Ihe ojoo na-eme ka ngwugwu dopamine bu amphetamine kpatara mmetuta nke mmekorita ndi mmadu n'otu umu umu mmadu (2010)

Ihe riri ahụ, dị ka ihe na-akpali agụụ mmekọahụ riri ahụ, na-egbochi mmemme njikọ abụọ site na oke dopamineNucleus na-akpakọba dopamine na-eme ka amphetamine butere mmebi nke mmekọrịta mmadụ na ibe ya n'ụdị òké otu nwanyị.

Proc Natl Acad Sci US A. Jan 19, 2010; 107 (3): 1217–1222.

E biputara na intaneti Dec 29, 2009. doi:  10.1073 / pnas.0911998107

PMCID: PMC2824263

Neuroscience

Nke a bu zoro aka na ya ndị ọzọ na PMC.

Gaa:

nkịtị

Preri vole (Microtus ochrogaster) umu anumanu di na nwunye nke na eme ka ha nwee nmekorita nke oma site na nmekorita ya, bu akuko nke dopamine (DA). N'ebe a, anyị jiri ụmụ nwoke prairie voles nyochaa ihe nlele ọgwụ na-akpata na njikọta ọnụ na njikọta akwara. Na nnwale anyị nke mbụ, a nyochachara omume amphetamine (AMPH) site na iji ụdị ntụrụndụ ọnọdụ (CPP) ma gosipụta na ọ bụ onye mgbasa ozi nke ndị nnabata nke D1-DA. Ọzọ, anyị nyochale nsonaazụ nke ikpughe AMPH ugboro ugboro na njikọta ọnụ. Arụmọrụ na saline emechara nwoke gosipụtara nwoke chọrọ ịlụ, ebe ụmụ nwoke mere AMPH na usoro onyonye iji mee ka CPP ghara igosipụta mmasị mmekọ ibe. Treatmentdị ọgwụgwọ AMPH dị otú a mekwara ka D1 dịkwuo mma, mana ọ bụghị D2, DA na-anabata nnabata na njiko ngọngọ nucleus (NAcc). Ọzọkwa, mgbochi nke ọgwụ ọgwụ nke D1 dị ka DA na-anabata ndị nọ na NAcc napụtara ndị mmekọ mmekọ nwoke na nwoke inwete na AMPH. N'ịkakọ ọnụ, data anyị na-egosi na ikpughe AMPH ugboro ugboro nwere ike imebelata akparamagwa nke ụmụ nwoke prairie voles site na usoro nke usoro nnabata nke DA na NAcc, nke na-ebute mbibi nke njikọ nwoke na nwanyị.

Keywords: vole, CPP, D1 Nnabata

Ọ bụ ihe a nabatara nke ọma na akparamagwa na mmụọ mmetụta na-akwalite ahụ mma bụ usoro nhazi ụbụrụ gụnyere ụbụrụ mesolimbic dopamine (DA) (1, 2). Ọ bụ ezie na usoro a na-emetụtakarị oriri nri yana omume mmekọahụ (3, 4), ọ pụtakwara na akparamagwa ndị ọzọ na-eme ebilite, dị ka egwuregwu mmekọrịta n'etiti ụmụaka na mmekọrịta nwa na nne na nna na ụmụ (5-9). Mgbe mgbe enweghi nyocha na nyocha bụ njikọta mmekọrịta n'etiti mmadụ na ibe ya, ya bụ, nkekọ abụọ. Nnyocha e mere na nso nso a na-eji ụdị otu ụdị otu sobe otu nwanyị, prairie vole (prairie vole)Microtus ochrogaster) (10-12), na-egosi na ọtụtụ iwu akwara dị na ya na –ekwe ka njikota na njigide na - apụta na ngwongwo akwara (NAcc)13-15) - mpaghara ụbụrụ mesolimbic dị oke mkpa maka ịme ka akparamàgwà ndị kpaliri (1, 2, 16).

