Ho natefisoa-Ho Fumana Ntho ea Bohlokoa ho Senseletsa Likarabo tsa Gamma-Aminobutyric Acidbens Shell (2013) e fumanoang ho tsoa ho Nucleus Accumbens Shell (XNUMX)

. Mongolo o ngotsoeng ka letsoho; e fumanehang ho PMC 2014 Jan 8.

PMCID: PMC3885159

NIHMSID: NIHMS537768

inahaneloang

Background

Ho na le tjantjello e kholo ea ho lekola hore na phepelo e tsamaisoang ke moputso e ka hlahisa polasetiki e kang lithethefatsi bokong. Sisteme ea gamma-aminobutyric acid (GABA) e ka har'a mothapo oa methapo e bokellanang (Acb), e hlophisang li-system tsa phepo ea hypothalamic, e behiloe hantle ho "usurp" taolo ea homeostatic ea ho fepa. Leha ho le joalo, ha ho tsejoe hore na neuroadaptations e matlafatsang e etsahala tsamaisong ena.

mekhoa

Lihlopheng tse arohaneng tsa "ad libitum-rats" tse bolokiloeng li ile tsa pepesetsoa khafetsa ea ho ja lijo tse nang le mafura a mangata, khatello ea tse ling, kapa infra-Acb shell infusions tsa d-amphetamine (2 kapa 10 μg) kapa μ-opioid agonist D- [Ala2, N-MePhe4, Gly-ol] -enkephalin (DAMGO, 2.5 μg), ea qholotsoa ka ho kenella ha Gra-Acb khetla ea khofuA agonist, muscimol (10 ng).

Results

Ho pepesehela mafura a monko o monate o khothalelitsoeng ke ho fepa hoa muscimol. Sensitization e ne e le teng ka beke ea 1 kamora ho khaotsa mokhoa o monate oa ho fepa empa o ile oa fokotseha ka libeke tsa 2. Likhoto tse senotsoeng mafura a hlabositsoeng ha lia ka tsa bontša karabelo e fetotsoeng ea ho fepa ka tlhoko ea lijo. Litlolo tse entsoeng khafetsa tsa "intb-acb" tsa DAMGO (2.5 μg) li boetse li khothalelitse phepelo e tsamaeang ka har'a intra-Acb. Leha ho le joalo, ha ho khafetsa intra-Acb shell d-amphetamine infusions (2 kapa 10 μg) kapa ho pepesehela maikutlo a khothalletsang (khatello ea kelello) e fetotseng kutlo ea muscimol.

Nahanisisa

Ho fepa ka mokhoa o fumanehang ho fana ka likarabo tsa hypersensitivity ea likarabo tsa Acb shell GABA; phello ena e ka kenyelletsa ho lokolloa ha tšusumetso ea li-peptide tsa opioid. Phihlelo e phahameng ea ho tsosa, liphihlelo tse ferekanyang, kapa phetisetso ea catecholamine e le 'ngoe ha ea lekana ho hlahisa sephetho,' me sephetho sa ho fepa ka tlala ha se lekane ho hlahisa sephetho.. Liphumano tsena li senola mofuta oa nouroadaptation o khothalletsoang ke lijo ka har'a Acb; ho ka buisanoa ka litlamorao tsa kutloisiso ea litlamorao tsa crossover lipakeng tsa moputso oa lijo le moputso oa lithethefatsi.

Keywords: DAMGO, boitšoaro bo fepa, GABAA receptor, musimol, opioid, sensitization

