Mmekọrịta mmekọrịta mmadụ na ibe ya na-ebelata uru nkwụghachi nke Amphetamine site na usoro D1 Receptor-Mediated Mechanism (2011)

J Neurosci. Ihe odide onye edemede; dị na PMC Dec 1, 2011.

E bipụtara na ụdị edetu ikpeazụ:

PMCID: PMC3114880

NIHMSID: NIHMS300918

Onye mbipụta akwụkwọ ikpeazụ edezi ederede a enwere n'efu na J Neurosci

Hụ ihe ndị ọzọ na PMC na ebe isiokwu e bipụtara.

Gaa:

nkịtị

Ọ bụ ezie na edekọwo mmetụta nchebe nke mmekọrịta mmadụ na ibelata ọgwụ ọjọọ / iji ọgwụ ọjọọ eme ihe, anyị amachaghị banyere usoro ọgbụgba nke akwara ozi. Iji prairie vole (Microtus ochrogaster--a na-elekọta mmadụ monogamous òké nke na-etolite ogologo oge ụzọ agbụ mgbe mmekọahụ-anyị na-egosi na amphetamine (AMPH) conditioning mere ka a conditioned ebe mmasị (CPP) na mmekọahụ naïve (SN), ma ọ bụghị ụzọ-boded (PB), ụmụ nwoke. Ọ bụ ezie na ọgwụgwọ AMPH kpalitere ụdị ntọhapụ DA yiri nke ahụ na nucleus accumbens (NAcc) nke ụmụ nwoke SN na PB, ọ nwere mmetụta dị iche iche na njikọ NAcc D1 (D1R). Kpọmkwem, ọgwụgwọ AMPH mụbara njikọ D1R na SN, mana belatara njikọ D1R na ụmụ nwoke PB. NAcc D1R, mana ọ bụghị D2R, mmegide egbochiri AMPH na-ebute CPP n'ime ụmụ nwoke SN yana NAcc D1R arụ ọrụ tupu ọnọdụ AMPH nyere AMPH aka CPP n'ime ụmụ nwoke PB. Ọnụ, data anyị na-egosi na ahụmihe njikọkọ abụọ na-ebelata njirimara AMPH na-akwụghachi ụgwọ site na usoro mgbasa ozi D1R.

OKWU

A maara nke ọma na iji ọgwụ ọjọọ eme ihe na iji ọgwụ eme ihe na-arụpụta nnukwu nsogbu na akparamagwa mmekọrịta dị iche iche, gụnyere nkekọ mmekọrịta (Na-eto eto et al., 2011a). N'otu aka ahụ, ihe ndị metụtara mmekọrịta, dị ka ọnụnọ ma ọ bụ enweghị njikọ mmekọrịta siri ike n'oge mmepe ma ọ bụ n'oge ọ bụ okenye, nwere ike imetụta iji ọgwụ ọjọọ eme ihe na adịghị ike nke ịṅụ ọgwụ ọjọọ. Dịka ọmụmaatụ, njikọ siri ike nke ndị nne na nna na-eto eto ejikọtawo na mbelata nke nsogbu iji ọgwụ eme ihe (Ellickson et al., 1999; Bell et al., 2000). Na mgbakwunye, n'ime ndị ahụ riri ahụ, ezigbo mmekọrịta dị n'etiti di na nwunye na-enyere aka napụta na ọgwụ riri ahụ (Kosten et al., 1987). N'ụzọ dị iche, njikọta mmekọrịta na-adịghị ike nwere ike ịbawanye nsogbu ị substanceụ ọgwụ ọjọọ n'ihi na ụdị ndị okenye na-ejikọtakarị n'ụzọ dị mma na mmanya na ị substanceụ ọgwụ ọjọọ.Brennan na Shaver, 1995; Vungkhanching et al., 2004; Caspers et al., 2005).

Usoro akwara na-akpata mmekọrịta dị n'etiti mmekọrịta mmadụ na ibe ya na iji ọgwụ eme ihe / iji ọgwụ eme ihe bụ nke amabeghị, agbanyeghị, usoro mesolimbic dopamine (DA) - ọkachasị DA neurotransmission n'ime nucleus accumbens (NAcc) - nwere ike itinye aka ((NAcc).Na-eto eto et al., 2011a). Mmụta dị na praịmarị vole (Microtus ochrogaster) —Ọbụ otu na-anọ n'otu mmekọrịta na-etisa n'etiti ibe nwoke na ụmụ okenye (ya bụ, ihe abụọ)Insel na Hulihan, 1995; Mattson et al., 2001) —Egosipụtara na NAcc DA na-ebunye ndị ọzọ ọnụ na imezi nkekọ abụọ (Gingrich et al., 2000; Aragona et al., 2003; Aragona et al., 2006). Ọzọkwa, NAcc DA neurotransmission na-eme ka ọgwụ niile a maara eme ihe na-eme ihe (Di Chiara na Imperato, 1988; Bergman et al., 1990; Koob na Nestler, 1997; Nestler, 2005) na ugboro ugboro ekpughere psychostimulant ọgwụ na-agbanwe DA ntọhapụ na nnabata uche yana ya morphology nke NAcc neurons (Henry et al., 1989; Robinson na Kolb, 1999). A na-eche na mgbanwe ndị a na-ebute mgbanwe ndị ọgwụ ọjọọ kpatara na akparamagwa (Robinson na Becker, 1986), gụnyere omume mmekọrịta mmadụ na ibe yaFiorino na Phillips, 1999).

