Ka hopena o ka hōʻike o ka ΔFosB ma ka opioid a me ka cannabinoid pūnaewele i hoʻokomoʻia ma ka hōʻailona maha (2011)

ʻO Neuropharmacology. 2011 Dec;61(8):1470-6. doi: 10.1016/j.neuropharm.2011.08.046.

ʻO Sim-Selley LJ, Kāleka Cassidy, Sparta A, Zachariou V, Nestler EJ, Selley DE.

kahi

Ke Keʻena Hana Hana Hana'Āina a me ka Hoʻonaʻauaoʻokoʻa a me ka Institute for Drug and Alcohol Studies, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.

Hōʻuluʻulu Manaʻo

Ke hoʻokomoʻia ka mea helu hoʻokolohua ΔFosB i loko o ke kalapila (NAc) ma muli o ka hōʻike pinepineʻana i kekahi mau lāʻau hōʻino wale, a me ka'ōlelo transgenic o ka ΔFosB i ka striatum e hoʻonui i nā waiwai maikaʻi o morphine a me ka cocaine. Eia naʻe,ʻaʻole i hoʻomaopopo maopopoʻia nā kumu hana o kēia mauʻike. Ua hoʻohana mākou i keʻano o ka mouse bitransgenic me ka hoʻonāukiuki o ka ΔFosB i loko dopamine D (1) receptor / dynorphin-i loko o nā neuronsʻonika no ka hoʻoholo i ka hopena o ka'ōlelo ΔFosB ma ka'āpana opioid a me ka cannabinoid e kuhikuhi ana ma ka NAC. Nā hualoaʻa hōʻikeʻia ua hoʻonuiʻia ka hana G-protein a me ka hanaʻole o adenylyl cyclase ma ka NAC o nāʻiole i hōʻikeʻia i ka ΔFosB. Pēlā nō, ua hoʻonuiʻia ka kappa opioid hana a adenylyl cyclase i kaʻiole ΔFosB e hōʻike ana i nāʻiole. I ka hoʻohālikeʻana,ʻaʻole i hoʻokaʻawaleʻia ka hōʻailona hōʻailona cannabinoid hōʻailona ma waena o nā mice overexpressing ΔFosB a me nāʻiole mana. Tʻike nā hopena e hōʻike ana heʻano hoʻohālikelike ka opioid a me ka hōʻailona cannabinoid i ka hōʻikeʻana o ka ΔFosB, a hōʻike i ka hua'ōlelo o ka ΔFosB e hiki ke hoʻopuka i kekahi o kona mau hopena ma o ka hoʻonuiʻiaʻana o ka mu a me ka kappa optioid receptive e kuhikuhi ana i ka NAc.

Keywords: G-protein, adenylyl cyclase, striatum
E hele:

1. Introduction

ʻO nā mea loaʻa o ka Opioid a me ka cannabinoid CB1 nā kelike (CB1R) nā pahuhopu neurobiological no nā papa hana lāʻau laulā maʻamau i loaʻa nā morphine, heroin a me nā opioids i kauohaʻia a me ka mariuana (Δ9-tetrahydrocannabinol (THC)), kēlā me kēia. ʻO nā hopena nui o nā opioids a me nā cannabino e pāpāluaʻia e nā mea hōʻiliʻili G-protein a me nā kinikini i hoʻohuiʻia e hoʻomaka mua i Gi / o nā pale a hoʻoulu i nā hopena hana kūlohelohe e like me ke kāpaeʻana o adenylyl cyclase (Kidsers, 1991, Childers, et al., 1992, Howlett, et al., 2002). ʻO ka motuka, ka hoʻopiliʻana i ka hoʻomanaʻo a me nā hopena ahana o ka Δ9Hoʻonohoʻia e ka CB1R (Huestis, et al., 2001, Zimmer, et al., 1999), i hoʻonui mauʻia i ka lolo, me nā kiʻekiʻe kiʻekiʻe ma nā ganglia basal, hippocampus a me cerebellum (Herkenham, et al., 1991). ʻO nā hana analgesic a me nā mea maikaʻi o ka maikaʻi o ka lāʻau opioid kūpono a me ka hoʻohanaʻinoʻia i keʻano o nā'ōpili opioid (MOR)Matthes, et al., 1996), i hoʻonuiʻia i ka lāʻau limbic a me ka lolo (Mansour, et al., 1994). ʻO ka'ōpana mesolimbic, i hoʻonohonohoʻia me nā hanana dopamineric mai ka'āpana hoʻokipa o ke keʻena (VTA) i ka nucleus accumbens (NAc), he hapa nui i ka hopena maikaʻi o nā opioids a me nā cannabino (ʻO Bozarth a me ka Mea Hoʻonaʻauao, 1984, Vaccarino, et al., 1985, Zangen, et al., 2006), a me nā lāʻau lapaʻau lāʻau'ē aʻe (ʻO Koob a me Volkow, 2010). Eia kekahi, pili nā opioid a me nā pūnaepa cannabinoid i nā hopena maikaʻi o nāʻano he nui o nā lāʻau lapaʻauʻona (Maldonado, et al., 2006, Trigo, et al., 2010). No laila, he mea nui e hoʻolālā i nā mechanical e ka opioid a me CB1Hāʻawiʻia ka hōʻailona R ma ka NAc.

ʻO ka nīnau nui i ka lāʻau lapaʻau lāʻau,ʻo ia ka hōʻoiaʻana i nā palekana e pale i ka hoʻololi mai kahi'ākea i nā hopena lōʻihi o nā lāʻau lapaʻau. ʻO ka mea helu hoʻonaʻauao AP-1 ΔFosB he mea maʻalahi no ka mea he kumuhana hoʻolālā i hoʻolālāʻia e hoʻonuiʻia ka huahana o ka fosb ka ulu i loaʻa i kaʻike pinepineʻia i nā lāʻau lapaʻau a me nā uku kūlohelohe (McClung, et al., 2004, Nestler, 2008, Nestler, a me., 1999). Uaʻike mākou ua hoʻokomoʻia ka ΔFOSB i ka lolo ma hope o ka hōʻike pinepineʻana i morphine, Δ9-CC, cocaine a me ethanol, me kēlā me kēia lāʻau lapaʻau e hana ana i kahi hiʻohiʻona āpana āpau o ka'ōlelo ΔFosB (Perrotti, et al., 2008). ʻO kahi maʻamau i loaʻa i nā lāʻau lapaʻauʻo ia ka mea i hoʻokomo nuiʻia ka ΔFosB i ka striatum, kahi i hoʻokomoʻia ai nā lāʻauʻawaʻawaʻehā i ka ΔFosB i loko o ka NAc kumu a me nā mea a pau koe kaʻA9Ua hoʻohālikelikeʻia ka manaʻo o ka CC i loko o ka NAC shell a me ka caudate-putamen.