Ho nahanoa hore sesosa se ka sehloohong sa "lefu la seoa" la ho ba le botona ke keketseho ea lijo tse theko e tlase, tse matla haholo tse matla tse fanang ka boits'oaro bo sa foleng ka thepa ea bona e ruisang haholo (-). Hobane lijo tsena li na le litsela tse ts'oanang tse kenyelletsang bokhobeng ba (-), ho bile le thahasello e kholo ea ho fumana hore na ho ja ha bona ho tlisa liphetoho tsa neuroplastic joalo ka tse hlahisoang ke lithethefatsi tsa tlhekefetso. Lisebelisoa tse amohelang tlhokomelo e kholo ntlheng ena ke litsamaiso tsa dopamine le opioid ho li-nucleus accumbens (Acb). Lihlopha tse 'maloa li bontšitse hore ho pepesehela khafetsa phepelo e monate, haholo lijong tse nontšitsoeng tsoekere kapa mafura, li fetola matla a methapo ea methapo, kutloisiso ea liphatsa tsa lefutso, le polelo ea liphatsa tsa lefutso ka har'a lits'ebetso tsena mme li hlahisa mekhoa e kang ea ho iphepa le liphetoho tse ling tsa boits'oaro tse hopotsang lits'ebetso tsa bokhoba ba ho lemalla. (-).

Sebapali se seng se ka sehloohong taolong ea neural ea boitšoaro ba takatso ea lijo ke tsamaiso ea Acb-localised gamma-aminobutyric acid (GABA). Ho thibela ka matla ha li-neuron tsa Acb tse nang le li-agonists tsa GABA ho etsa hore ho be le karabelo e matla ho likhoto tse satiated; phello ena e ba har'a li-syndromes tse hlollang ka ho fetisisa tsa hyperphagia e entsoeng ka lithethefatsi e tsoang kae kapa kae ka har'a brain (-). Hyperphagia ena, ka karolo e tsoa ho ho bokelloa ha litsamaiso tsa hypothalamic tsa peptide tse kenyellelitsoeng molaong oa matla a matla (-). Ntle le moo, khetla ea ka ntle ea Acb ke sona feela sebaka sa telencephalic se tsejoang ho ts'ehetsa ts'usumetso ea GABA e kentsoeng ts'ebetsong ea ho latsoa tatso ea hedonic (). Ka hona, khetla ea Acb e hlahisitsoe e le sebaka sa bohlokoa marangrang matla a motlakase a tsamaisang matla a theohelang molemong oa ho hokahana le lits'ebetso tse amehang / tse khothalletsoang. (-). Nete ​​ea marang-rang e nang le thepa ena e ka emela sebaka sa bohlokoa sa neuroplasticity se matlafatsang; ka mokhoa o makatsang, leha ho le joalo, sistimi ea Acb shell GABA ha e so ithutoe ka sena.

Morero oa rona thutong ena e ne e le ho lekola hore na boiphihlelo bo pheta-phetang bo nang le meputso e tsamaisoang ke moputso, e seng nonofo ea phepelo ea lihlahisoa tsa Acb. Re ile ra fumana hore mokhoa o ikhethileng oa tšebeliso ea mafura a monate butle-butle o khotsofatsa likarabo tse matlafatsoang ke ho susumetsa ka kotlolloho ho GABAA li-receptors ka har'a khetla ea Acb. Re fuputse mekhoa ea boits'oaro le ea lithethefatsi tse tlatsetsang phello ena, ka ho totobatsa ho kenya letsoho ha mekhoa ea lehae ea Acb shell opiatergic le dopaminergic.

Mekhoa le Lisebelisoa

Lihlooho

Male Sprague-Dawley rats (Harlan Laboratories, Madison, Wisconsin) e nang le boima ba 300 ho 325 g ha e fihla e ne e kentsoe lihlopha ka bobeli ka koekoeng e hlakileng e nang le phihlello ea ho tseba lijo le metsi (ntle le liteko tse ling tse hlalositsoeng kamora nako) ka khanya le mocheso -Variari e laoloang. Li ne li bolokiloe tlasa lebili la 12-h leseli / lefifi (mabone ho 7: 00 AM). Lits'ebeletso tsohle le lits'ebetso li ne li tsamaisana le tataiso mabapi le ts'ebeliso ea liphoofolo le tlhokomelo tse tsoang ho Likolo tsa Naha tsa US tsa Bophelo mme li ne li beiloe leihlo le ho amoheloa ke Komiti ea Tlhokomelo ea liphoofolo le Ts'ebeliso ea Yunivesithi ea Wisconsin.