Dị ka omume njikọ abụọ ahụ na iwu ya site na DA neurotransmission n'ime NAcc ka ejiri mara nke ọma na prairie vole (Gingrich et al., 2000; Aragona et al., 2003; Aragona et al., 2006), Emeela mbọ n'oge na-adịbeghị anya iji guzobe ụdị a dị ka ụdị anụmanụ iji nyochaa mmekọrịta omume dị n'etiti mmekọrịta mmadụ na ibe ya na iji ọgwụ eme ihe / iji ọgwụ eme ihe, yana usoro akwara ya dị n'okpuru. Egosiputara AMPH nwere akụrụngwa na-akwụghachi ụgwọ na prairie voles, ka AMPH conditioning na-ebute mmasị n'ọnọdụ nwere ọnọdụ (CPP) na nwoke na nwanyị abụọ.Aragona et al., 2007; Liu et al., 2010; Na-eto eto et al., 2011b), na usoro a bụ onye ogbugbo site na DA neurotransmission na NAcc (Curtis na Wang, 2007; Liu et al., 2010). Nke kachasị adọrọ mmasị, ikpughe AMPH ugboro ugboro na-egbochi guzobe mmasị ndị mmekọ na-eme ka nwoke na nwanyị prairie voles na mmebi nke AMPH na-akpata nke njikọta ụzọ abụọ na-achịkwa-opekata mpe akụkụ-site na NAcc DA D1 ụdị nnabata (D1R) (DXNUMXR).Liu et al., 2010). N'ime ọmụmụ ihe ugbu a, anyị nyochara nsonaazụ nke ahụmịhe njikọ abụọ na CPP butere AMPH. Anyị chere na ahụmịhe njikọta abụọ ga-ebelata nsonaazụ AMPH na-akwụghachi ụgwọ yana NAcc DA nwere ike itinye aka na omume omume a.

AKỤRỤNGWA NA ỤZỌ

Ndị isi

Ihe ndi ozo bu isi nwoke nke di (M. ochrogaster) site na ụlọ nyocha ụlọ nyocha. A napụrụ ndị mmadụ ara na ụbọchị 21 ma tinye ha n'otu ụzọ nwoke na nwanyị na-edina ụdị onwe n'ime oghere rọba (12 × 28 × 16 cm). E nyere mmiri na nri ad libitum. A na-edobe oghere niile n'okpuru okirikiri ọkụ-14:10 ma debe okpomọkụ na 20 Celsius. Ndị nọ n'ihe dị ka ụbọchị 75 ka ha na nwanne ha nwoke nwere mmekọahụ na-anọkọ n'ụlọ (ma si otú a na-enwe mmekọahụ (SN)) ma ọ bụ jikọta ya na nwanyị na-enweghị njikọ maka izu abụọ ka ọ bụrụ ihe jikọrọ (PB). A nwalere ma isiokwu SN na PB n'ihe dịka ụbọchị iri itoolu.

AMPH conditioning na ule CPP

Emere usoro ndị a dị ka akọwapụtara na mbụ (Liu et al., 2010; Na-eto eto et al., 2011b). Na nkenke, ngwa nyocha maka CPP nwere oghere abụọ (12 × 28 × 16 cm); otu oji nke nwere elu igwe na otu ọcha nke nwere ntupu n'elu, jikọtara ya na tube oghere (7.5 × 16 cm). Ọ bụ ezie na prairie voles n'ozuzu na-ahọrọ ndị ọcha karịa ọnụ ụlọ gbara ọchịchịrị (Aragona et al., 2007), enwere nnukwu ọdịiche dị n'otu n'otu na mmasị a. Ya mere, n'ụbọchị 1, anyị nwalere isiokwu niile maka mmasị mbụ ha n'oge ule 30 min. N'oge ule a, a na-ahapụ isiokwu niile ohere ịnweta oghere abụọ ahụ ma anyị gbakọọ oge ole onye ọ bụla nọrọ n'ime oghere ọ bụla. N'ụbọchị 2-4, isiokwu natara oge nhazi nkeji 40 abụọ, awa 6 dịpụrụ iche. Na nnọkọ ụtụtụ, isiokwu natara 1.0 mg / kg AMPH (Sigma, St. Louis, MO, USA) gbazere na 0.9% saline (SN-AMPH na PB-AMPH otu) ma ọ bụ saline naanị (SN-saline na PB-saline otu). ) ma tinye ya n'ime ọnụ ụlọ nke ha na-etinye obere oge n'oge ule tupu ule (njikwa conditioned). N'ime oge ehihie, a na-enye ihe niile dị n'okpuru mmiri ọgwụ ma tinye ya n'ime oghere ọzọ. N'ụbọchị 5, a nwalere isiokwu ndị ọzọ maka mmasị ụlọ n'ime nkeji 30 gachara ule. Ozugbo ule gasịrị, a na-ebipụ ihe ndị a na-achị ngwa ngwa na ụbụrụ ha jụrụ oyi na ice. E mechara hazie akụkụ ụbụrụ maka D1R na DA D2 ụdị nnabata (D2R) njide autoradiographic.

Microdialysis ụbụrụ na nyocha HPLC-ECD

Ejiri usoro nyocha Microdialysis dị ka akọwara na mbụ (Curtis na Wang, 2007) ma tinye ya na NAcc aka ekpe (nchịkọta stereotaxic sitere na bregma: anterior 2.1 mm, mpụta 0.6 mm, ventral 6.3 mm) n'okpuru sodium pentabarbitol anesthesia (1mg / 10kg arọ ahụ). E kwere ka ụmụ anụmanụ gbakee n'otu abalị wee nwalee n'ụtụtụ echi ya. A na-agbanye nyocha na-aga n'ihu na 2.3 µl / min na ngwọta isotonic maka sodium, potassium, calcium na magnesium (144 mM NaCl, 2.8 mM KCl, 1.2 mM CaCl2 na 0.9 mmMgCl2 (Sved na Curtis, 1993)).

