka ịchọ cocaine, yana ma ndị na-emegide ya na ndị agonists nwere ike wepụ ọrụ na windo a. Mmụba ụba nke ndị na-anabata D1 na-eso abstinence nwere ike gbanwee oke a, na-ebute mgbanwe na uche nke sistemu a. Echiche ọzọ bụ na ọrụ D1 nwere ike ime ka ọ gbanwee ọrụ na ndị na-anabata D2 (Nolan et al, 2007; Ọchị et al, 1999; Walters et al, 1987). Ihe data dị ugbu a na-egosi na nha nke D1 ruo D2 na-anabata ya na-agbanwe n'oge a na-ahapụ ya ma nwee ike si otú a gbanwee ịdị mma nke modulation a.

Ọ bụ ezie na, n'adịghị ka data dị ugbu a, enwere akụkọ banyere mbelata ọkwa nke ndị na-anabata D1 na-esochi nchịkwa onwe onye na-adịghị ala ala (cocaine).Moore et al, 1998a), nnukwu ọdịiche dị n'etiti ọmụmụ ihe ndị a, dị ka dose na ogologo ikpughe na cocaine, mkpokọta oriri, na otu njikwa ntụnyere. N'ịchịkọta ọnụ, ya mere, ịgbakọta ihe akaebe na-egosi n'ụzọ siri ike na usoro D1 na-enwe nnukwu mgbanwe na-esochi mwepụ na nchịkwa cocaine na-adịghị ala ala.

Mgbanwe Ndị na-ebufe Dopamine

Nchọpụta nke mkpokọta DAT dị elu n'ofe striatum nke anụmanụ ndị ekpughere cocaine mgbe ịkwụsị ọgwụ ọjọọ na-agbasawanye nke ọmụmụ anyị gara aga na-egosi mmụba nke saịtị njikọ DAT na-esonyere nchịkwa onwe onye cocaine na primates na-abụghị mmadụ. Ihe omuma a gosiputara na dysregulation a na-adigide n'oge mmalite nke abstinence. Ọzọkwa, ha na-atụ aro na mgbake iji chịkwaa ọkwa na-esote usoro ogologo oge (ruo ụbọchị 90 na ọmụmụ ihe ugbu a). N'ime ọmụmụ ihe anyị gara aga, anyị gosiri na n'agbanyeghị na amachibidoro ya na mpaghara ventral ventral striatal, mgbanwe na njupụta nke saịtị njikọ DAT gbasaa ka ọ gbasaa karịa akụkụ azụ na rostral nke striatum nwere ogologo oge ikpughe na cocaine.Letchworth et al, 2001; Porrino et al, 2004). N'ime ọmụmụ ihe ugbu a, nlọghachi na nchịkwa nchịkwa nke DAT n'oge abstinence pụtara ka ọ dị ukwuu ma dị ngwa ngwa na dorsal striatum karịa na ventral striatum, ma si otú a yie ka ọ na-agbaso ngbanwe nke ọdịdị ọdịdị ọdịdị nke mmetụta sitere na ikpughe cocaine na-adịghị ala ala. .

Ihe data dị ugbu a kwekọrọ na akụkọ sitere na ndị ọrụ cocaine mmadụ (Little et al, 1999; Malison et al, 1998; Mash et al, 2002; Staley et al, 1994) nke gosipụtara ọkwa dị elu nke njide na saịtị DAT na striatum ma e jiri ya tụnyere njikwa, yana mmụba kachasị akara dị na ventral striatum. N'oge na-adịbeghị anya, egosiri elu ndị a na-esonyere ya na mbelata dị ukwuu na vesicular monoamine transporter 2 (VMAT2) njikọ (VMATXNUMX).Little et al, 2003), na-egosi mfu nke neurons DA n'ezie. Ndị ode akwụkwọ kwubiri na DAT dị elu nwere ike ịbụ ozugbo n'ihi nzaghachi nkwụghachi ụgwọ maka mgbochi ọgwụ ọgwụ site na cocaine, ebe mbelata na VMAT2 yikarịrị ka ọ na-egosipụta mgbanwe niile na metabolism DA, na-ebute ọrụ hypodopaminergic.