Ua hōʻikeʻia nā haʻawina hoʻomau Pharmacological i ka hui pūʻana o ka dopamine D1 ka loaʻa (D1R) ua kāohi ka mea palekana SCH 23390 i ka hoʻoukaʻana o ka ΔFosB i ka NAc a me ka caudate-putamen ma hope o ka cocaine kuhi a me ke kāpena morphine, e hōʻike ana i ka pono o D1Nā hōʻailona R-wehewehe (ʻO Muller a me Unterwald, 2005, Nye, et al., 1995). Uaʻikeʻia ka hopena o ka hoʻomohala ΔFosB ma nāʻano hana i ke olakino i ka hoʻohanaʻana i nā mice bitransgenic e hōʻike ana i ka ΔFosB ma nā heluna neuronal pono o ka NAc a me ka dorsal striatum (Chen, et al., 1998). Mice e hōʻike ana i ka ΔFosB ma dynorphin / D1ʻO ke kūpono o ka hopena o ka NAC a me dorsal striatum (laina 11A) i nā pane i hoʻololiʻia i nā lāʻau lapaʻau, e hoʻonui pono i ka noʻonoʻo i nā hopena maikaʻi o ka cocaine a morphine (Colby, et al., 2003, Kelz, et al., 1999, Zachariou, et al., 2006). Ua hoʻololiʻia kēia mau hoʻololi i ka hikiʻole o nā loli i nā kiʻekiʻe o MOR a iʻole nāʻano puʻupuʻu G-protein. Eia naʻe, ua ho'ēmiʻia nā'āpana mRNA i dynorphin i ka NAC o ka ΔFosB e hōʻike ana i nāʻiole (Zachariou, et al., 2006), e manaʻo ana i kahi pahuhopu o ka ΔFosB he gen e hoʻopili ana i kahi peptide opioid opioid. Hiki i ka hoʻokuʻuʻana o ka PΔFosB i nā hoʻololi halihali ma o ka hoʻoponoponoʻana i ka mea e loaʻa ana i ka lolomi ma ka NAc, akāʻaʻole iʻimiʻia kēia mea. No laila, ua hoʻohanaʻia e nā haʻawina o kēia manawa keʻano'ōnaehana mousele bitransgenic e hoʻoholo ai i ka hoʻonuiʻia o ka ΔFosB ma dynorphin / D1Loaʻa i nā hua'ōlelo stranotal ke hoʻololi i ka hana G-protein i MOR a me MOR- a me KOR ma kahi o ka nec kecicylyl cycse. Ka hopena o ka ΔFosB ma CB1Hanaʻia ka hoʻolālā G-protein i pāpāʻia no ka mea Δ9-E hoʻoponopono ka hoʻoponopono o ka'Āpana ΔFosB ma ka NAc (Perrotti, et al., 2008) aʻo ka endocannabinoid pūnaewele kaʻikeʻia e hoʻoponopono i nā kaʻa hilinaʻi o ka lolo (ʻO Gardner, 2005, Maldonado, et al., 2006), akā,ʻaʻole iʻimiʻia ka hopena o ka ΔFOSB ma ka system endocannabinoid.

E hele:

2. Nā Pono a me nā Una

2.1. Hoʻopaʻi

[35S] GTPIES (1250 Ci / mmol), [α-32P] ATP (800 Ci / mmol) a me [3H] cAMP (26.4 Ci / mmol) i kūʻai mai mai PerkinElmer (Shelton, CT). Hoʻokumuʻiaʻo ATP, GTP, GDP, CAMP, serin albumin, kalamine phosphokinase, papaverine, imidazole a me WIN-55212-2, mai Sigma Aldrich (St. Louis, MO). Ua kūʻaiʻiaʻo GTPIES mai kā Roche Diagnostic Corporation (Chicago, IL). Ua hoʻolakoʻia ka DAMGO e ka Polokalamu Drug Supply o ka National Institute on Drug Abuse (Rockville.). Ua loaʻaʻo Econo-1 i ka wai scintillation mai Fisher Scientific (Norcross, GA). Loaʻaʻia ka wai o ka lipopili e Ecolite mai ICN (Costa Mesa, CA). Loaʻa nā huahana'ē aʻe mai Sigma Aldrich a iʻole Fisher Scientific.

2.2. Mice

Ua hanaʻia nāʻiole male bitransgen mai NSE-tTA (laina A) × TetOp-ΔFosB (laina 11) e like me ia i ho'ākākaʻia ma Kelz et al. (Kelz, et al., 1999). Ua hāpaiʻia nā mice o ka Bitransgenic a hānaiʻia ma luna o doxycycline (100 μg i loko o ka wai inu) e kāohi i ka'ōlelo transgene. Ma ka 8 mau makahiki o ka makahiki, ua hoʻohemoʻia ka doxycycline mai ka wai no ka hapalua o nāʻiole eʻae i ka hua'ōlelo o ka transgene, akāʻo nā keiki i koe i hoʻomauʻia ma ka doxycycline e hoʻopau i ka transgene. Hoʻokomoʻia nā'ōpū i nā wiki 8 ma hope mai,ʻo ka manawa i loaʻa ai ka hua'ōlelo o ka hua'ōlelo o ka ΔFosB (ʻO McClung a me Nestler, 2003). Ua hoʻohanaʻia kekahi laina louse maheleʻelua i kahi e hoʻonāʻia aiʻo'AΔc-Jun, kahi mea kū'ēʻole ma waena o c-Jun, ma D1R / dynorphin a me D2R / nā pūnaewele enkephalin o ka striatum, ka hippocampus a me ka corietx 'Peakman, et al., 2003). C-Jun a me nā lālā o kaʻohana Jun e pili ana me nā protein family Fos a hoʻopaʻa i ka pūnaewele AP-1 o nā genes mua e hoʻoponopono i ka palapala. Eia naʻe,ʻo ka'āpana o ka N-terminus o c-Jun (Δc-Jun) e hoʻololi i ka liʻiliʻi liʻiliʻi a hikiʻole ke kāohi i ka hoʻopaʻaʻana o DNA i nā'āpana AP-1 hana. Ua loaʻa nāʻiole male bitransgen mai NSE-tTA (laina A) × TetOp-FLAG-Δc-Jun (laina E) e like me ia i ho'ākākaʻia ma Peakman et al. (Peakman, et al., 2003). Ua hāpaiʻia nā mice o ka Bitransgenic a hānaiʻia ma luna o doxycycline (100 μg i loko o ka wai inu) e kāohi i ka'ōlelo transgene. Ua hoʻomahaʻia nā Pup i nā 3 weeks, genotyped, a ua hoʻokaʻawaleʻia i mau hui, me ka hapalua i hoʻomauʻia i ka wai me ka wai mexicline a me ka hapalua o ka wai inu maʻamau no ka hoʻouluʻana i ka'ōlelo FLAG-Δc-Jun. Hoʻokomoʻia nā'ōpū i nā wiki he 6 ma hope mai,ʻo ka manawa i kauʻia ai nā kūlana kiʻekiʻe o FLAG-Δc-Jun (Peakman, et al., 2003). Ua mālamaʻia nā kaʻina hana holoholona a pau e like me nā National Institute of Health Guide no ka mālamaʻana a me ka hoʻohanaʻana i nā mea laʻau.