Na-esochi mgbake n'otu abalị, a chịkọtara ihe nlele ndabere nkeji anọ 20 n'ime vials nwere 5µl nke 0.1N perchloric acid. Mgbe nke ahụ gasịrị, ndị mmadụ natara ọgwụ intraperitoneal (ip) nke AMPH (1.0mg / kg) na dialysate samples na-anakọta na-aga n'ihu na nkeji 20 nkeji maka awa 3. A na-ajụ oyi ozugbo na -80ºC ruo mgbe nyochachara ihe nlele dialysate. Achọpụtara ọnụọgụ DA na DOPAC na nlele ọ bụla site na iji chromatography mmiri na-arụ ọrụ dị elu yana nchọpụta electrochemical (HPLC-ECD) dị ka akọwara na mbụ (Curtis na Wang, 2007). N'ọgwụgwụ oge nlele ahụ, a chụrụ ihe ndị e ji amụ ihe iji nyochaa ntinye nyocha.

DA receptor autoradiography

A na-ahazi akụkụ ụbụrụ coronal (20 µm) na oge 120-µm maka njide DA receptor autoradiographic iji usoro guzosiri ike (Aragona et al., 2006). Na nkenke, a sachara akụkụ na 50 mM Tris-HCl (pH 7.4) wee tinye ya na 50 mM Tris-HCl ion buffer nwere 120 mM NaCl, 5 mM KCl, 2 mM CaCl.2 na 1 mmMgCl2 ya na obula [125I] SCH23982 (D1R ligand) ma ọ bụ [125I]2'-iodospiperone (D2R ligand) (PerkinElmer). Mgbe nke ahụ gasịrị, a na-edozi akụkụ na 0.1% paraformaldehyde ma sachaa ya nke ọma na Tris-HCl ion buffer. A na-etinye ihe mmịfe n'ime mmiri a gbanyere agbaze, fụọ nkụ wee kpughee na ihe nkiri BioMax MR (Kodak) iji mepụta autoradiograms. Agụpụtara njupụta anya nke D1R na D2R na NAcc na CP n'ime akụkụ ụbụrụ 3 dabara adabara maka anụmanụ ọ bụla site na autoradiograms site na iji mmemme onyonyo kọmputa (NIH IMAGE 1.64).

Stereotaxic cannulation na microinjection

Ejiri sodium pentobarbital na 26-nlele bilateral igwe anaghị agba nchara (Plastics One Inc., Roanoke, VA) stereotaxically etinyere na ebumnuche na NAcc, dị ka akọwara na mbụ.Aragona et al., 2003). A na-ahapụ ihe ndị ahụ ka ha gbakee maka ụbọchị 3-7. Na nke ọ bụla n'ime ụbọchị 3 nke oyi, 30 min tupu ịgbanye AMPH, ndị mmadụ natara microinjections nke ma ọ bụ mmiri cerebrospinal artificial (CSF; 200nl / akụkụ) ma ọ bụ CSF nwere D1R agonist, SKF 38393, D1R antagonist, SCH 23390, ma ọ bụ D2R antagonist, eticlopride (Sigma, St. Louis, OH). Mgbe ule CPP gasịrị, a na-ewepụ isi ihe niile ngwa ngwa ma wepụta ụbụrụ ha iji chọpụta ebe ịgba ọgwụ mgbochi ọrịa. Ewepụrụ ndị nwere cannulae na-ezighi ezi na nyocha data.

Ntụle data na nyocha ọnụọgụgụ

Ejiri ihe nlele jikọtara CPP t nwalee oge atụnyere oge ihe ọmụmụ nọrọ n'ụlọ nwere ntụ oyi n'etiti ule tupu na mgbe ule gasịrị. A tụlekwara ndenye ọnụ n'etiti ule mbụ na mgbe ule gasịrị site na a t nwalee iji chọpụta ma AMPH ma ọ bụ agonist D1R ma ọ bụ D1R ma ọ bụ D2R antagonist metụtara ọrụ locomotor. Atụnyere oke ndabere DA na DOPAC na dialysates n'etiti otu na-eji a t nwale. Maka ntule nke mmetụta AMPH n'ofe oge, ọnụọgụ DA na DOPAC na ntọala nke ọ bụla na ihe nlele post-AMPH ka egosipụtara dị ka pasent nke ego ntọala pụtara. A na-enyocha ụkpụrụ ndị a site na usoro ugboro ugboro ANOVA sochiri ule nwa akwụkwọ-Neuman-Keuls (SNK) posthoc. N'ikpeazụ, a na-enyocha ọdịiche otu dị na njupụta nke D1R na D2R na NAcc na CP site na ụzọ abụọ ANOVA na-esote ule SNK posthoc.

Nlekọta ahụmahụ

Emebere nnwale 1 iji kpughee nsonaazụ nke ahụmịhe njikọta abụọ na CPP butere AMPH. A nwalere ụmụ nwoke SN na PB n'ime ngwa CPP. E kewara ha n'ime ìgwè 4 natara injections nke saline (n = 5 maka SN na n = 9 maka ụmụ nwoke PB) ma ọ bụ AMPH (1.0mg / kg; n = 8 maka SN na n = 8 maka ụmụ nwoke PB) n'oge nhazi ụtụtụ. nnọkọ n'ime ụbọchị atọ na-esote (Liu et al., 2010). Mgbe nke ahụ gasịrị, isiokwu niile nwetara CPP n'ule nyocha.