Ọ bụ ezie na circuitry na-akpali akpali kwalitere nkwalite mmega ahụ dịka nri, ịkọ nri, na njikọta mmekọrịta.1, 17), ọ bụ ngwangwa usurpation keakamere site ọgwụ ọjọọ eme ihe (8). Dịka ọmụmaatụ, nchịkwa nke ọgwụ psychostimulant nke mkparị, dịka cocaine na amphetamine (AMPH), na-ebute mgbanwe na-adịgide adịgide nke ọrụ mesolimbic DA (18, 19). A na-atụ aro mmetụta siri ike na sekit a site na ọgwụ ndị a na ndị ọzọ na-eri ahụ iji belata uru a na-enweta site na mkpali sitere n'okike (20), gụnyere ndị sitere n'obodo ha (8). Ọ bụ ezie na a maara na ndị ọgwụ ọjọọ riri ahụ na-egosi omume mmekọrịta ọha na eze (21), ụkpụrụ ọgbụgba nke mmekọrịta dị n'etiti ahụmịhe ọgwụ yana njikọta mmekọrịta adịghị nke ọma. Nke a bụ n'ihi na, n'otu akụkụ, mmekọrịta dị otú ahụ siri ike ịme ka ụlọ ọrụ nyocha ụlọ ọdịnala na-anaghị egosipụta njikọta mmekọrịta n'etiti ndị okenye.

A mụọ neurobiology nke njikọta mmekọrịta dị otú a, nkekọkọtara ọnụ n'etiti ndị okenye, agụwo n'ọtụtụ ọmụmụ na prairie vole (10-12), n’oge na-adịbeghị anya, e guzobewo ụdị a dị ka ihe atụ nwere ike ịtụle uru mkpali AMPH (22). Ọzọkwa, njikọta nke abụọ na nkwalite AMPH na-agbaghachite, ma ọ dịkarịa ala na akụkụ, site na nnyefe DA n'ime NAcc (14, 15, 23). Ya mere, ihe omumu a gosiputara uzo omuma iji gosiputa akparamagwa nke omume iji hu ihe omimi banyere nzipu nke ogwu na mmekorita ndi mmadu ma lebara anya na usoro ntinye aka nke NAcc DA iji kpughee usoro irighiri akwara nke na-egosi ihe omume ndi a.

Results

AMPH-Induced Ọnọdụ Ọnọdụ (CPP) na-atụgharị uche site n'aka DA na Akwụkwọ ntuziaka Receptor-Specific.

Etuputara nguzobe nke CPP site na mmụba dị ukwuu na oge ejiri na ọnụ AMPH-jikọrọ ọnụ n'oge posttest, mgbe ụbọchị 3 nke AMPH dị, na-emetụta pretest. Ma inyinye saline ma ọ bụ nnu nwere ihe abụọ dị ala nke AMPH anwale (0.1 na 0.5 mg / kg) gbanwere usoro nchekwa (Fig. 1A). Agbanyeghị, ụmụ nwoke nwere ntụpọ dị elu nke AMPH, gụnyere 1.0 (t = 2.87, P <0.01), 3.0 (t = 3.63, P <0.01), ma ọ bụ 5.0 mg / kg (t = 3.03, P <0.01), gosipụtara CPP (Fig. 1A).

1 fig.

(A) Ụmụ nwoke ndị natara ip injections nke saline ma ọ bụ obere doses nke AMPH (0.1 ma ọ bụ 0.5 mg / kg) n'ime ụbọchị 3 nke nhazi egosighi CPP. Agbanyeghị, ụmụ nwoke nwere ọnọdụ AMPH na oke doses (1.0, 3.0, na 5.0 mg / kg) na-etinye oge karịa. ...

N'ihi na AMPH dị elu na-abawanye DA neurotransmission na prairie voles (24), na DA na-eme ka nkwalite AMPH dịkwuo n'ụdị ndị ọzọ (23) Anyị nyochara usoro nlekọta nnabata DA (DAR) nke AMPH na-ebute CPP na voir male. Ihe ndị dị mkpa na usoro CPP, a na-emeso ha saline ma ọ bụ saline nwere usoro dị iche iche nke nonselective DAR antagonist (haloperidol) tupu inyocha AMPH (1.0 mg / kg) mgbe ụbọchị 3 dị mma, wee nwalee maka CPP na posttest. Isiokwu ndị a na-eji saline eme ihe (t = 2.69, P <0.01) ma ọ bụ saline nwere mkpụrụ ọgwụ abụọ kacha ala nke haloperidol (0.1 mg / kg; t = 3.62, P <0.01; 1.0 mg / n'arọ; t = 3.89, P <0.01) tupu nkwonkwo AMPH gosipụtara CPP na-emetụta AMPH, ebe haloperidol na 5.0 mg / kg gbochiri AMP na-emetụta CPP, na-egosi ntinye nke DAR na mmetụta omume nke AMPH (Fig. 1B). Iji chọpụta nke DAR subtype na-agbazi AMPH na-eweta CPP, anyị na-esote na-eweta D1 dị ka antagonist a kapịrị ọnụ (SCH23390) ma ọ bụ D2-like antagonist (eticlopride) tupu inPors nke AMPH n'oge agba oyi. D2-like antagonism egbochighị CPP AMPH na-ewetat = 3.15, P <0.01 maka 0.5 mg / kg na t = 2.60, P <0.05 maka 5.0 mg / kg eticlopride) mana mgbochi nke ndị nabatara D1 dị ka ndị kpochapụrụ AMP-emetụta CPP (Fig. 1B), na-egosi na AMPH na-eweta CPP bụ onye ogbugbo site na ịgbalite nke D1-like, mana ọ bụghị D2-like, ndị na-anabata ya na voirie prales.