2.3. Hoʻomākaukau Membrane

Hoʻopiliʻia nā umauma i -80 ° C a hiki i ka lā o ka hōʻailona. Ma mua o ka ho'āʻoʻana, ua hoʻohaʻahaʻaʻia kēlā me kēia lolo, a ua hoʻokaʻawaleʻia ka NAc ma ka hau. Hoʻohuiʻia kēlā me kēia mela i ka 50 mM Tris-HCl, 3 mM MgCl.2, 1 mM EGTA, pH 7.4 (ka pehu membrane) me nā'āpana 20 mai kahi hui homogenizer ma 4 ° C. Hoʻohuiʻia ka homogenate ma 48,000 × g ma 4 ° C no ka 10 min, i hoʻopiʻiʻia i ka palemena membrane, centrifuged hou ma 48,000 × g ma 4 ° C no ka 10 min a hoʻomahaʻia ma 50 mM Tris-HCl, 3 mM MgCl.2, 0.2 mM EGTA, 100 mM NaCl, pH 7.4 (kahi hānai koi). Ua hoʻoholoʻia nā pae kinuapili e ke ala o Bradford (ʻO Bradford, 1976) e hoʻohana ana i ka serum albumin (BSA) e like me ke kūlana.

2.4. Hoʻoponoponoʻia ka Agonist-[35S] GTPYS Binding

Ua hoʻokumuʻia nā Membranes no nā minuke 10 ma ka 30 ° C me ka adenosine deaminase (3 mU / ml) ma kahi pahu paʻi. Hoʻopiliʻia nā Membranes (5-10 μg) i ka 2 hr ma 30 ° C ma kahi pahu pahu hana i loaʻa me ka 0.1% (w / v) BSA, 0.1 nM [35S] GTPIES, 30 μM GDP a me adenosine deaminase (3 mU / ml) me ka ma waho o ka nui o DAMGO a iʻole WIN55,212-2. Ua kākiʻia ka laikini kiko'ī me 20 μM GTPγS. Ua hoʻopauʻia ka hoʻolālā ma o ka filtration ma o nā filima fiber GF / B, a holoiʻia e 3 me 3 ml 50 mM Tris-HCl hauʻoli, pH 7.4. Hoʻoponoponoʻia ka hanahana radioactive ma kahi spectrophotometry scintillation wai ma hope o ka weheʻana o ka mau kānana i nā kānana i loko o Econo-1 fluid scintillation.

2.5. Adenylyl Cyclase Assay

Ua mālamaʻia nā Membranes (5-25 μg protein) me adenosine deaminase e like me ia i ho'ākākaʻia ma luna, a laila hoʻopukaʻia no 15 min ma 30 ° C ma ke alo aʻaʻole paha o 1MM forskolin, me kaʻole a DAMGO paha, U50,488H a iʻole ka WIN55,212-2. 50 μM ATP, [α-32PN ATX (1.5 μCi), 0.2 mM DTT, 0.1% (w / v) BSA, 50 μM AMP hōkū, 50 μM GTP, 0.2 mM Papa, 5 mM phosphocreatine, 20 pūnaewele / ml creatine phosphokinase a me adenosine deaminase (3 mU / ml) ma ka puke hope loa o 100 μl. Ma lalo o kēia mau kumuhana, ka paukū [α-32ʻO ka pāʻani P] cAMP i loaʻa i lalo loa o ka 1% o ka huina kālā i hoʻonuiʻia [α-32P] ATP ma kēlā me kēia hiʻohiʻona. Ua hoʻopauʻia ka hopena ma ka papa hana no ka 3 min a [32P]ʻOihana AMP i hoʻokaʻawaleʻia e ke kolamu lua (Dowex a me alumina) o ka Salomon (Solomon, 1979). [3H] cAMP (10,000 dpm) i hoʻohuiʻia i kēlā me kēia tube i mua o ka chromatography ka pae ma keʻano he kūmole i loko. Hoʻolālāʻia ka radioactivity e ka spectrophotometry scintillation wai (45% ka pono no 3H) ma hope o ka pauʻana o ka 4.5 ml o kaʻelua i ka 14.5 ml o ka wai o ka lipopole Ecolite.

2.6. ʻIkeʻikepili

Ināʻole i hōʻikeʻokoʻaʻia,ʻikeʻia kaʻikepili e like me keʻano o nā mea ± SE o nā 4-8 hōʻike hoʻokoeʻana, ua hanaʻia kēlā me kēia mea ma kahiʻekolu. Nā Net-hoʻonāukiʻia [35ʻO ka paʻaʻana o ke GTPIES e heluʻia e like me ka'āpana-hoʻonā i ka hoʻokumuʻiaʻana o ke kāpili basal. Hanaʻia kaʻenehana Net noskolin-hoʻonāukiuki i kaʻoihana cycse e like me ka hana forskolin-hoʻonāukiuki - hana basal (pmol / mg / min). Hoʻohālikelike kaomi no ka hana forskolin-hoʻonāukiuki adenylyl cyclaseʻoihana (net forskolin-hoʻonāukiʻia i ka hanaʻole o ka hana agonist - net forskolin-hoʻonāukiʻia i mua o agonist / net noskolin-hoʻonāukiʻia i kaʻole o ka agonist) × 100. Ua hoʻohanaʻia nā kānana kūpono a me nā'ikepilihelu e Prism 4.0c (GraphPad Software, Inc., San Diego, CA). Ua nānāʻia nā pā i ka hoʻohālikelikeʻana ma o ka hoʻopiʻiʻoleʻana o ka lainaʻole e loaʻa iā EC50 a me Emax nā koina. Ua hoʻoholoʻia ka'ikepilihelu o kaʻike i kaʻikepili-manaʻo ma o keʻano o ka hoʻopiʻiʻelua o ka hoʻopiʻi (ANOVA), me ka hoʻohanaʻana i ka dose o ka mea hana a me ka hoʻopihapiha (ma luna a ma waho paha) i nā kumu nui. ʻO ke kūlana helu o nā koina o nā pale (Emax aiʻole EC50) i hoʻoholo ʻia e ka haumāna T-hōʻike lua-huelo ʻole o ka hoʻāʻo, me ka hoʻohana ʻana i ka hoʻoponopono a Welch a i ʻole ka hoʻololi ʻana o ke aʻa i kahi ʻikepili e pono ai e hoʻoponopono no nā ʻano kaulike ʻole (i ʻike ʻia e ka hōʻike F) ma EC.50 nā koina.