Nnwale 2 tụnyere AMPH-induced DA ntọhapụ na NAcc n'etiti SN (n=6) na PB (n=5) ụmụ nwoke. Ejiri nyocha microdialysis tinye ihe ndị a na-achọ na NAcc. Mgbe mgbake abalị na-aga n'ihu nke ngwọta isotonic site na nyocha ahụ, a na-anakọta ihe nlele dialysate baseline 20 min 1.0. Mgbe nke ahụ gasịrị, ndị mmadụ natara ip nke AMPH (20mg/kg) na dialysate samples na-aga n'ihu na-anakọta kwa 3 mins maka 3,4 awa. A na-enyocha ihe nlele ndị a maka DA na XNUMX-Dihydroxyphenylacetic acid (DOPAC) site na iji nyocha HPLC-ECD (Curtis na Wang, 2007).

Nnwale 3 nyochara mmetụta nke mmekọrịta dị n'etiti njikọ abụọ na ọgwụgwọ AMPH na njikọ DA receptor na NAcc. A na-ahazi akụkụ ụbụrụ sitere na isiokwu ndị a nwalere na nnwale 1 maka njide D1R na D2R site na iji autoradiography nke nnabata.

Nnwale 4 nwalere ọrụ nke ndị na-anabata NAcc DA na AMPH na-ebute CPP. Akụnyere ụmụ nwoke SN na cannulae ndu nke ejiri ụzọ abụọ gbadoro anya na NAcc. Mgbe mgbake 3 d gasịrị, isiokwu natara CPP tupu ule wee kenye ya na-enweghị usoro n'ime otu n'ime otu nnwale 5 natara intra-NAcc injections nke CSF (n = 8) ma ọ bụ CSF nwere obere (4ng / akụkụ; n = 8). ) ma ọ bụ elu (100ng / akụkụ; n = 6) dose nke D1R antagonist, SCH 23390, ma ọ bụ dị ala (4ng / akụkụ; n = 8) ma ọ bụ elu (100ng / akụkụ; n = 7) dose nke onye na-emegide D2R, eticlopride. N'ime nkeji iri atọ ka e mesịrị, ndị mmadụ natara ọgwụ AMPH (1.0mg/kg; ip). Emeghachiri usoro a maka ụbọchị atọ n'usoro n'oge nhazi AMPH. Mgbe nke ahụ gasịrị, isiokwu nwetara CPP ule nleba anya.

Nnwale 5 nyochara ọrụ NAcc D1R na-agbazite CPP na-ebute AMPH n'ime ụmụ nwoke PB. E kewara ihe ndị PB n'ime otu atọ natara intra-NAcc injections nke CSF (n = 10) ma ọ bụ CSF nwere D1R agonist, SKF 38393 (0.4ng / akụkụ; n = 12), ma ọ bụ D1R antagonist, SCH 23390 (4ng/ akụkụ, n=10), tupu ntụnye AMPH. Mkpọ ụbụrụ ụbụrụ, injections AMPH, na ule CPP bụ otu ka akọwara na Nnwale 4.

IHE

Ahụmịhe njikọta ụzọ abụọ na-ebelata njirimara AMPH na-akwụghachi ụgwọ

N'ime ọmụmụ ihe anyị gara aga, ọgwụgwọ AMPH na-emebi mmasị onye mmekọ na-eme ka nwoke na nwanyị prairie voles, na-egosi mmetụta mgbochi nke ikpughe AMPH na omume njikọta abụọ (Liu et al., 2010). N'ime ọmụmụ ihe dị ugbu a, anyị nwalere njikọta mmekọrita: nsonaazụ nke ahụmịkọ njikọ ọnụ na ụgwọ ọrụ AMPH. Daysbọchị atọ nke 1.0 mg / kg AMPH butere CPP na ụmụ nwoke SN (t = 2.45, p <0.05) ma obughi nwoke nke ejikọtara ya na nwanyi rue izu 2 (yabụ, ụmụ nwoke PB) (Nyocha 1a). Ngwunye saline enweghị mmetụta na otu ọ bụla. N'ụzọ dị mkpa, ọ dịghị ihe dị iche iche a hụrụ na ugboro ole nke oghere anụ ọhịa na-agafe n'etiti ule mbụ na mgbe ule gasịrị, na-atụ aro na CPP nwere nkwarụ na ụmụ nwoke PB abụghị n'ihi mgbanwe mgbanwe nke locomotor n'oge ule omume.Nyocha 1b).

Nyocha 1  

Amphetamine (AMPH) ntụ oyi na-ebute mmasị n'ọnọdụ nwere ọnọdụ (CPP) na agụụ mmekọahụ (SN) mana ọ bụghị ihe jikọrọ ọnụ (PB) nke nwoke prairie voles. (a) SN ma ọ bụ PB ụmụ nwoke natara saline (SN-saline ma ọ bụ PB-saline, n'otu n'otu) n'ime ụbọchị 3 nke nhazi. ...

Usoro ọgwụgwọ AMPH na-eme ka mwepụta DA na NAcc ma ụmụ nwoke SN ma PB

Enweghị nnukwu ọdịiche dị n'etiti ụmụ nwoke SN na PB n'ụzọ zuru oke nke DA ma ọ bụ DOPAC n'omume usoro ihe omimi microdialysis (Nyocha 2, insets). Nlekọta AMPH mepụtara mmụba dị ukwuu na extracellular DA (F(12, 108) = 8.42, p <0.001). Otú ọ dị, ịdị ukwuu na oge nke mmụba ndị a adịghị iche n'etiti ụmụ nwoke SN na PB-DAdị ọkwa dị elu karịa ọkwa dị na abụọ maka nke ọ bụla n'ime oge nlele abụọ mbụ (40 min ngụkọta) wee jiri nwayọ laghachi na ntọala (Nyocha 2, n'elu panel). Nlekọta AMPH belatara nke ukwuu DOPAC extracellular na NAcc n'ime ụmụ nwoke SN na PB (F(12, 108) = 13.54, p <0.001) na, ọzọ, mmetụta ndị a yiri na otu abụọ ahụ. Ma ụmụ nwoke SN ma ọ bụ PB enwetaghachila ọkwa mmalite tupu njedebe nke nlele (Nyocha 2, obere panel).