Tlhatlhobo ea ho buoa le ho beoa

Lits'ireletso tsa li-cannulae tsa tšepe tsa tšepe tse se nang sekheo tse nang le sepheo sa polasetiki ea Acb (23-gauge) li ile tsa kenngoa ho latela lits'ebetso tse tloaelehileng tsa stereotaxic [bakeng sa lintlha, bona Baldo le Kelley ()]. Li-coordinates tsa sebaka sa infusion (ka limilimithara ho tloha bregma) e ne e le + 3.2 (anteroposterior); + 1.0 (hamoraoomedial); −5.2 e tsoang ho lehata la lehata (dorsoventral). Mefuta ea terata e kentsoe ka har'a cannulae ho thibela blockage, mme likhoto li ile tsa hlaphoheloa ho fihlela matsatsi a 7 pele ho liteko. Qetellong ea tlhahlobo e 'ngoe le e' ngoe, ho beoa li-cannulae ho ile ha khethoa ka ho sheba likarolo tsa bongoana tsa Nissl tlas'a leseli le bobebe (bakeng sa lintlha tse ling, bona Tlatsetsa 1). Likhoto tse nang le litekanyetso tse fosahetseng tsa cannulae li ile tsa tloheloa ho tsoa tlhahlobisong ea lipalopalo; boholo ba sehlopha bo fanoeng karolong ena bo emela boholo ba sehlopha sa ho qetela kamora lithuto tse sa nepahalang li sa tloheloa.

Lithethefatsi le Microinfusions

Li-injection tsa tšepe tse se nang tšepe (30-gauge) li ile tsa theoleloa ho atolosa 2.5 mm ka mor'a ntlha ea tataiso ea cannulae. Liente tsa khatello ea pelo li ile tsa etsoa ka pompo ea microdrive. Lithethefatsi li ne li kenngoa ka tekanyo ea .32 μL ka motsotso. Nako eohle ea infusion e ne e le 93 sec, e ileng ea hlahisa palo ea infusion e felletseng ea .5 μL ka lehlakoreng le leng. Ka mor'a infusions, li-injection li ile tsa siuoa sebakeng sa 1 min ho lumella ho kenngoa ha jektheri pele ho khutšoe mekhoa. Muscimol, D- [Ala2, N-MePhe4, Gly-ol] -enkephalin (DAMGO), le d-amphetamine (AMPH) kaofela li felisitsoe ho .9% saline e se nang letsoai.

Regimen e Ntle ea Phepo

Likhoto li ile tsa pepesetsoa likarolo tse peli tsa 30-min (karolo ea hoseng le ea thapama) ka letsatsi bakeng sa matsatsi a 5 a latellanang. Lithupelo tsena li etsahetse liphuputsong tsa liteko tsa Plexiglas ka mokhoa o ts'oanang le mekotla ea lapeng, ntle le ka terata ea terata ea terata ho lumella ho bokelloa habonolo ha litšenyehelo tsa lijo. Sebokeng sa hoseng (11: 00-11: 30 AM), likhoto li ne li fuoa mafura a natsoang (sehlopha sa liteko; n = 14) kapa chow e tloaelehileng (sehlopha sa taolo; n = 14) hape e lumelletsoe ho ja ka bolokolohi. Mafura a monko o monate e ne e le teko ea liteko ea Teklad (TD 99200) e kenyelletsang ho khutsufatsa ka sucrose ea 10%, ka matla a 6.2 kcal / g (bakeng sa lintlha tse ling, bona Tlatsetsa 1). Metsi a ne a fumaneha bakeng sa lihlopha tsena ka bobeli. Ba ne ba khutlisetsoa malapeng a bona, lijo le metsi li fumaneha ka bolokolohi. Likarolong tsa thapama (3: 00-3: 30 PM), likhoto li ile tsa beoa hape mekotla ea liteko, empa lihlopha tseo ka bobeli li ile tsa fuoa chow (le metsi) tse tloaelehileng. Kahoo, likhoto sehlopheng sa liteko li ile tsa fumana lijo tse fumanehang habonolo le chow tse tloaelehileng tikolohong ea liteko. Sena se ne se etsoa ho nolofalletsa sehlopha sa liteko hore se fuoe chow mekhoeng ea liteko, hobane chow e sebelisitsoe karolong ea bobeli ea boiteko (bona "Low Dose Muscimol Phephetso Tikolohong ea Teko," ka tlase). Ts'ebetso ea lintho tse koalang ka lekeke e tlalehiloe letsatsi le leng le le leng. Standard chow (Teklad rodent laborator ea lijo) le metsi li ne li fumaneha ka linako tsohle ho koaletsoeng malapeng.