Ahụmahụ AMPH na-agbanwe Mpempe Usoro Mmekọ Onye Mmekọ.

Agbanyeghi na AMPH na-eweta CPP choro ka ebugharị D1-like receiptors (Fig. 1B), anyị gosipụtara na mbido nke nnata ozi nke D1 dị ka ndị na - egbochi imekọ njikọta njikọta nke abụọ14). Ya mere, anyị siri n'echiche na ịmebata AMPH ga - egbochi nnabata ihe nwoke na nwanyị na - ekekọta onwe ya. E kewara ụmụ nwoke na otu anọ na-enwetaghị ọgwụ inje ọ bụla (arụrụ ọrụ), saline injections, ma ọ bụ inje nke 1.0 ma ọ bụ 5.0 mg / kg AMPH maka ụbọchị 3 (ihe ntụtụ iji zuru CPP). N'ụbọchị nke anọ, ụmụ nwoke niile nwere mmekọ nwoke na nwanyị na-anabata mmekọahụ maka 24 h wee nwalee maka mmasị onye mmekọ. Dabere na ọmụmụ gara aga (14, 25-27), ụmụ nwoke na ụmụ nwoke na-adịbeghị anya natara saline injection maka ụbọchị 3 tupu mating gosiputara mmasị ndị mmekọ nwoke na nwanyị. t = 3.05, P <0.01, saline na-agbanye ụmụ nwoke; t = 3.21, P <0.01; Fig. 2A). Agbanyeghị, ụmụ nwoke e jiri mee ihe AMPH mee ihe maka ụbọchị 3 tupu mating egosiputaghị mmasị onye ibe (Fig. 2A). Ihe dị mkpa bụ, nnabata AMPH emetụtaghị ugboro ole ọkọlọtọ n'oge emekọ ọnụ (F(3, 26) = 0.26, P = 0.85; Fig. 2B) ma ọ bụ ọrụ locomotor n'oge nnwale mmasị ibe (F(3, 26)= 2.34, P = 0.10; Fig. 2C), na-egosi na AMPH batara kpọmkwem na mmekọ onye ọlụlụ chọrọ ịlụ.

2 fig.

(A) Mgbe awa 24 gachara, ụmụ nwoke na-edobeghi anya gosipụtara mmasị ndị mmekọ site n'itinye oge ka ukwuu na kọntaktị n'akụkụ n'akụkụ n'etiti di na nwunye maara nke ọma na nwanyị na-amaghị nwoke. Ndị nwoke natara egosikwara mmasị onye mmekọ a kpalitere ...

Ahụmịhe AMPH na-ebulite ndị nnata D1 na NAcc.

Nyere na nnabata nnabata nke AMPH nwere mmechuihu nke AMPH na anya CPP (lee nke di elu) na njikọta uzo (14) nke NAcc DA na-achịkwa, anyị chetara na AMPH ga-agbanwe obere mbubata ọgwụ DA DA na prairie voles. A haziri ụbụrụ ihe omume ndị ae kwuru n'elu omume omume nnabata maka ịkọwa akara MRNA. Lesmụ nwoke e mesoro AMPH (1.0 mg / kg) gosipụtara mmụba dị ukwuu na onye na-anabata D1 (D1R; t = 3.06, P <0.01), ma obughi onye natara D2 (D2R), akara mRNA n'ime NAcc, ma e jiri ya tụnyere nwoke na-anata nnu nnu (Fig. 3 A-C). Otú ọ dị, ọ dịghị otu esemokwu dị na njupụta nke akara mRNA maka tyrosine hydroxylase (TH), DA transporter (DAT), ma ọ bụ D2Rs n'ime mpaghara ventral tegmental (VTA) - mpaghara ụbụrụ nke na-enye ntinye dopaminergic bụ isi na NAcc (Fig. 3 D-G). Ngosiputa nke ngosiputa nke D1R na NAcc ka enwetakwuru site na ihichapu Western)t = 1.90, P <0.05; Fig. 3 H na I). Ọnụ, data ndị a na-egosi na ikpughe AMPH nwere ihe nnabata-yana nsonaazụ saịtị akọwapụtara na sistemu nke praolie menolim - nke na-abawanye ọkwa nke D1R na NAcc.