Nyocha 2  

Ọkwa nke extracellular dopamine (DA) na 3,4-Dihydroxyphenylacetic acid (DOPAC) na nucleus accumbens (NAcc) nke agụụ mmekọahụ (SN) na ụmụ nwoke jikọtara (PB) na-eso ọgwụgwọ amphetamine. Ọnụ ego DA na DOPAC zuru oke na dialysates ntọala ...

Usoro ọgwụgwọ AMPH dị iche na-agbanwe ihe jikọrọ D1R na NAcc nke SN na ụmụ nwoke PB

Ọmụmụ ihe ọmụmụ gara aga gosipụtara na ọgwụgwọ AMPH na-eme ka nrịpụta mkpụrụ ndụ NAcc D1R na nkwupụta protein (Liu et al., 2010). Na mgbakwunye, ahụmịhe njikọta abụọ na-ebuli njide D1R (Aragona et al., 2006) na NAcc nke nwoke prairie voles. Ya mere, anyị jiri echiche chegharịrị na mgbanwe na DA na-agbakọta na NAcc nwere ike ime ka mmekọrịta dị n'etiti njikọta ọnụ na ụgwọ ọrụ AMPH. Anyị haziri ngalaba akụkụ ụbụrụ site na isiokwu ejiri na ule CPP maka njikọta ihe nnabata autoradiographic DA. Nyocha ụzọ ANOVA abụọ gosipụtara mmekọrịta dị ukwuu n'etiti ahụmịhe mmekọrịta (SN ma ọ bụ PB) na ụdị ntụtụ (saline ma ọ bụ AMPH) na ntinye D1R na NAcc (F(1, 29) = 17.63, p 0.01). Nnwale posthoc ahụ gosipụtara na njupụta nke D1R na-ejikọta na NAcc nke SN-AMPH na PB-saline dị iche iche ma dị elu karịa nke SN-saline na PB-AMPH.Nyocha 3a). Ma ọgwụgwọ AMPH ma ọ bụ ahụmịhe njikọta abụọ gbanwere njupụta nke njikọ D2R na NAcc (Nyocha 3b). Na mgbakwunye, ọnweghị ndịiche otu ahụrụ na njikọ D1R ma ọ bụ D2R na caudate putamen (anaghị egosi data).

Nyocha 3  

Njikọ abụọ na AMPH na-emekọrịta ihe iji metụta njikọ nnata DA. (a) AMPH conditioning mụbara njupụta nke NAcc D1R na ụmụ nwoke SN (SN-AMPH), ma e jiri ya tụnyere njikwa injected saline (SN-saline). Otú ọ dị, a gbanyere ụmụ nwoke PB saline ...

Nrụpụta ọrụ NAcc D1R na-agbazi ụgwọ ọrụ AMPH na ụmụ nwoke SN

N'ime ụmụ nwoke prairie voles, injections dị n'okpuru nke D1R, mana ọbụghị D2R, onye na-emegide ihe tupu oge mmemme AMPH kpochapụrụ CPP AMPH na-eweta.Liu et al., 2010). Nyere nguzosi ike nke NAcc DA na ugwo AMPH na umu anumanu ndi ozo (Yokel na Amamihe, 1975; Kehoe et al., 1996), anyị chere na ịnweta D1Rs na NAcc n'oge nhazi dị mkpa maka AMPH na-ebute CPP na SN male prairie voles. Anyị chọpụtara na ụmụ nwoke SN natara injections cerebrospinal fluid (CSF) n'ime NAcc gosipụtara CPP nke AMPH kpatara (t = 2.90, p <0.01) (Nyocha 4). Otú ọ dị, nchịkwa intra-NAcc nke onye na-emegide D1R, SCH 23390, ma ọ bụ obere (4 ng / akụkụ) ma ọ bụ elu (100 ng / akụkụ) dose tupu oge nhazi, kpochapụ AMPH na-ebute CPP (Nyocha 4). N'ụzọ dị iche, nchịkwa intra-NAcc nke onye na-emegide D2R, eticlopride, ma ọ dị ala (4 ng / n'akụkụ; t = 3.25, p <0.01) ma ọ bụ elu (100 ng / n'akụkụ; t = 2.30, p <0.05) dose, egbochighị CPP nke AMPH kpatara (Nyocha 4). Achọpụtaghị ihe dị iche na ugboro ugboro nke obe cross n'etiti ule mbụ na post-ule na otu ọ bụla, na-egosi enweghị mmetụta ọgwụgwọ na ọrụ locomotor (data egosighi).

Nyocha 4  

Ntinye aka nke NAcc DA D1-ụdị (D1R) na ụdị D2 (D2R) ndị na-anabata ya na AMPH na-ebute CPP na agụụ mmekọahụ nwoke prairie voles. Isiokwu niile natara AMPH n'oge nhazi oyi. Na nke ọ bụla n'ime ụbọchị 3 nke ntụ oyi, nkeji 30 tupu AMPH ...