Regimen ea khatello ea khatello ea maikutlo

Mokhoa ona o bolotsana o kopilitse kemiso ea matsatsi a phepo ea 5, ntle le hore likhoto tse sehlopheng sa liteko (n = 11) e amohetse tšusumetso e matla (khatello ea papatso), ho ena le lijo tse monate, mananeong a hoseng. Rosa e ngoe le e 'ngoe e ne e beoa letsatsi le leng le le leng ka har'a kara ea tšepe e sirelelitseng (7 ho × 8 ho × 9 ho) e neng e beheletsoe 5 min kahare ho ntlo ea teraka ea Ferret (senokoane sa tlhaho sa likhoto). Makhoakhoa a sirelelitsoeng a ne a lumella liphoofolo ho bonana, ho utloa le ho fofonela Boemo bona ba ho pepeseha bo tsejoa ka ho phahamisa haholo maemo a plasma corticosterone le ho phahamisa botle bo phahameng le ho falimeha bo tšoarellang bonyane metsotso ea 30 ntle le ho felisoa ha tlhahiso e hlakileng (,). Laola likhoto (n = 10) li kentsoe ka har'a masekoana a tšireletso a ts'oanang 'me a fetisetsoa bukeng, empa ho se na lehlakore (ke hore, ha ho na li-ferrets), phapusing. Ka mor'a ho pepesetsoa 5-min ferret kapa ho pepeseha ho se nke lehlakore, litekolo tsa liteko le taolo li tlositsoe mekotleng e nyane mme hang-hang tsa kenngoa mekotla e tloaelehileng ea tlhahlobo ea Plexiglas (bona "Palatable Feeding Regimen" bakeng sa lintlha) ka phapusing ea liteko e fapaneng le kamore e thata kapa e sa nke lehlakore , bakeng sa seboka sa 30-min (11: 00-11: 30 AM). Lijo (rat rat e tloaelehileng) le metsi li ne li fumaneha ka bolokolohi. Likhoto tsohle li ile tsa khutlisetsoa malapeng a bona kamora seboka sena. Ho ntšetsa pele kemiso ea lijo tse matlafatsoang, likhoto tsohle li ile tsa fuoa lenaneo la bobeli la 30-min letsatsi le leng le le leng (3: 00-3: 30 PM) ka mekotleng e le 'ngoe ea liteko tse lekanang le mekotla ea bona ea hoseng, empa ba sa pepesehe (kapa ba sa jele paate). . Hape, lijo le metsi li ne li fumaneha ka bolokolohi ketsahalong ena ea thapama. Likhoto li ile tsa khutlisetsoa malapeng a tsona ha li qeta ho hlahlojoa.