3 fig.

Foto onyonyo na-egosi igosipụta D1RAna D2R (B) mRNA na NAcc na caudate putamen (CP) nke nwoke prairie voles natara ip injections nke saline ma ọ bụ AMPH (1.0 mg/kg) maka ụbọchị 3. AMPH ọgwụgwọ budata ụba njupụta nke ...

Ndị na-anabata D1 na NAcc Mediate AMPH erughi oke nke Mmasị Mmekọ.

Ayi egosiputala na, na prairie voles, activation nke D1Rs n'ime NAcc gbochiri mmekorita nke onye ibe (14), na ọmụmụ ihe dị ugbu a na-egosi na ikpughe AMPH na-edozi D1Rs na NAcc (Fig. 3). Ya mere, anyị nwalere hypothesis bụ na D1Rs bụ onye ogbugbo nke AMPH na-ebute mmekpa ahụ nke mmekọ ibe ya. Receivedmụ nwoke natara stereotaxic cannulation nke dị n'otu ntinye aka na mkpo NAcc (Fig. 4A). Ọkpụkpụ mmiri akwara (CSF) naanị ma ọ bụ CSF nwere ọnụọgụ dị iche iche nke D1-receptor antagonist SCH23390 ka etinyere aka na NAcc tupu ọgwụ ịgba AMPH (1.0 mg / kg) n'oge ụbọchị 3. Mgbe nke ahụ gasiri, ejikọtara ọnụ nke nwanyị na nwanyị maka 24 h wee nwalee maka mmasị onye mmekọ. Dị ka nnwale dị n'elu (Fig. 2), Ikpughe AMPH gbochiri mmasị ịlụ mmekọ nwoke na nwanyị na ụmụ nwoke natara intra-NAcc injections nke CSF ma ọ bụ obere ọnụọgụ nke SCH23390 (Fig. 4B). Agbanyeghị, ụmụ nwoke etinyere ọnụego dị ukwuu nke SCH23390 (100 ng / kg) gosipụtara mmasị ndị mmekọ (t = 2.55, P <0.05), na-egosi na mgbochi D1R na NAcc kpochapụrụ mmerụ nke AMPH nke mmekorita mmasị mkpakọrịta (Fig. 4B). Onweghi ihe n’otu n’otu n’otu ahutara n’oge uto n’oge a na-ebikọ ma o bu n’onye na-eme ihe n’otu n’uche onye ibe.

4 fig.

(A) Foto onyonyo na eserese foto nke na - egosi saịtị irighiri ihe dị na NAcc nke ụbụrụ praịie vole. Anyị lekwasịrị anya na NAcc shei n'ihi na nke a dị n'okpuru ala na-emezi mmekọrịta nwoke na nwanyị chọrọ ịlụ. (B) Ụmụ nwoke natara intra-NAcc ...

Nkwurịta

N'ime ọmụmụ ihe a, anyị na-emegharị nchọpụta anyị gara aga na ngosipụta AMPH na-akpali CPP na voir male (prairie voles)22) ma gosipụta na mbugharị D1R na NAcc dị mkpa maka omume a, nsonaazụ kwekọrọ na ọmụmụ na ụdị ndị ọzọ nwere oke (28). Nchọpụta a, yana ọmụmụ ihe ndị mbụ, na-egosi na usoro DAergic dị iche iche na NAcc na-achịkwa AMPH- na omume ndị na-akpali mmụọ: AMPH-kpaliri omume (CPP) bụ onye mgbasa ozi nke D1R, ebe omume mkpali nke mmekọ (ihe ndị mmekọ) na D2R Ntughari D1R na-egbochi ma na-egbochi ya13-15). [Ọ dị mkpa iburu n'obi na, na NAcc, ngagharị D2R na-emegharị onye ọgwụ ọgwụ CPP na-eweta n'okpuru ọnọdụ ụfọdụ (29) na ntinye D1R na-etinye aka na akparamagwa ndị ọzọ metụtara mmekọrịta mmadụ na ibe ya, dịka ndị a tụbara na ụmụ (7, 30)].