Mgbapụta nke D1Rs na NAcc na-enyere CPP aka ike AMPH n'ime ụmụ nwoke PB

Ọmụmụ ihe gara aga egosila na ịgbalite NAcc D1R dị mkpa maka AMPH na-ebute CPP na iwe iwe, na-emebi nhazi mmasị ndị mmekọ na nwoke prairie voles.Aragona et al., 2006; Liu et al., 2010). Nyere ọrụ nke D1Rs n'omume ndị ahụ na ịchọpụta na ntinye NAcc D1R dị ala na ụmụ nwoke PB-AMPH karịa na PB-saline na ụmụ nwoke SN-AMPH (Nyocha 3a), anyị chere na mbelata ọrụ D1R na NAcc nwere ike bụrụ ihe kpatara enweghị CPP na-ebute AMPH na ụmụ nwoke PB. Iji nwalee echiche a, anyị gbara CSF ma ọ bụ CSF nwere D1R agonist ma ọ bụ saịtị antagonist-kpọmkwem n'ime NAcc tupu nke ọ bụla n'ime oge nhazi atọ wee nwalee maka ọnụnọ AMPH na-ebute CPP. Dị ka a tụrụ anya ya, ụmụ nwoke PB natara injections CSF egosighi CPP nke AMPH kpatara (Nyocha 5). Agbanyeghị, ụmụ nwoke PB natara inje-NAcc injections nke agonist D1R (t = 4.69, p <0.001), ma obughi onye na-emegide ya, gosipụtara CPP nke nwere AMPH (Nyocha 5). Enweghị ọdịiche dị na ugboro ole nke obe n'etiti ule tupu na nyocha maka otu ọ bụla (egosighị data).

Nyocha 5  

Ịkwalite ụdị DA D1 ụdị nnabata (D1R) na NAcc na-enyere AMPH aka CPP n'ime ụzọ abụọ jikọtara ọnụ nke prairie voles. Ejikọrịrị isiokwu niile wee nata AMPH n'oge oge nhazi. Na nke ọ bụla n'ime ụbọchị 3 nke ntụ oyi, nkeji 30 tupu AMPH ...

NKWASỊTA

Mmụta na ụmụ mmadụ na ụdị anụmanụ egosipụtawo mmekọrịta siri ike n'etiti iji ọgwụ ọjọọ / mmegbu na omume mmekọrịta mmadụ na ibe ya.Na-eto eto et al., 2011a). N'ihi ọrụ a maara nke ọma na ọgbọ nke omume mkpali, usoro mesolimbic DA nọ n'ọnọdụ dị mkpa iji dozie mmekọrịta dị n'etiti ọgwụ ọjọọ na omume ọha mmadụ. Anyị egosipụtala n'oge na-adịbeghị anya na mkpughe ugboro ugboro na AMPH na-emebi njikọ njikọ abụọ na prairie voles na NAcc DA na-edozi mmetụta a (Liu et al., 2010). N'ime ọmụmụ ihe ugbu a, anyị na-egosi na ahụmihe njikọkọ abụọ na-emebi CPP AMPH na-akpata yana NAcc DA na-akwadokwa mmetụta a. N'ịchịkọta ọnụ, ọmụmụ ihe ndị a na-egosi mmekọrịta dị n'etiti njikọ abụọ na ụgwọ ọrụ AMPH ma na-atụ aro ọrụ maka NAcc DA n'ịhazi mmekọrịta dị otú ahụ.

N'ime ọmụmụ ihe ugbu a, anyị jiri usoro CPP guzobere na mbụ (Liu et al., 2010; Na-eto eto et al., 2011b) iji nyochaa mmetụta nke ahụmịhe njikọta abụọ na njirimara AMPH na-akwụghachi ụgwọ. Anyị na-eji okwu na-edoghị anya 'ihe na-akwụghachi ụgwọ' iji kọwaa mmetụta AMPH na nhazi ọnọdụ n'ihi na ọ na-enye anyị ohere ikwu okwu n'otu oge n'otu oge ahụ akụkụ nke ụgwọ ọrụ-gụnyere hedonics, mmụta mmekọrịta, na mkpali mkpali.Berridge na Robinson, 2003) —Gịnị ka a pụtara na usoro a na-ahụ n'okpuru ebe obibiHnasko et al., 2005; White et al., 2005; Cunningham na Patel, 2007), na-enweghị ọdịiche dị n'etiti ha. Nsonaazụ anyị na-egosi na ntụnye AMPH butere CPP na SN, mana ọ bụghị PB, voles nwoke, ya mere, na-enye ihe akaebe izizi na ahụmịhe njikọkọ ọnụ na-ebelata uru na-akwụghachi ụgwọ nke AMPH. Ọ bụ ezie na nke a bụ naanị ọmụmụ iji nyochaa mmetụta nke ahụmahụ njikọ abụọ na-enye ụgwọ ọrụ nke ọgwụ ọjọọ eme ihe, nchọpụta gara aga egosila na ahụmahụ/ihe ndị ọzọ na-elekọta mmadụ nwekwara ike imetụta ụgwọ ọrụ ọgwụ. Dịka ọmụmaatụ, oke ndị a zụlitere na ọtụtụ ndị otu na-elekọta onwe ha na-elekọta obere AMPH (Bardo et al., 2001) na cocaine (Schenk et al., 1987) ugboro ugboro karịa oke na-azụ naanị. N’otu aka ahụ, oke na etolite na gburugburu ebe ihe mara mma nke nwere ihe ọhụụ na njikọta mmekọrịta mmadụ na ibe ya nwere AMPH dị ala, kpochapụ omume nchịkwa onwe onye na oge adịghị anya, na achọrọ oke AMPH dị elu iji nwetaghachi ọgwụ na-achọ ọgwụ karịa oke a na-etinye naanị ya.Bardo et al., 2001; Green et al., 2002; Uzo ije et al., 2006; cf, Schenk et al., 1988; Bardo et al., 1995). Dika ozo, umu azum umu nwanyi zuliri ighaa ahihia cocaine gosiri na azịza ha pere mpe mgbe ha tụụrụ ime ma soso mmuo.Hecht et al., 1999), na-atụ aro na usoro omumu na mgbanwe neurobiological metụtara ahụmịja nwa nwere ike belata akụrụngwa na-agba ume nke cocaine. Nkwado a gosiri na oke ụmụ oke na-amaghị nwoke họọrọ mpaghara metụtara cocaine ma kọwapụta CPP na-eweta ka ọ dị mfe (Seip et al., 2008), ebe ịdọ mmiri mmiri agbadoro agbadobere mpaghara metụtara pọmpụ karịa ihe metụtara cocaine.Mattson et al., 2001). Ọnụ, ọmụmụ ihe ndị a na-egosi na ihe gbasara mmekọrịta mmadụ na ibe ya nwere ike ibelata njirimara na-akwụghachi ụgwọ nke psychostimulants. Nsonaazụ anyị na-agbatị nchoputa ndị a wee gosi na ahụmihe njikọkọ abụọ na-emebi ụgwọ ọrụ AMPH na prairie voles.