A kọwo na ndị na-eri cocaine riri ahụ mmadụ belatara mkpokọta DA na ventral striatum, dị ka atụpụtara ya na PET, na nzaghachi na ihe ịma aka methylphenidate ma e jiri ya tụnyere njikwa ahụike.Volkow et al, 1997). Na nso nso a, Martinez et al (2007) kọrọ na ndị ọrụ cocaine nwere nzaghachi na-enweghị isi maka ihe ịma aka amphetamine na ventral striatum na putamen. Ọzọkwa, mbelata a na ntọhapụ DA nke amphetamine kpatara na-ejikọta ya na nhọrọ maka cocaine na nnọkọ nchịkwa onwe onye dị iche iche, dị ka ndị ọrụ ahụ nwere ogo kachasị elu nke DA ntọhapụ na nzaghachi amphetamine nwere ike ịhọrọ cocaine n'elu ihe mgbakwunye ọzọ (Martinez et al, 2007). Nnyocha e mere n'oge na-adịbeghị anya n'ụdị òké iji cocaine na-akwadokwa echiche a. Mateo et al (2005), dị ka ihe atụ, kọrọ na ikpughe na cocaine na-adịghị ala ala nchịkwa na-ejikọta na mgbanwe na ọrụ DAT. Ndị nchọpụta a gosipụtara na mmụba DA ndabere abawanyela, na-ebute mkpochapụ ngwa ngwa nke synaptic DA, yabụ, belata ọkwa basal nke extracellular DA, ma ọ bụ ọnọdụ hypodopaminergic. Ya mere, ọ ga-abụ na mmụba DAT na-abawanye na-esochi mwepụ na nchịkwa onwe onye na-adịghị ala ala nke a na-ahụ na nyocha a na-anọchi anya nzaghachi ụgwọ, na-ebute ọkwa dị ala nke extracellular DA.

Mgbanwe Nnabata D2

Otu nsonaazụ sitere na ọmụmụ ihe dị ugbu a bụ na ntinye nke ọkwa nnabata D2 laghachiri na ụkpụrụ njikwa na-esochi ụbọchị 30 nke abstinence, ma e jiri ya tụnyere mbelata dị ukwuu a hụrụ na ụmụ anụmanụ na-enweghị oge iwepụ.Nader et al, 2002). N'adịghị ka nyocha dị ugbu a, ọmụmụ ihe onyonyo mmadụ achọpụtala n'ozuzu na ọkwa nnabata D2 dị ala karịa nke njikwa na-eso ogologo oge abstinence na ikpughe cocaine na-adịghị ala ala.Martinez et al, 2004; Volkow et al, 1993). Enwere ike ịkọwa ọdịiche dị n'etiti ọmụmụ mmadụ ndị a na nyocha primate ugbu a na-abụghị nke mmadụ gụnyere ọdịiche dị na ụkpụrụ na ogologo oge ịṅụ cocaine, yana ohere nke ịdị adị nke ọkwa dị ala nke ndị na-anabata D2 na ndị na-eri ahụ mmadụ.

N'ikwekọ n'echiche ikpeazụ, enwere ihe akaebe na-egosi na ọkwa basal dị ala nke ndị na-anabata D2 na ahụike mmadụ na-ebu amụma na-abawanye nrụpụta ike nke mkpali dị ka. methylphenidate (Volkow et al, 1999), na n'otu aka ahụ na enwe, ọkwa ntọala nke ndị na-anabata D2 buru amụma na ọ ga-enwe ike ịchịkwa cocaine.Morgan et al, 2002; Nader et al, 2006). N'ikwekọ na ọdịdị nke nchoputa ndị a n'ofe ụdị, ma mmadụ (mmadụ).Volkow et al, 1993) na primate na-abụghị mmadụ (Nader et al, 2006) Ọmụmụ ihe onyonyo egosila ọkwa dị ala nke nnweta nnabata D2 na-eso abstinence na ikpughe cocaine. N'ụzọ doro anya, nhazi oge nchịkwa nke cocaine na nnwale ikpeazụ (Nader et al, 2006) dị ka usoro nkwado e ji mee ihe n'ọmụmụ ihe a. Ya mere, nsonaazụ ndị dị iche na ọmụmụ abụọ a enweghị ike ịbụ n'ihi ọdịiche nke usoro, dị ka nhazi oge nkwado ma ọ bụ nchịkọta ọnụ n'oge nchịkwa cocaine.

Nkọwa nwere ike ịbụ na-agụnye ọrụ ike nke sistemụ DA. A kọwapụtara usoro nnweta nnabata D2 na PET dị ka 'na-arụ ọrụ' n'ihi na mgbaàmà ahụ metụtara ọnụọgụ protein (n'okwu a njupụta nke ndị na-anabata D2) yana ọkwa nke neurotransmitter na-ekesa. (lee Laruelle, 2000; Nader na Czoty, 2008 maka nkwurịta okwu ọzọ). IN'ụzọ dị iche, autoradiography nke nnata adịghị emetọ ya site na-ekesa ọkwa nke DA. Ya mere, ọmụmụ ihe dị ugbu a, yana ọrụ anyị mbụ, na-egosi na njupụta nke ndị na-anabata D2 na-ebelata site na nchịkwa onwe nke cocaine, mana ọkwa ndị nabatara na-apụta na-agbake n'oge abstinence. N'ime otu ihe ọmụmụ PET mere (Nader et al, 2006), Achọpụtara mgbake na atọ n'ime enwe ise. Nchọpụta ndị dị ugbu a na-egosi na enwe ndị a nwere ike ọ bụghị dị iche na njupụta nke ndị na-anabata D2, mana ikekwe nzaghachi nke sistemụ DA (ya bụ ọkwa nke ịgbasa DA n'oge abstinence) dị iche n'etiti isiokwu 'agbake' na 'anaghị enwetaghachi'.