Usoro DAergic dị iche iche nke CPP na nhazi onye ga - achọkarị onye ga - enweta ihe dịgasị iche site na ogo nke mkpali-ịchụpu DA ị na - eme ihe dị iche iche DAR. N'ihi ọdịiche dị n'etiti njikọta njikọta, achọrọ ịdị elu na DA ịchọrọ iji mee ka mmekọrịta dị ala D1Rs, ebe mmụba dị ala na mkpokọta DA na-eme ka mmekọrịta dị elu D2Rs31). Na praị voles, AMPH na-a increasesụ nnukwu mmụba na DA ịta ahụhụ (24) tụnyere nke achọrọ site na mating (15, 25). Ihe omuma ndi a na-enye echiche na a na-abawanye n ’ịta ahụhụ DA mgbe oge mmekọrịta mmadụ na ibe ya.15, 25) ekwekwa ka nkwalite nke mmekọ ihe dị elu D2R ma nwekwaa ike ijikọ njikọ ọnụ. N'aka nke ọzọ, mmụba siri ike na mkpesa DA na-esochi nchịkwa AMPH nwere ike zuru ezu iji rụọ ọrụ mmekọrịta D1R dị ala, si otú ahụ na-eme ka CPP na-eweta AMPH.

Rekpụrụ omume metụtara usoro nke DA na-agbanwe agbanwe na usoro mmụta electrophysiological extracellular na oke na-emegharị oke na-egosi na a na-edozi ọgwụ na mkpali sitere n'okike site na ọnụ ọgụgụ dị iche iche nke neuronal n'ime NAcc (32). Ọ bụ ezie na usoro ọmụmụ electrophysiological enweghị ike ịkọwapụta ụdị nnabata DA na-egosipụta na neurons nke mmadụ, ọmụmụ anatomical na-egosi na NAcc nwere ntụpọ neurons nke na-egosipụta D1Rs ma ọ bụ D2Rs nwere ntakịrị coexpression (33). Psychostimulants na-arụ ọrụ rụọ ọrụ ụzọ mgbaàmà intracellular na-agbadata site na D1Rs (dị ka ekpebisiri ike site na ịba ụba nke mkpụrụ ndụ na-egosi).34) anyị egosikwa na mbụ na mgbalite ọrụ nke ụzọ mgbaàmà ndị a na-egbochi imepụta mmasị nke mmekọ (35). Ya mere, n’agbanyeghi na nnyefe DA n’ime usoro NAcc na-arụ ọrụ dị mkpa na nzaghachi AMPH na ịmepụta nke ndị mmekọ, o nwere ike ịbụ na omume ndị a bụ ndị agbaziri agbaziri site na microcircuiteri dị iche iche nke nwere sistemu ọkụ33, 36). Nke a bụ ọkacha mmasị n'ihi na njikọta njikọta ọnụ na-ebugharị site na nkwalite nke D2R-na-ekwupụta neurons ndị na-ebu ụzọ rụọ ọrụ na palidum ventral (33), mpaghara ụbụrụ ọzọ dị mkpa maka njikọkọ ọnụ (26).

N'ime ọmụmụ a, anyị na-enye ihe akaebe na ahụmịhe AMPH na-egbochi njikọta njikọta nke ibe. Dika emere nnweko nke nnweko na nnwale ndi a gosiputara 48 h mgbe ekpughechara AMPH ikpeazu (ya bu, mgbe emechara ogwu ahu ka arua aru), data ndi a na egosiputa nnabata AMPH na ntukwasi obi. Otu usoro nwere ike, kwekọrọ na mmetụta AMPH na ụdị ndị ọzọ (37, 38), nke AMPH nwere ike imebi ụzọ ejikọtara ọnụ bụ site na mmụba nke ngosipụta D1R n'ime NAcc. A na - akwado echiche a site na nkwenye ọrụ nke NAcc D1R na njiko mmasị onye mmekọ (14, 24) sitekwa na nke ugbu a data na-egosipụta nnapụta nke mmasị mmekọ mmekọ na-ebute site na mgbochi intra-NAcc D1R n'ime anụmanụ AMPH mesoro (Fig. 4). N'ụzọ na-akpali mmasị, anyị gosipụtara na, na prairie voles, nhazi nke NAcc D1Rs mgbe izu 2 nke ejikọtara ọnụ na-eme ka iwe ọkụ megide ndị bịara abịa, gụnyere ụmụ nwanyị na-anabata mmekọahụ, na-atụ aro na plastik a dị ọhụrụ bụ usoro mgbanwe sitere n'aka nke ụmụ nwoke na-eji jisie ike na nkekọ nkekọ (14). Ọmụmụ ihe ọmụmụ ugbu a na-atụ aro na AMPH na-ebute ihe nzuzu a na-eduga n'ịdị adị nke AMPH. Ọ ga - ekwe omume na ụmụ nwoke ndị a na - emeso AMPH nwere ike ijikọ nwanyị ahụ na ọnọdụ nnabata nke AMPH, ma yabụ mkpakọrịta a na - adịghị mma nwere ike ime ka nsogbu AMPH ghara inwe nkekọ. Ọmụmụ ihe gara aga gosipụtara na iwepụ na usoro ịgbatị oke nke d-amphetamine na-emebi omume mmekọahụ na oke oke (39). Na omumu anyi, otodi, voles di iche-iche di iche-iche gosiputara udiri mmachi dikaFig. 2B), na-egosi na ikekwe ha anọghị n'ọnọdụ steepụ na amphetamine. Na agbanyeghị, enwere ike a chọọ nyocha ọzọ.