Ngwongwo na-akwụghachi ụgwọ nke ọgwụ psychostimulant nke mmetọ, dị ka AMPH, dabere na mmụba nke ọgwụ na-akpata na mwepụta NAcc DA na ntinye nke ndị nnata DA na-esote.Yokel na Amamihe, 1975; Di Chiara na Imperato, 1988; Bergman et al., 1990; Kehoe et al., 1996). Ya mere, mgbanwe na nke ọ bụla n'ime ihe ndị a nwere ike ịkpata mmetụta nke ahụmahụ njikọ abụọ na ụgwọ ọrụ AMPH. Ejikọtala ọkwa nke DA ewepụtara chiri anya yana mmetụta dị mma nke ọgwụ ọjọọ eme ihe (Volkow et al., 1999; Drevets et al., 2001; Leyton, 2010) na ntọhapụ NAcc DA na-akpata psychostimulant agbanweela site na ahụmịhe ọha na eze n'ọnọdụ ụfọdụ (dịka ọmụmaatụ, ikewapụ n'oge ndụ: (Kehoe et al., 1996; Kosten et al., 2005)), ma ọ bụghị ndị ọzọ (dịka ọmụmaatụ, ụlọ obibi bara ụba): (Bardo et al., 1995)). N'ime ọmụmụ ihe ugbu a, ọgwụgwọ AMPH mụbara ọkwa nke extracellular DA na NAcc, nke kwekọrọ na akụkọ ndị gara aga (Di Chiara na Imperato, 1988; Curtis na Wang, 2007; McKittrick na Abercrombie, 2007). Ọzọkwa, AMPH butere mgbada nke ọ bụla na ogologo oge na DOPAC extracellular dị n’otu abụọ ahụ. Nchọpụta a kwekọrọ na nke ọmụmụ gara aga na ọrụ a maara AMPH na mgbochi nke monoamine oxidase — enzyme nke gụnyere mbibi nke DA (Green na el Hait, 1978; Jones et al., 1998; Curtis na Wang, 2007). N'okwu abụọ ahụ, ịdị ukwuu na oge nke mgbanwe mgbanwe extracellular na NAcc bụ ihe dị n'etiti ụmụ nwoke SN na ụmụ nwoke PB, na-atụ aro na ọ bụ enweghị ike na nsonaazụ nke njikọta na ụgwọ ọrụ AMPH metụtara ntọhapụ ma ọ bụ metabolism nke NAcc DA.

Ọ bụ ezie na ahụmịhe njikọ abụọ emetụtaghị AMPH-induced DA ntọhapụ ma ọ bụ metabolism, ọ metụtara mmetụta AMPH na njikọ NAcc DA nnabata (ya bụ, nkwupụta nnabata DA na/ma ọ bụ mmekọrịta). Dịka ọmụmaatụ, kwekọrọ na ọmụmụ ihe gara aga, ọgwụgwọ AMPH mụbara okwu NAcc D1R na ụmụ nwoke SN (Liu et al., 2010) na ahụmịhe njikọkọ abụọ kwalitekwara njikọ NAcc D1R (Aragona et al., 2006). Otú ọ dị, mmetụta AMPH na njikọ NAcc D1R gbanwere na ụmụ nwoke PB ma e jiri ya tụnyere ụmụ nwoke SN, dịka ụmụ nwoke PB gosipụtara mbelata dị ukwuu na njide D1R na-esote ọgwụgwọ AMPH. Enweghị ọdịiche otu ahụrụ na njikọ NAcc D2R na ọmụmụ ugbu a ma ọ bụ nke gara aga (Aragona et al., 2006; Liu et al., 2010). Ọnụọgụ data ndị a na-egosi na ahụmihe njikọkọ na mkpughe AMPH nke ọ bụla na-eduga na mgbanwe D1R akọwapụtara n'ime NAcc nke ụmụ nwoke SN. Ọzọkwa, dị ka AMPH na-emetụta NAcc D1R na-ejikọta na SN na PB voles, data anyị na-egosi na mmekọrịta mmadụ na ibe ya nwere ike ịbụ ihe dị mkpa mgbasa ozi na mmetụta AMPH na usoro mesolimbic DA. N'otu aka ahụ, achọpụtara cocaine ka ọ na-ebute mgbanwe nrịbama ọbara-oxygen-level-based (BOLD) na-agbanwe agbanwe n'ime usoro mesolimbic DA na ụmụ nwanyị na-amaghị nwoke, ma nzaghachi BOLD na-adịghị mma na mmiri mmiri na-enye nwa ara, dị ka atụpụtara site na onyonyo resonance magnet na-arụ ọrụ.Ferris et al., 2005) - na-egosikwa na ahụmahụ mmekọrịta mmadụ na ibe / mmekọahụ nwere ike ịrụ ọrụ dị mkpa na nzaghachi neurobiological na ọgwụ ọjọọ. Mgbanwe na njide nnabata, dị ka ndị akọwara n'elu, nwere ike inwe mmetụta dị ukwuu na omume n'ihi na ha na-agbanwe nzaghachi ụbụrụ na-anabata ndị neurotransmitters wepụtara. N'ime ụmụ nwoke SN, dịka ọmụmaatụ, mmụba AMPH na-abawanye na njide D1R nwere ike ịrụ ọrụ dị mkpa n'oge ọnọdụ AMPH dị ka mgbochi intra-NAcc nke D1R, ma ọ bụghị D2R, na-egbochi AMPH-induced CPP-nchọta kwekọrọ na ndị dị na ụdị ndị ọzọ.Baker et al., 1998; Pitchers et al., 2010). N'ihi ya, n'ime ụmụ nwoke PB, mbelata NAcc D1R njikọ nwere ike ime ka enweghị AMPH na-ebute CPP dị ka NAcc D1R na-arụ ọrụ n'oge AMPH kwadoro CPP na-ebute AMPH n'ime ụmụ nwoke PB. Na mkpokọta, data ndị a na-egosi na mbelata AMPH na-akpata na NAcc D1R nkwupụta / mmekọ nwere ike bute nsonaazụ nke ahụmịhe njikọta abụọ na ụgwọ ọrụ AMPH.