Regimen e phetoang

Mokhoa ona o bolokile o hlophisitse kemiso ea matsatsi a phepo e ntle ea 5, ntle le hore likhoto sehlopheng sa liteko li fumana infusions ea maqhubu ea kharebe ea AMB letsatsi le leng le le leng, ho fapana le lijo tse fumanehang, bakeng sa linako tsa tsona tsa hoseng tsa hoseng. Litla-morao tsa Intra-Acb likhetla tsa AMPH (2 kapa 10 μg, n = 11 bakeng sa lethal dose le leng le le leng) kapa saline (n = 20) li fanoe hang hang pele likhoto li kenngoa ka har'a mekotla ea liteko bakeng sa lithuto tsa bona tsa hoseng (11: 00-11: 30 AM). Tekanyetso e tloaelehileng ea rat le metsi li ne li fumaneha ka bolokolohi ka nako ena, 'me ho ne ho tlalehiloe lijo tse ngata. Hyperacuction e entsoeng ke AMPH e ne e beiloe leihlo ke motho ea lekang hore a se ke a alafa kalafo, a sebelisa mokhoa oa ho lekola boitšoaro ba nako eo ho bonahaleng palo ea liketsahalo tse 'ne (tloaelo ea ho tšela likhoele, ho holisa, ho fufuleloa le ho koetlisoa) ka 20-sec nako e tlamisa metsotso e meng le e meng ea 5 bakeng sa rat e ngoe le e ngoe. Likhoto tse tsoang tekong ea khatello ea tse jang tse ling li sebelisitsoe hape bakeng sa sehlopha sa 2-μg AMPH.

Likhoto tsohle li fumane tlhaiso ea bobeli ea letsatsi le letsatsi litsing tsa liteko (3: 00-3: 30 PM) e nang le standard chow le metsi a teng empa e se na infusions ea lithethefatsi. Likhoto li ile tsa khutlisetsoa malapeng a tsona ha li qeta ho hlahlojoa.

Phephetso ea Muscimol ea Low-Dose tikolohong ea Teko

Kamora matsatsi a 5 a ho pepesehela mafura a monate, khatello ea peleho, kapa manolo a pheta-phetoang a AMPH, likhoto li amohetse liphephetso tse ikhethileng tsa intra-Acb ka letsoai le muscimol (10 ng / .5 μL ka lehlakoreng le leng) tikolohong ea liteko. Saline e ile ea fuoa likhoto ka letsatsi la botšelela (ke hore, ka letsatsi la 1 kamora ho khaotsa ho sebelisa mananeo a kalafo a 5 ka letsatsi), le intra-Acb shell muscimol ka letsatsi la bosupa. Ka le leng la matsatsi ana, likhoto li ile tsa fumana infusions ea eona ea mothapo oa Acb hang pele li kenngoa ka har'a mekotla ea liteko nakong ea tloaelo ea bona ea motšeare (3: 00-3: 30 PM). Ha ho na mananeo a hoseng a fanoeng ka matsatsi ana. Lijo (standard chow) le metsi li ne li fumaneha ka bolokolohi. Ho ja ho ile ha lekanngoa, 'me likhoto li khutlisetsoa matlong a tsona ha li qetile tlhahlobo. Chow e sebeliselitsoe mohato ona oa teko hobane lihlopha tsohle li ne li kile tsa amohela chow maemong a tlhatlhobo, ka hona, tsa felisa ho ferekana ha lijo tse ncha. Ntle le moo, hobane litheko tsa mantlha tsa ho ja li ne li le tlase, ho ne ho na le monyetla o fokolang oa ho kopana le litlamorao tsa hyperphagia ea muscimol.

Setsi sa likhoto se fumanehang ho mofuta o fumanehang habonolo oa phepo (n = 10 mafura a monko o monate, n = Lits'ebetso tsa 10 chow) li amohetse mats'oafo a mang a saline le muscimol 7 matsatsi a kamora ho fela ha protocol e pepesehileng ea mafura a se nang phello e monate pakeng tsa. Moralo oa boraro oa tlhahiso ea letsoai / muscimol o ile oa fuoa matsatsing ana a 14 kamora ho fela ha protocol, hape ntle le ho pepeseha ha nakoana mafura a monate.

Hlokomela hore taelo ea saline le muscimol infusions li ne li sa hanyetsanoe (ke hore, letsoai le lula le tla pele), e le hore karabo kapa likarabo tse felletseng tsa tšebeliso ea cue li ka fumanoa ka letsatsi la phephetso ea letsoai ntle le tšitiso ea pherekano ea muscimol e fetileng. phephetso. Hape hlokomela hape hore bakeng sa sehlopha sa 10-μg AMPH, phephetso e eketsehileng ea muscimol (50 ng) e fanoe ka Letsatsi la 8.