Ọ bụ ihe emebere ka ọ pụta ìhè na plasticity neural na-akpata bụ ihe dị mkpa maka iri mmadụ ahụ riri ahụ (40). Psychostimulants gbanwere plastik sistemu na sistemu na usoro41) enwere ihe akaebe iji gosi na mgbanwe ndị dị otú a na-adịgide karịa na D1 na-ekwupụta neurons (37). Ọzọkwa, usoro ọmụmụ electrophysiological egosiwo na ahụmịhe cocaine nwere ike belata neuroplasticity na-esochi n'ime NAcc (42). N’ezie, ịhazi ọgwụ ụgbụ a ọgwụ emepụtara ọgwụ NAcc na - eme ka ịhazigharị ọgịga na - esote ọnọdụ izizi gburugburu ogige dị egwu (43). Yabụ, agbanyeghị na ọgwụ ndị riri ahụ ka amaara dịka nsogbu mmụta na ebe nchekwa (1, 40, 44), a naghị amatakarị ya na ọnwụ na - akpata ọnwụ ike iji nwetakwuo mgbanwe na sekit mesia nwere ike ịbụ ihe dị mkpa maka iri mmadụ ahụ. Mbelata dị otú ahụ na plasticity nwere ike amachi oke ịkpa oke na ịchọ ọgwụ. Ọ bụ ya mere ọ bụghị ihe ịtụnanya na AMPH mesoro voles gosipụtara belata njikọ ejikọ ọnụ. Mmetụta mmetụta AMPH dị ugbu a na njikọta njikọta kwekọrọ na ọmụmụ gara aga na-egosipụta mmetụta zuru oke nke psychostimulants na akparamagwa ndị ọzọ, gụnyere akparamagwa nne (45-47) na egwuregwu ndị mmadụ (48-50). N'ịkakọ ọnụ, ụdị ọrụ ahụ na-enye nkwa na nyocha nke otu ọgwụ na -eme ka mkparịta ụka si emetụta ụbụrụ nwere ike ime ka nghọta anyị sie ike na mmekọrịta dị n'etiti omume na mmekọrịta mmadụ na ibe ya.21).

Akụrụngwa na ụzọ

Isiokwu.

Ihe ndi ozo bu nwoke nwoke nwere nmekorita nke nwoke site na ulo ozuzu ahihia. Apụrụ ihe ndị dịpụrụ adịpụ na ụbọchị 21 wee tinye ọnụ ụzọ nwanne nwoke na nwanyị n'otu mkpuchi plastik (12 × 28 × 16 cm) ebe enyere mmiri na nri mgbasa ozi libitum. Echebere mkpuchi niile n'okpuru otu 14: 10 light-dark network, ma ọ̀dịdị dị ihe dịka 20 Celsius. Ihe ọmụmụ niile dị ihe dị ka ụbọchị 90 dị afọ mgbe anwalere ha. Akọwaala stereotaxic na nnabata nke ọgwụ ọgwụ DA n'ụzọ zuru ezu ebe ndị ọzọ (14).

Nnwale Omume.

E mere nnwale CPP dị ka akọwapụtara na mbụ (22) na ndị na-esoghị. Ekpebiri oghere nke mbụ maka isiokwu ọ bụla na 30-min pretest n'ụbọchị 1. Emeziri ihe dị iche iche, n'oge oge nkeji 40, ya na AMPH na ngịga na-abụghị nkọwapụta na saline ka enwere oghere (ma AMPH na inine intictions enyere n'otu ụbọchị, 6 h iche) maka ụbọchị 3 sochiri (ụbọchị 2 – 4). Mgbe nke ahụ gasiri, a nwalere isiokwu (posttest) maka ọnụnọ nke CPP na ụbọchị 5.