E hele:

3. Nā hualoaʻa

3.1. Ka hopena o ka'ōlelo ΔFosB ma luna o ka opioid a me ka cannabinoid i hoʻokomo i kahi G-protein i hoʻokumuʻia

E hoʻoholo ai inā MOR- a me CB paha1Ua hoʻololiʻia ka hoʻolālā G-protein i ka pākīkiko R e nā'ōlelo transgenic i hoʻokomoʻoleʻia o ΔFosB i ka NAc, nā mea hoʻonāukiʻia e agonist [35ʻO ka paʻaʻana o SQ GTGS i nā mea i hoʻonohonohoʻia ma kēia māhele o nāʻiole bitransgenic e hōʻike ana (ΔFosB ma) aʻaʻole paha e wehewehe (ΔFosB a hala) ka Transgene ΔFosB. Ua hoʻohanaʻia ka 'analogic enkephalin maʻamau e DAMGO i ka hoʻohanaʻana i ka MOR a me ka cannabinoid aminoalkylindole WIN55,212-2 i hoʻohanaʻia e ho'āʻo ai i CB1R. Ua hōʻike muaʻia kēia mau loina i piha i nā mea hana kūʻokoʻa ma MOR a me CB1R, kēlā me kēia (Breivogel, et al., 1998, Selley, et al., 1997). ʻAʻole hiki ke nānā i kahiʻoihana G-protein i pāpākūʻia e KOR no ka mea, ua emi loa ka hōʻailona ma ke koʻokoʻo rodent (Childers, et al., 1998). Ua hōʻikeʻia nā hopena i ka hoʻonāukiʻana i nā hana G-protein ma DAMGO a me WIN55,122-2 ma NAC mai ka ΔFosB a me ka ΔFosB ma nāʻiole (Hōʻike 1). No ka hana DAMGO-hoʻonāukiukiʻia (Hōʻike 1A), ʻaoʻao ʻelua ANOVA o ka ʻikepili manaʻo paʻa i hōʻike i nā hopena nui o ke kūlana ΔFosB (p <0.0001, F = 22.12, df = 1) a me ka noʻonoʻo DAMGO (p <0.0001, F = 29.65, df = 5) me ka ʻole pilina pilina (p = 0.857, F = 0.387, df = 5). ʻO ka loiloi ʻole nonlinear regression o nā curves hopena hopena i hōʻike i kahi DAMGO E. ʻoi aku ka nuimax ke kumukūʻai ma ka ΔFosB ma nāʻiole (Emax = 73 ± 5.2% hoʻonui) e pili ana i nāʻiole ΔFosB (Emax = 56 ± 4.1% hoʻonāukiuki; p <0.05 ʻokoʻa mai ΔFosB ma nāʻiole e ka hoʻāʻo t Student). ʻO DAMGO EC50 ʻaʻoleʻokoʻa nā helu ma waena o ka ΔFosB a me nāʻiole ΔFosB (302 ± 72 nM ma kahi o 212 ± 56 nM, i kēlā me kēia, p = 0.346).

Hōʻike 1 

Ka hopena o ka'ōlelo ΔFosB ma luna o ka hoʻonāukiʻia o ka'āpana [35S] GTPIES e hoʻopaʻa ana i ka NAC. Ua ho'āʻoʻia nā Membranes mai ka ΔFosB-hōʻike (ΔFosB ma) a iʻole ka mana (ΔFosB off) i nāʻiole e like me ia i ho'ākākaʻia ma nāʻano hoʻohanaʻana i nā hoʻololi kūikawā ...

I ka hoʻohālikeʻana i nā hualoaʻa i loaʻa me ka DORGO agonist MOR,ʻaʻole iʻikeʻia nāʻano likeʻole o ka'AΔFosB i ka hoʻouluʻana i ka G-protein me ka agonist cannabinoid WIN55,212-2 (Hōʻike 1B). ʻO ANOVA ʻaoʻao ʻelua o ka WIN55,212-2 ʻikepili hopena hopena i hōʻike i kahi hopena nui o ka hopena WIN55,212-2 (p <0.0001, F = 112.4, df = 7), ʻaʻole naʻe no ke kūlana osFosB (p = 0.172 , F = 1.90, df = 1) a ʻaʻohe pilina (p = 0.930, F = 0.346, df = 7). Pēlā nō, ʻaʻohe hopena o ke kūlana ΔFosB ma WIN55,212-2 Emax (ʻo 103 ± 6% me ka 108 ± 8% ka hoʻonāukiukiʻana ma ka ΔFosB ma luna a hemo aku i nāʻiole, penei, p = 0.813 ma ka ho'āʻo o nā haumāna) aiʻole ke EC50 ke kumu waiwai (103 ± 20 nM me ka 170 ± 23 nM ma ka ΔFosB ma luna a hemo aku i kaʻiole, p = 0.123).

Ma muli o keʻano o nā pale a me ka mea i hōʻikeʻia e ko mākou mau papa i ka hōʻikeʻana o ka pahū-helu WIN55,212-2 biphasic i ka lolo (Breivogel, et al., 1999, Breivogel, et al., 1998), ua nānā pūʻia hoʻi nā pākuhi WIN55,212-2 ma o ka hoʻolālā pālua. Uaʻikeʻia kaʻikepili o nāʻike iʻikeʻia i kahi hoʻonui ikiʻana o ka maikaʻi o ka hoʻokomoʻana i keʻano o nā hiʻohiʻona lua-ʻaoʻao (R2 = 0.933 a me 0.914, hōʻuluʻulu o nā'āpana = 3644 a me 5463 ma ka ΔFosB ma luna a me nāʻiole, i kēlā me kēia) i hoʻohālikelikeʻia me ke kūlana o kahi pūnaewele hoʻokahi (R2 = 0.891 a me 0.879, ka nui o nā kaha = 6561 a me 6628 ma ka ΔFosB ma luna a hemo aku paha i nāʻiole). Eia naʻe,ʻaʻole i loaʻa nāʻano likeʻole ma waena o ka ΔFosB ma luna a me nāʻiole ma ka Emax aiʻole EC50 nāʻike o nā pae kiʻekiʻe kiʻekiʻe a iʻole nā ​​mea liʻiliʻi paha (Ka Papa Hana 1), akā naʻe he mau kaʻina i kahi ala lalo50 ka nui ma ka pūnaewele nui ma nāʻiole me ΔFosB ma (EC50kiʻekiʻe = 28.0 ± 10.6 nM) ke hoʻohālikelikeʻia me ka poʻe i hoʻokuʻuʻia me ka ΔFosB (EC50kiʻekiʻe = 71.5 ± 20.2 nM; p = 0.094). Eia kekahi,ʻaʻohe hopena o ke kūlana o ka ΔFOSB ma ka basal [35S] GTPIES e hoʻopaʻa ana i nā membran o ka NAc (253 ± 14 i ka 226 ± 14 fmol / mg ma ka ΔFosB ma luna a me kaʻiole, p = 0.188). Hōʻike kēia mauʻikepili i ka hoʻonuiʻia o ka transgenic expression o ka ΔFosB i ka NAC o nāʻiole i hoʻonuiʻia ka G-protein i ka MOR i hanaʻiliʻia me ka nuiʻole o ka CB.1Hana pāʻani R-pākiki a basal paha.