-agaghị emeli

Otu mmachi dị mkpa nke ọmụmụ ihe ugbu a bụ na ọmụmụ ihe anyị enweghị ike ileba anya na ọrụ nke ndị na-anabata D1 na D2 ma ọ bụ nke DAT. Kama, anyị nyochara naanị mgbanwe na njupụta nke protein nnabata. Ọ bụ ezie na nsonaazụ ya nwere mmetụta maka ọrụ ndị nwere ike ịrụ ọrụ nke usoro ndị a, a ga-achọkwu ọmụmụ ihe iji mee ka ìhè pụta ìhè na nsonaazụ omume nke mgbanwe ndị a gosipụtara ebe a. Mgbochi ọzọ nke ọmụmụ ihe a bụ na autoradiographic ligands na-adakarị ikewa n'etiti intracellular na cytoplasmic ọnọdụ nke ha lekwasịrị anya, dị ka rediolabeled antagonists na-abụkarị membrane permeable. Little et al (2002) gosipụtara na ikpughe na-adịghị ala ala na cocaine na-eduga n'ịkwalite DAT dị ịrịba ama n'elu akpụkpọ ahụ, n'otu oge na mbelata na ntinye uche DAT intracellular, na sel ebugharị. Na nso nso a, Samuvel et al (2008) kọrọ otu nchoputa ahụ na nkwadebe striatal synaptosomal oke. Nsonaazụ ndị a na-egosi na mgbanwe na nkesa DAT a hụrụ na ọmụmụ ihe ugbu a nwere ike ịnọchite anya mgbanwe n'elu akpụkpọ ahụ, karịa saịtị intracellular.

N'ikpeazụ, e kwesịrị ịdọ aka ná ntị ụfọdụ na nkọwa nke ọmụmụ nke ogologo oge (90 ụbọchị) abstinence, dị ka nchoputa ndị a dabeere na a dịtụ obere ìgwè anụmanụ (N=3). N'agbanyeghị ọnụ ọgụgụ dị nta nke isiokwu, data e nwetara site na otu a na-agbanwe agbanwe, dị ka a pụrụ ịhụ na nchịkọta mgbasa ozi nke egosiri na. Nyocha 2. Nleba anya nke saịtị njikọ nnabata D1 n'ofe striatum gosipụtara obere mgbanwe n'ime otu, na-atụ aro ntụkwasị obi nke nchoputa ndị a. Nkwekọrịta yiri nke ahụ pụtakwara na data sitere na ndị nnata D2 na nyocha njide DAT. Agbanyeghị na ekwesịrị ịkpachara anya, data ndị a na-atụ aro na mweghachi nke mkpokọta DAT na ndị nnabata DA n'ime striatum nwere ike ime na abstinence ogologo oge.

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Nkwenye

Na mmechi, ikpughe na nchịkwa onwe nke cocaine mepụtara mgbanwe dị ukwuu na nhazi usoro DA nke nọgidere na-aga n'ihu n'oge mmalite (ụbọchị 30 mbụ) nke abstinence. Nke a pụtara ìhè nke ukwuu na nhazi nke ntinye nke ndị na-anabata D1 na DAT, ma n'ihe gbasara oke mgbanwe ha na oke topographical ha. N'ụzọ dị iche, enwere ihe akaebe maka ịhazigharị ya na ogologo oge nke abstinence na ikpughe cocaine, n'ihi na ntinye nke DAT, D1, na ndị na-anabata D2 mgbe ụbọchị 90 nke abstinence gasịrị adịghị iche na nke njikwa na-abụghị nke ọgwụ. TSistemu hese, agbanyeghị, ọ bụchaghị ịgbaso otu usoro mgbake nke nwa oge, na-atụ aro na enwere ike ịnwe enweghị ntụkwasị obi na nhazi nke ọkwa DA ọkachasị n'oge abstinence.. Dysregulation dopaminergic a nwere ike imetụta ịdị irè nke ọgwụ ọgwụ ọ bụla nwere ike inye ndị na-eri ọgwụ cocaine abstinent, ọkachasị ma ọ bụrụ na ọgwụ ahụ dabere na sistemụ DA maka usoro ya.

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Notes

AGBA/Ọgbaghara nke mmasị

Ndị ode akwụkwọ enweghị esemokwu nke mmasị igosipụta.

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