Emere nnwale mmasị ndị mmekọ dịka akọwara ha na mbụ (14). Na nkenke, ngwa nnwale mejupụtara oghere dị n'etiti (12 × 28 × 16 cm) jikọtara ọnụ na oghere oghere (7.5 × 16 cm) na oghere abụọ yiri ibe ha na-arụ ọrụ mkpuchi ụlọ nke ọ bụla ụlọ nwere anụmanụ na-akpali akpali. Anụmanụ na-akpali akpali bụ 'onye ibe' a na-ahụkarị (onye nwanyị nke isiokwu ahụ) na "onye ala ọzọ" (nwanyị na -ababeghị na mbụ) nke na-ekekọta n'ime akpa ha iche na-enweghị ibe ha. Na nnwale nke 3-h, a na-etinye okwu ndị ahụ n'ime ebe etiti ma nyekwa ha ohere ịgafe na ngwa niile. Edekọrịtara omume site na iji usoro ndekọ vidiyo oge gboo. Ndi okacha mara anya na mkpachapu a nyochachara teepu a na akuko omume edere. Ekwuputara onye mmekọ dịka ihe eji eme ka oge dị ukwuu na iji ya na onye ọlụlụ karịa nke ọ na-amaghị, dị ka ihe nlere na-ejikọta. t ule (27).

Na Ọnọdụ Hybridization na Western Immunoblotting.

Riboprobes na-egbu egbu (Isiokwu 1) Ejiri D1R, D2R, TH, na DAT na label mRNA label. Ejiri aha mmado mee ihe 35Ihe nyocha S-labeled na njikwa mRNA nke akara akara DA nke ọ bụla akọwapụtara na mbụ (51). Na nyocha nke iwepu ọdịda anyanwụ, ewepụtara protein DAR site na ike nke anụ ahụ NAcc ma wakpo ya dịka akọwara ya na mbụ (52).

Ntọala 1.

nyocha CDNA maka akara akara mRNA na ụbụrụ praịche vole

Nyocha data na nyocha.

Ihe nlele CPP na nke onye n’ebute n’onyinye mebere ya t ule. Ndi AN iche sitere na ndi ANOVA nyochaa akwukwo ndi di iche na ntunye onu na oge mbu nke 6. A na - esonye akara nke D1R na D2R mRNA na NAcc yana akara TH, DAT, na D2R mRNA na VTA site na sistemụ ihe onyonyo (NIH IMAGE 1.64). E gosiputara data dika mgbanwe pasent nke ihe ndị otu nnu nnu na - enyocha ihe dị iche site na nyocha t ule. N'ikpeazụ, ọnụọgụ ngwa anya nke D1R na D2R na-egosi na fim x-ray sitere na nyocha nkwụsịcha ọdịda anyanwụ. t ule.

Ihe nlere.

Nlere 1a guzobere usoro-nzaghachi usoro maka CPP na-eweta AMPH. Edebere isi ihe dị na ngwa CPP n’ụbọchị 1, ekenyeghị aka n’otu n’ime otu nnwale isii natara ip (ip) inje nke saline nwere nnukwu AMPH [0]n = 12), 0.1 (n = 8), 0.5 (n = 9), 1.0 (n = 12), 3.0 (n = 12), ma obu 5.0 mg / kg (n = 13)] n'oge ụbọchị 3 (ụbọchị 2 – 4) nke nhazi, wee nwalee maka CPP na posttest n'ụbọchị 5.

Nlere anya 1b kpughere ọrụ nke ndị na-anabata DA na CPP AMPH webatara. Ihe ndị dị na CPP na-edobe isi okwu ndị ọzọ ma kesaa ha n'onye otu n'ime nyocha asatọ natara ntụtụ sal (sc)n = 10) ma ọ bụ saline nwere ihe dị iche iche nke onye na-ekwenye ekwenye ekwenye ọgwụ antagonist [haloperidol; 0.1 (n = 8), 1.0 (n = 8), ma obu 5.0mg / kg (n = 8)], ma obu D1-dika nke doro anya (SCH23390; 0.5 (n = 7) ma ọ bụ 5.0 mg / kg (n = 7)] ma ọ bụ D2-dịka kpọmkwem DA receptor antagonist [eticlopride; 0.5 (n = 8) ma ọ bụ 5.0 mg / kg (n = 8)]. Mgbe nkeji iri atọ gachara, a ga-eji AMPH mee ihe ọ bụla (1.0mg / n'arọ), nke butere CPP na Ahụhụ 1a, maka ọnọdụ AMPH. Mgbe ụbọchị 3 nke ọnọdụ AMPH gasịrị, isiokwu niile natara CPP posttest.