3.2. Ka hopena o ka ΔFosB ma ka opioid a me ka cannabinoid receptor-mediated inhibition o adenylyl cyclase

No ka loiloiʻana i ka hopena o ka'ōlelo transgenic i hoʻokomoʻoleʻia o ΔFosB ma ka hoʻololi o ka hana hana ma lalo mai o MOR a me CB1R, hoʻolālāʻiaʻo 1 μM forskolin-hoʻonāukiʻia ka adenylyl cyclaseʻoihana i nānāʻia ma nā membranes NAc. Ma waho o ka MOR a me CB1Ua kāohiʻiaʻo R-i kāwiliʻia i ka hana adenylyl cyclase, nā hopena o ka hana KOR ma ka hoʻohanaʻana i ke kikowaena U50,488 piha piha KOR-koho (Zhu, et al., 1997), no ka mea o nā hualoaʻa i hōʻike muaʻia, he pahuhopu kēia o dynorphin mRNA i ka ΔFosB ma keʻano bitransgenic (Zachariou, et al., 2006). Ua hōʻike nā hopena i ka hōʻikeʻana o DAMGO, U50,488, a me WIN55,212-2 i ka hana palekana no ka hana adenylyl cyclase ma ka ΔFosB a me ka ΔFosB ma nāʻiole (Hōʻike 2). 'Ala'ōleloʻelua o kaʻaoʻao ANOVA o kaʻikepili hoʻopau helu DAMGO (Hōʻike 2A) hōʻike i nā hopena nui o ke kūlana ΔFosB (p = 0.0012, F = 11.34, df = 1) a me ka noʻonoʻo DAMGO (p <0.0001, F = 29.61, df = 6), akā ʻaʻohe pilina koʻikoʻi (p = 0.441, F = 0.986 , df = 6). ʻO ka loiloi ʻole nonlinear regression o DAMGO curves hopena hopena i hōʻike i kahi DAMGO EC haʻahaʻa haʻahaʻa50 waiwai ma ΔFosB ma nāʻiole (101 ± 11 nM) i hoʻohālikelike ʻia me nā ʻiole ΔFosB (510 ± 182 nM, p <0.05 e ka hoʻāʻo t haumāna). Eia nō naʻe, ʻaʻohe ʻokoʻa nui ma DAMGO E.max ke kumu waiwai (20.9 ± 1.26% me ka 19.8 ± 1.27% ka hana 'ana ma ka ΔFosB ma luna a me kaʻiole, p = 0.534).

Hōʻike 2 

Ka hopena o ka'ōlelo ΔFosB ma ka hanaʻoleʻana i ka hana adicylyl cyclase ma ka NAc. Ua ho'āʻoʻia nā Membranes mai ka'ĀAa Kūkā (ΔFosB) ma luna o ka'āpana (ΔFosB off) e like me ka ho'ākākaʻia ma nāʻano i mua o 1 μM ...

Uaʻano likeʻole ka hana kuʻuna o adenylyl cycse KOR ma keʻano he hana o ka'ōlelo transgenic inducible o ΔFosB (Hōʻike 2B). ʻO ANOVA ʻaoʻao ʻelua o ka U50,488 ʻike kūhohonu hopena i hōʻike i nā hopena nui o ke kūlana ΔFosB (p = 0.0006, F = 14.53, df = 1) a me ka hoʻoliʻiliʻi U50,488 (p <0.0001, F = 26.48, df = 3 , me ka launa ʻole koʻikoʻi (p = 0.833, F = 0.289, df = 3). Ua hōʻike ʻia ka nānā ʻana o ka nonlinear regression o nā curves hopena hopena i kahi U50,488 ʻoi aku ka nuimax waiwai ma ΔFosB ma nāʻiole (18.3 ± 1.14% kaohi) hoʻohālikelike ʻia me iceFosB ma nāʻiole (12.5 ± 2.03% kaohi; p <0.05 ʻokoʻa mai ΔFosB ma o ka hoʻāʻo t Student), me ka ʻokoʻa nui ʻole ma U50,488 EC50 ke kumu waiwai (310 ± 172 nM me ka 225 ± 48 nM ma ka ΔFosB ma luna a hemo aku i kaʻiole, p = 0.324).

I ka hoʻohālikeʻana i nā hopena iʻikeʻia me MOR a me KOR,ʻaʻohe mea nui o ka'ōlelo transgenic i hikiʻole ke hanaʻia i ka hanaʻana i ke adenylyl cyclase ma o ka canonbinoid agonist WIN55212-2 (Hōʻike 2C). ʻO ANOVA ʻaoʻao ʻelua o WIN55,212-2 ʻikepili hopena hopena i hōʻike i kahi hopena koʻikoʻi o ka hoʻoliʻiliʻi lāʻau (p <0.0001, F = 23.6, df = 2), ʻaʻole naʻe no ke kūlana ΔFosB (p = 0.735, F = 0.118, df = 1) ʻaʻole hoʻi kahi pilina koʻikoʻi (p = 0.714, F = 0.343, df = 2). Eia kekahi, ʻaʻohe hopena o ke kūlana ΔFosB ma ka basal a i ʻole forskolin-stimulated adenylyl cyclase ka hana me ka loaʻa ʻole o kekahi agonist. ʻO ka hana Basal adenylyl cyclase he 491 ± 35 pmol / mg / min ma ΔFosB ma nāʻiole i hoʻohālikelike ʻia me 546 ± 44 ma ΔFosB ma nāʻiole (p = 0.346 e ka hoʻāʻo t Student). Pēlā nō, hana adenylyl cyclase ma ke alo o 1 µM forskolin 2244 ± 163 pmol / mg / min ma ΔFosB ma nā ʻiole a me 2372 ± 138 pmol / mg / min i ka iceFosB maʻiole nāʻiole (p = 0.555).