Ihe abụọ na-adọrọ mmasị dị n'etiti nchọpụta anyị na ndị sitere na nchọpụta ndị ọzọ nke nyochaworo mmekọrịta dị n'etiti ọgwụ ọjọọ na omume ọha mmadụ kwesịrị ịkọ. Nke mbụ, njikọta ụzọ abụọ na mkpughe AMPH ugboro ugboro nke ọ bụla n'onwe ya rụpụtara mgbanwe ndị yiri ya na mesolimbic DA nke ụmụ nwoke prairie voles (ya bụ nkwalite D1R njikọ).Aragona et al., 2006) na okwu (Liu et al., 2010) na NAcc). N'otu aka ahụ, ahụmahụ mmekọahụ na ikpughe ugboro ugboro na psychostimulants ọ bụla mụbara njupụta nke spines dendritic na ọkara spiny neurons n'ime NAcc shei na oke.Robinson na Kolb, 1999; Pitchers et al., 2010). Ọzọkwa, pup na-ackụ ara maka mgbochi mmiri na nchịkwa cocaine na ụmụ nwanyị na-amaghị nwoke mere ka ụdị ihe a dị mma na-arụ ọrụ BOLD na usoro mesocorticolimbic (Ferris et al., 2005). Ọnụọgụ data ndị a na-akwado echiche na ọgwụ ọjọọ na-eji usoro akwara ozi na sekit na-emezi omume mgbanwe (Panksepp et al., 2002). Nke abuo, data anyi na-egosi na nzaghachi neurobiological di iche na AMPH na ndi nwoke SN na PB nwere ike mebie esemokwu otu na omume AMPH. N'otu aka ahụ, oke ndị na-enye nwa ara gosipụtara nkwụsị nke ọrụ n'ime usoro mesocorticolimbic DA na nzaghachi cocaine (na-emegide mmụba nke ọrụ a chọpụtara na ụmụ nwanyị na-amaghị nwoke) (Ferris et al., 2005) na mbelata na nchịkwa onwe cocaine (Hecht et al., 1999), na-akwado echiche ahụ na mgbanwe mgbanwe anụ ahụ metụtara na mmekọrịta mmadụ na ibe ya nwere ike ime ka ọnụọgụ nke ọgwụ ọjọọ eme ihe na-akwụghachi ụgwọ.

Ọnụnọ nke njikọta mmekọrịta siri ike n'oge mmadụ toro eto nwere ike belata mmerụ ahụ maka ị (ụ ọgwụ ọjọọ (Kosten et al., 1987). Otú ọ dị, usoro akwara ozi na-akpata ihe omume omume a bụ ihe a na-amaghị ama-ikekwe n'ihi enweghị ụdị anụmanụ kwesịrị ekwesị. N'ime ọmụmụ ihe ugbu a, anyị guzobere prairie vole dị ka ihe atụ anụmanụ iji nyochaa usoro akwara ozi na-akpata mmetụta nchebe nke mmekọrịta ọha na eze ndị okenye na adịghị ike nke ịṅụ ọgwụ ọjọọ. Nchọpụta anyị na-egosi na ahụmihe njikọkọ abụọ na-ebelata uru na-akwụghachi ụgwọ nke AMPH yana na sistemụ mesolimbic DA — ọkachasị DA neurotransmission na NAcc — na-ebute mmetụta a. Nchọpụta ndị a, yana ndị sitere na ọmụmụ anyị gara aga (Liu et al., 2010), tọọ ntọala maka nchọpụta ọdịnihu nke usoro akwara ndị dị n'okpuru mmekọrịta dị n'etiti ị betweenụ ọgwụ ọjọọ / mmetọ na njikọta mmekọrịta, nke nwere ike ị nweta nghọta dị mkpa banyere mgbochi ma ọ bụ ọgwụgwọ nke iji ọgwụ ọjọọ eme ihe.

Acknowledgements

Anyị na-ekele Claudia Lieberwirth, Kelly Lei, Melissa Martin na Adam Smith maka ọgụgụ isi ha na-agụ ihe odide a. N'ịgbakwụnye, anyị na-ekele Terry E. Robinson maka ịgụpụta ihe odide mbụ nke ihe odide a na maka ịnye aro ya bara uru. Ụlọ ọrụ ahụike mba kwadoro ọrụ a DAF31-25570 nye KAY, HDR01-48462 ruo JTC, na DAR01-19627, DAK02-23048, na MHR01-58616 nye ZXW.

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