Nlere 2 nyochara ma ahụmịhe AMPH gbochiri njikọrịta abụọ. A na-ekenye ndị nọ n’otu n’otu n’ime otu n’ime nyocha mmadụ atọ natara ọgwụ ịgba nke saline (n = 8) ma ọ bụ saline nwere 1.0 mg / kg (n = 8) ma ọ bụ 5.0 mg / kg (n = 7) AMPH otu ugboro kwa ụbọchị maka ụbọchị 3 dị otua - ihe atụ nke butere CPP na ọkwa nwoke. N'ụbọchị nke anọ, e jikọtara ọnụ nke nwanyị estrogen-primed maka 24 h (14) wee lelee ha na ule nyocha nke mmekọ nke 3-h. Iji chịkwaa nsonaazụ nke injections na njikọ nwoke, ìgwè nyocha nke anọ ụmụ nwoke na-anabataghị injections ọ bụla (n = 6) jikọtara ya na ụmụ nwanyị estrogen-primed maka 24 h wee nwalee maka nhọrọ mmekọ. Nyocha akparamagwa niile dị na teepu maka nyocha nke mating. E kwubiri na oge nke ihe ndị bịara na mkpakọrịta na onye ya na ya na onye ahụ bịara abịa amabughị. Na mgbakwunye, a na-agụta ugboro ugboro nke mkpakọ n'oge 6 h nke njikọta na ọrụ locomotor (nke a na-egosi site na ngagharị). Mgbe nnwale nyocha nke mmekọ, a gbagburu ndị mmadụ ozugbo. A na-egbute ụbụrụ niile, kpụkọrọ akpụkọ na ice kpụkọrọ akpụkọ, wee chekwaa na NUM3 Celsius C maka nke dị na akara hybridization nke DA marker mRNAs.

Nlere anya 3 nyochara ma AMPH nwere njikọ ejikọtara ọnụ na mgbanwe na ọrụ mesolimbic DA. Insbụrụ si na isiokwu natara saline (n = 8) ma ọ bụ 1.0 mg / kg AMPH (n = 8) na Nlere 2 e gbuara ha na cryostat na ngalaba coronal (14 μm ọkpụrụkpụ) nke na-ama jijiji n’elu akwa Superfrost / gbakwunyere na slides (Fisher Scientific). A haziri akụkụ ụbụrụ na oge 98-μm maka aharịrị hybridization nke D1R, D2R, TH, na DAT mRNA. N'ihi na voles nwere 1.0 mg / kg AMPH gosipụtara mmụba na D1R, mana ọ bụghị D2R, akara mRNA na NAcc, ma e jiri ya tụnyere njikwa nnu, nnupụtara abụọ ndị ọzọ nke isiokwu ndị natara injection nke saline (n = 6) ma ọ bụ 1.0 mg / kg AMPH (n = 6), 24 h nke mating, weezie nnwale nke mmekọ dị ka akọwara n’elu. Emebiri ihe ndi di iche iche wee kpuo ha nke oma na cryostat n'ogo 300 μm. A na-esite na ntanetị tissue punches na NAcc maka D1R na D2R Western hichapụ.

Nlere 4 nyochara ma rụọ ọrụ nke ndị nnabata ụdị D1 na NAcc bụ maka AMPH-imebi nke njikọ ọnụ. E tinyere ndumodu ndị nwere ntụzịaka cannulae bilaterally gbadoro ụkwụ na mkpo NAcc. Mgbe ụbọchị 3 gbakere, ekenyela ha n'enweghị otu n'ime otu nnwale atọ ha natara intra-NAcc injections nke CSF (200 nL / side, n = 11), ma ọ bụ CSF nwere 0.4 (n = 6) ma ọ bụ 100 ng / akụkụ (n = 7) SCH23390. Nkeji iri atọ ka nke ahụ gasịrị, ha natara injections nke 1.0 mg / kg AMPH. Emeghari usoro a maka ubochi ndi 3. N'ụbọchị nke anọ, ụmụ nwanyị na estrogen-primed jikọtara ọnụ maka 24 h wee nwalee maka mmasị onye mmekọ.

Nkweta

Ndị ode akwụkwọ na-ekele Kyle Gobrogge, Claudia Lieberwirth, Kelly Lei, na Melissa Martin maka ịgụcha ihe odide a. Enyemaka Ụlọ Ọrụ Na-ahụ Maka Ahụ Ike Mba MHR01-58616, DAR01-19627, na DAK02-23048 ruo ZW kwadoro ọrụ a.

Ihe odide ala

Ndị na-ede akwụkwọ ekwupụtaghị mmasị ọ bụla.

Isiokwu a bu PNAS Direct Submission.

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