3.3. Ka hopena o ka ΔcJun ma ka opioid a me ka cannabinoid receptor-inhibition of adenylyl cycse

Ma muli o ka hōʻike transgenic inducible o ka unuhiʻana o ka hōʻailona hōʻailona o ka ΔFOSB mai MOR a me KOR i adenylyl cyclase ma ka NAc, he mea nui e hoʻoholo inā he mea hoʻonāukiuki kūponoʻole o ka transcription o ka ΔFosB e hoʻololi i ka hōʻailona opioid e kuhikuhi ana ma keʻano'ē aʻe. No ka paneʻana i kēia nīnau, ua kāohiʻia ka hana hana no ka hana noskolin-hoʻonāukiuki adenylyl cycse e DAMGO a me U50,488 ma nā membrane i hoʻomākaukauʻia mai ka NAC o nāʻiole bitransgenic e hōʻike ana i ka ΔcJun. ʻAʻole i hōʻikeʻia nā hualoaʻa i ka hopena nui o ka'ōlelo a'AΔCJ no ka hanaʻoleʻana o ka hanaʻo cyenus adenylyl e MOR a iʻole KOR (Hōʻike 3). ʻO ANOVA ʻaoʻao ʻelua o DAMGO curves hopena hopena i hōʻike i kahi hopena nui o ka nui o DAMGO (p <0.0001, F = 20.26, df = 6), ʻaʻole naʻe no ke kūlana ΔcJun (p = 0.840, F = 0.041, df = 1) aʻaʻohe pilina koʻikoʻi (p = 0.982, F = 0.176, df = 6). Pēlā nō, ʻaʻohe ʻokoʻa nui ma Emax aiʻole EC50 ka nui ma waena o nāʻiole me ΔcJun ma (Emax = 23.6 ± 2.6%; EC50 = 304 ± 43 nM) aiʻole ΔcJun (Emax = 26.1 ± 2.5%, p = 0.508; EC50 = 611 ± 176 nM, p = 0.129). Ua ʻike ʻia nā hopena like me U50,488, e like me nā ʻaoʻao ʻelua ANOVA o nā piko hopena i hōʻike i kahi hopena koʻikoʻi o ka noʻonoʻo (p <0.0001, F = 11.94, df = 6), ʻaʻole naʻe no ke kūlana ΔcJun (p = 0.127 , F = 2.391, df = 1) a ʻaʻohe pilina koʻikoʻi (p = 0.978, F = 0.190, df = 6). Pēlā nō hoʻi, ʻaʻohe ʻokoʻa nui ma Emax aiʻole EC50 ka nui ma waena o nāʻiole me ΔcJun ma (Emax = 14.8 ± 2.9%; EC50 = 211 ± 81 nM) a iʻole paha (Emax = 16.7 ± 1.8%, p = 0.597; EC50 = 360 ± 151 nM, p = 0.411).

Hōʻike 3 

Ka hopena o ka'ōlelo ΔcJun i ka hanaʻana i ka hana adicylyl cyclase ma ka NAC. Ua hoʻonāʻia nā Membranes mai ka'AΔcJun-wehewehe (ΔcJun ma) a iʻole ka mana ('AΔcJun off) i nā maka i mua o DAMGO (A), U50,488H (B) a iʻole WIN55,212-2 ...

ʻAʻole pili ka ʻōlelo ΔcJun i ka pāpā ʻana o adenylyl cyclase i ka NAc e ka agonist cannabinoid. ʻO ANOVA ʻaoʻao ʻelua o nā WIN55,212-2 curve hopena hopena i hōʻike i kahi hopena nui o ka hopena WIN55,212-2 (p <0.0001, F = 15.53, df = 6), akā ʻaʻole ka genotype (p = 0.066, F = 3.472, df = 1) a ʻaʻohe pilina koʻikoʻi (p = 0.973, F = 0.208, df = 6). Pēlā nō hoʻi, ʻaʻohe ʻokoʻa nui ma WIN55,212-2 ʻEmax ke kumu waiwai (13.0 ± 2.3% a me 13.6 ± 0.9% ka hana 'ana i ka ΔcJun ma nāʻiole ma waho, p, X = NOH) a me EC paha.50 (ʻo ka 208 ± 120 nM a me ka 417 ± 130 nM ma ΔcJun ma nāʻiole ma waho, p = 0.270). No laila, no ka mea, heʻanoʻano iki no ka emi ikiʻana o ka WIN55,212-2 i nāʻiole e hōʻike ana i ka ΔcJun,ʻaʻole i hoʻololi nui ka transgene i ka hana a cannabinoid o adenylyl cyclase. Eia kekahi,ʻaʻohe hopena o ke kūlana ΔcJun ma ke kīkalima basal a noskolin-hoʻonāukiuki i ka hana adenylyl cyclase. ʻO ka hanaʻo Basal adenylyl cyclaseʻo 1095 ± 71 pmol / mg / min a me 1007 ± 77 pmol / mg / min (p = 0.403) ma nāʻiole me ΔcJun iʻole aiʻole. ʻO Adenylyl cyclaseʻoihana i hoʻouluʻia e 1 μM noskolinʻo 4185 ± 293 pmol / mg / min ma kahi o 4032 ± 273 pmol / mg / min (p = 0.706) ma nāʻiole a me ΔcJun ma luna a ma waho paha.

3.4. Kōkua

Ua hōʻikeʻia nā hopena o kēia haʻawina i ka hoʻonuiʻiaʻana o ka G-protein i ka MOR a me ka hanaʻana i ka adenylyl cyclase ma ka NAC o nāʻiole me ka'ōlelo transgenic inductible o ΔFosB i dynorphin / D1R me nā neu. Ua hoʻonuiʻia ka hana kuʻuna KOR i ka hana adenylyl cyclase ma ka NAc o ka ΔFosB e hōʻike ana i nāʻiole, e manaʻo ana e hoʻoponopono ka ΔFosB i ka'ōnaehana opioid hope loa ma ka NAc. ʻO ka DAMGO Emax uaʻoi aku ka nui o ka waiwai no ka MOR-hoʻonuiʻia [35S] GTPIES, a me kona EC50 ua emi ke kumukūʻai no ka hōʻailona adenylyl cycse, ma nāʻiole hoʻonāʻo'AΔFosB e hoʻolālikelikeʻia me nāʻiole mana. ʻO kēia mau hopena e hōʻike ana i ka hiki ke mālamaʻia ka hoʻopiʻi kūpono no ka hoʻokō ponoʻana akāʻaʻole ka hana G-protein i lalo o nāʻano koi i nānāʻia. ʻO kaʻikeʻana i ka hana nuiʻana o ka adenylyl cyclase ma ka'āpana KOR i hoʻololiʻia e ka'ōlelo a ka ΔFosB e hōʻike i kahi mea mālama kūpono no ka paneʻana o ka KOR, e like me nā haʻahaʻa haʻahaʻa o nā kikowaena paʻa KOR i ka lolo (Unterwald, et al., 1991). Akā,ʻo CB1Hanaʻoleʻia ka hana G-protein a me ka hanaʻole o adenylyl cyclase ma ka'ōlelo ΔFosB, ke manaʻo nei eʻano likeʻole nā'ōnaehana opioid a me nā cannabinoid i kā lākou paneʻana i ka ΔFosB ma kēia mau neo NEK.

ʻO ka hopena o ka ΔFosB ma ka hōʻailonaʻikepili liʻiliʻi opioid e like me ko kā mākou hōʻike mua i hōʻikeʻia ka'ōlelo ΔFosB ma ka striatum i nā maʻi a me nā hopena o morphine (Zachariou, et al., 2006). ʻO kekahi meaʻike o kēia noiʻana,ʻo ia kaʻiole me ka hōʻikeʻana o ka ΔFosB i dynorphin / D1Uaʻoi aku ka maʻalahi o nā neurons i ka morphine ma kahi hoʻokūkūʻana ma mua o nā mana. Eia kekahi, ua hanaʻia kēia hopena ma muli o kaʻikeʻana o ka hua'ōlelo o ka ΔFosB ma kahi hoʻohui pūnaewele i loko o ka NAC. Kūlike kēia mauʻike i nā hopena o kēia manawa e hōʻike ana i ka hōʻailona MOR i hoʻonuiʻia i ka NAc.

Ua hōʻike mua mākou i ka pūnaewele e hoʻopili ana dynorphin e like me ka pahuhopu o ka ΔFosB, a ua hoʻohālikelike e like ana me ka hoʻohanohano i nā mea waiwai o morphine ma nāʻiole ΔFosB bitransgenic. (Zachariou, et al., 2006). Hōʻike nā hualoaʻa i kēia manawa e hōʻano houʻia ka hana a KOR i ka adenylyl cycse ma ka NAc i ka hōʻikeʻana o ka mice i ka ΔFosB, e hoʻonui ana i ka hoʻonuiʻana i kaʻike KOR ma muli o ka dynorphin i hoʻemiʻia. Ua hōʻike nā haʻawina mua e hōʻikeʻia ana ke kānāwai o ka KOR ma kekahi mau lolo o nā kiokoki knockout, e like me NAc (Clarke, a me al., 2003).

I ka hoʻohālikeʻana i ka ΔFosB, ka'ōlelo transgenic inducible o ΔcJun, ka mea i hoʻohuiʻia i ka'āpana o ka mea hui paʻa o ka ΔFosB partner CJun,ʻaʻole ia i hoʻololi i ka adenylyl cyclase hoʻohala e MOR a iʻole KOR agonists. Hōʻike nā hopena i nā kumu basal o ka'ōlelo ΔFosB, heʻuʻuku liʻiliʻi,ʻaʻohe hoʻokō nui i ka mālamaʻana i ka hōʻailona opioid ka hōʻailona ma kēia pae o ka unuhiʻana ma ka NAc. ʻO ka mea i hōʻemiʻia ka hopena maikaʻi o morphine e ka ΔcJun'ōlelo i kā mākou aʻo mua (Zachariou, et al., 2006) ke kuhikuhi nei i ka hoʻopiʻiʻana o ka morphine o ka ΔFosB i ka wā o ke kaukōwai he mea nui i ka hoʻoponoponoʻana i nā pane o ka halihali i ka lāʻau a iʻole ka hopena o nā hua'ōlelo o ka ΔFosB ma mua o ka poʻe e pili ana i ka hōʻailonaʻana o nā haipina opioid e pākuʻi i ka uku opioid. I ka hopena, ua hōʻike maopopo nā hualoaʻa o kēia haʻawina i kēia manawa, i ka manawa e hoʻonuiʻia ai ka pane o ka ΔFosB ma luna o nā taumata basal ma ka dynorphin / D1ʻO ka hua'ōlelo R-weheweheʻana, aia he piʻi nui ma ka huiʻana o MOR a me KOR i ka hanaʻana o adenylyl cyclase ma ka NAc.

Ke hoʻomaopopoʻoleʻia nāʻano e hanaʻia e MOR a me KOR-iʻikeʻia e ka ΔFosB overexpression, akā, ua hōʻike mua mākou i nā helu MOR, i hoʻolālāʻia e [3H] naloxone e hoʻopaʻa ana,ʻaʻoleʻokoʻa i ka NAC o ka ΔFOSB ma luna o nāʻiole ma waho (Zachariou, et al., 2006). Uaʻikeʻia kaʻike hoʻokahi i loaʻa iā GaiʻO ka 1 a me ka 2 pūmua i ka hopena ma ka'āpana ΔFosB. Eia naʻe, hōʻike mua nā hōʻikeʻana o nā pūʻulu hōʻike i ka Gaoo Ua hoʻolālāʻiaʻo MRNA ma ka NAC o ka'AAFOSB ma nāʻiole (ʻO McClung a me Nestler, 2003). E noʻonoʻo i nā noiʻi e hiki mai ana e nānā pono i nā hopena o ka hua'ōlelo ΔFosB transgenic i ka'ikeʻano G-protein ma ka pae protein a me ka hōʻikeʻana o nā kinamele pono'ī G-protein.

He meaʻoluʻoluʻaʻole i hoʻonuiʻia ka'ōlelo a ka ΔFosB i ka CB1Hōʻailonaʻikeʻiaʻo R i ka NAc. Hiki hiki ke hoʻololi i ka CB1Loaʻa ka kahaʻai R i kahi heluna kūlana o nā neurones iʻikeʻoleʻia i loko o ka hoʻomākaukau holoʻokoʻa NAC a pau. Eia kekahi laʻana, ka hoʻomaluʻana o ka Δ9- Hoʻokomo nui ʻo THC iā ΔFosB i ke kiko, akā ʻaʻole ka pūpū, o ka NAc (Perrotti, et al., 2008). ʻO waume ka loiloi, ua hōʻikeʻia i kēlā paio me Δ9-Hihai ma hope o ka hoʻomau houʻana o ka'AA9Hoʻonuiʻia ka nui o ka dopamine i ka NAc kumu, akā, emi mai ka hoʻokuʻuʻana i loko o ka shell (Cadoni, et al., 2008). He mea nui hoʻi e hoʻomaopopo i ka'āpana 11A o nāʻiole bitransgenic e hōʻike i ka ΔFosB wale nō ma dynorphin / D1ʻO ke kumuhana kālaihana spiny neurons o ka striatum, akāʻo CB1Hōʻikeʻiaʻo R i nā dynorphin / D1R a me ka enkephalin / D2R mau mea neurons (ʻO Hohmann a me Herkenham, 2000), e like me nā 'āpana o nāʻauwai kai eʻe (Robbe, et al., 2001). ʻO ka ho'ākākaʻana o ka luna hoʻomaluʻole o ka transcription mediated o ΔFosB,ʻo'AΔcJun,ʻaʻohe mea nui i ka hōʻailona puʻupuʻu cannabinoid,ʻoiai ua ho'ākāka ponoʻiaʻo ΔcJun ma D1 a me D2-e pili ana i ka heluna o nā neʻeneʻe hiʻi i loko o kēia mauʻiole (Peakman, et al., 2003). E hiki nō naʻe, akā, ua lawa ka haʻawina o ka basal ΔFosB i hikiʻole ai iā'AΔcJun ke hoʻoili i ka hōʻailona o ka hōʻailona, ​​e like me ka manaʻo i nā hopena me MOR a me KOR. He hiki nō hoʻi iā CB1Hōʻikeʻia ka hōʻailona R e ka haʻahaʻa o ka ΔFosB basal, no ka mea,ʻo ka hoʻonuiʻana i ka'ōlelo a ka ΔFosB a iʻole ia e kāohi ana i kāna mau hana me ka ΔcJun, he mau hopenaʻuʻuku wale nō ia i hikiʻole ke piʻi i ke kūlana helu. Hiki keʻikeʻia ke kōkuaʻana no ka unuhiʻana ma ka hōʻailonaʻana i ka WIN55,212-2 EC50 nā koina i waena o nāʻiole e hōʻike ana i ka'AΔcJun ma mua o ΔFosB. ʻO ka lakene o ka WIN55,212-2 EC50 ke kumu kūʻai no ka adenylyl cyclase inhibition ma nāʻiole me ka'ōlelo i hoʻokomoʻia o ΔcJun i kona EC50 ʻo ke kumu no ka hoʻonuiʻia G-protein i nāʻiole me ka'ōlelo i hoʻokomoʻia o ka ΔFosBʻo 4.0 ia, akāʻo ka mahele like me nā mice me kaʻole o ka hoʻokomoʻana o ka transgene,ʻo ia ka 1.2.

Ma keʻano'ē aʻe, hiki i nā cannabinoids ke hoʻonāukiuki i ka'ōlelo ΔFosB me ka loaʻaʻole o ka hopena kūpono ma CB1R hōʻailona. Ma kēia hanana, hiki i ka cannabinoids ke hoʻololi i ka paneʻana i nā hopena ahana o nā lāʻau'ē aʻe e pili ana i ka'ōlelo transcriptional ΔFosB-mediated. ʻO waun n, ka hooponopono o Δ9-Ne loaʻa ka mea hoʻohālike i ka opioids a me ka amphetamine (Cadoni, et al., 2001, Lamarque, et al., 2001), e like me kēia kuhiakau. Eia kekahi, ua hoʻopukaʻia ka hoʻoponopono houʻana o ka agonist cannabinoid CP55,940 i ka hoʻonuiʻana o ka G-protein i ka MOR ma ka NAC, e like me nā mice e hōʻike ana i ka ΔFosB ma ka haʻawina o kēia manawa (Vigano, et al., 2005). Ka hopena o ka hua'ōlelo ΔFosB ma ka Δ9ʻAʻole i noʻonoʻoʻia nā loiloi i nā poʻe i hanaʻoleʻia, akāʻaʻole nā ​​mea i kēia manawa e pale i kahi pilina. Nā hopena o kēia a me kā mākou aʻo mua (Zachariou, et al., 2006) hōʻike i nā hoʻololi o ka ΔFosB i MOR a me KOR / dynorphin ma ka striatum. Nā hopena hoʻomaikaʻi o ka Δ9-Ne, e like me ke anaʻana i ka wahi kahi, ua hoʻopauʻia i kaʻiole o ka MOR null, akā naʻe ka hoʻopauʻana o ka KOR i hoʻokoeʻia Δ9-Wi wahi huli a hōʻikeʻiaʻo Δ9Koho kahiʻoi loa o ka lā (Ghozland, et al., 2002). Penei hoʻi, kahi i hoʻolālāʻia i kaʻaʻa i Δ9Loaʻa ka THC i ka hoʻokūkū pro-dynorphin i ka hoʻohālikelikeʻana i nāʻioleʻano hihiu (Zimmer, et al., 2001). Hōʻike kēia mauʻike i ka 'Δ9Hiki paha ke hoʻonui i ka maikaʻi ma hope o ka hoʻokomoʻana o ka ΔFosB a me ka hoʻokomoʻana i ka MOR me ka hoʻohaʻahaʻaʻana i ka'ōlelo dynorphin.

I ka hōʻuluʻuluy, ua hōʻikeʻia nā hopena o kēia haʻawina i ka hōʻikeʻana o ka ΔFosB ma D1R / dynorphin mau nūnū neʻeneʻe i hoʻonuiʻia i ka MOR- a me ke KOR-i ke kikowaena i ke kūlana o ka hoʻomaluʻiaʻana o G-protein i ka hana adenylyl cyclase ma ka NAc. Ua like kēiaʻike me nā haʻawina i hōʻike i kahi kuleana no ka'ōnaehana opioid hope loa i ka uku (Trigo, et al., 2010), a hāʻawi i kahi mechanical pūnaewele no nā mea i loaʻa i ka PΔFOSB ma ka uku. Akā,ʻo CB1Hōʻikeʻoleʻia ka hōʻailona R-i loko o ka NAC i nā hua'ōlelo ΔFosB nui loa ma lalo o nā kūlana i nānāʻia,ʻoiai he mea hou kaʻikeʻana i ka hopena o ka hoʻokomoʻia o ka ΔFosB ma ka system endocannabinoid.

Nā Hōʻike Pāʻoihana

  • Hōʻailona ka MOR i kahi hoʻonuiʻia i ka nui o nāʻiole e hōʻike ana i ka ΔFosB
  • Hoʻomaopopoʻia ka hana pāʻani o adenylyl cyclase ma nāʻiole e hōʻike ana i ka ΔFosB
  • Hōʻike ka wehewehe o ka ΔFosB i ka hoʻopiʻiʻana iā CB1Hōʻike ka R i ke kikowaena o ka hale
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Paipai nā mea kākau iā Hengjun He, Jordan Cox a me Aaron Tomarchio no ke kōkuaʻano kōkua me ka [35S] GTPYS hoʻopaʻa hope. Ua kākoʻoʻia kēia noi e USPHS Grants DA014277 (LJS), DA10770 (DES) a me P01 DA08227 (EJN).

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