Phephetso ea ho tlosa lijo sebakeng sa liteko

Likhoto li ile tsa fuoa mofuta o fumanehang oa phepo ea phepo bakeng sa matsatsi a 5 joalo ka ha ho hlalositsoe pejana (n = 10 ea sehlopha sa mafura a monate, n = 11 ea sehlopha sa taolo ea chow). Ka letsatsi la botšelela, liphoofolo tsohle li ile tsa fumana infine ea letsoai 'me tsa lekoa sehlopheng sa tsona sa tloaelo sa motšehare (3: 00-3: 30 PM) e nang le standard chow le metsi a fumanehang. Ha ho seboka sa hoseng se fanoeng. Kamora moo, likhoto tsohle li ile tsa fumana phephetso ea khaello ea lijo eo lijo li tlositsoeng ho eona malapeng ka mor'a lihora tse 18 pele ho liteko (ke hore, ka shoalane ea letsatsi la phephetso ea saline). Letsatsing le hlahlamang, likhoto tsena tse sa felloang ke lijo li ile tsa fuoa infusions-acb ea khubung ea letsoai 'me tsa beoa ka mekotleng ea tlhahlobo (ka standard chow le metsi a teng) nakong ea tlhahlobo ea thapama, ho se na lenaneo la hoseng. Ho ja ho ile ha lekanngoa, 'me likhoto li khutlisetsoa matlong a tsona ha li qetile tlhahlobo.

DAMGO / Muscimol Cross-Sensitization

Re sebelisitse moralo o fapaneng hanyane bakeng sa teko ena, hobane 2.5-μg DAMGO e baka ts'oenyeho ponts'o ea lithethefatsi tsa pele tsa likhoto; sedation ena e lula e le haufi le 30 ho isa ho 45 min (moo likhoto li qalang ho e ja bakeng sa metsotso ea 90). Ka hona, re sebelisitse kemiso e le 'ngoe ea hora ea 2 e nkang letsatsi ntle le kemiso ea motšeare. Likhoto tsa Ad libitum-tse neng li bolokoa li ile tsa fuoa infusions tse 'ne tsa qoqotho tsa Acb (infusion e le' ngoe ka letsatsi, letsatsi le leng le le leng) ea letsoai .9% saline (n = 7) kapa DAMGO (2.5 μg / .5 μL ka lehlakoreng le leng; n = 6). Kamora ho kenngoa, likhoto li ile tsa kenngoa hang-hang mekotla ea liteko bakeng sa 2 h (11: 00 AM-1: 00 PM) le phihlello ea tloaelehileng le metsi. Lihora tse mashome a mane le metso e robeli kamora ho qetela kalafo e phetoang, lithuto li ile tsa fumana infraile ea letsoai ea Acb 'me tsa kenngoa ka har'a mekotla ea lihora tsa 2 ka chowoku le metsi a tloaelehileng. Matsatsi a mabeli hamorao, ba ile ba qholotsoa ka muscimol (10 ng / .5 μL), ba beoa hang-hang ka mor'a ho kenngoa ka har'a mekotla ea liteko bakeng sa lihora tsa 2 ka chowoku le metsi. Ka letsatsi le leng le le leng la tlhahlobo, ho ja ho ne ho tlalehiloe, 'me likhoto li ne li khutlisetsoa malapeng a bona hang hang kamora ho fela ha lenaneo la tlhahlobo.

Tlhahlobo ea Litekanyetso

Mabaka a mabeli a hlahlobisisang phapang (pheko ea letsatsi la ho phekola, kapa phephetso ea nalane ea kalafo, joalo ka ha ho loketse) ho ile ha sebelisoa lipapiso tse lekantsoeng ho lekola liphapang lipakeng tsa taolo-phetoho (lijo, kalafo ea lithethefatsi, khatello ea maikutlo) le taolo e itseng. Alfa e behiloe ho p <.05. Liphuputso li ile tsa etsoa ho sebelisoa software ea StatView (SAS Institute, Cary, North Carolina).

Results

Metsoako e Meholo ea Phallo ea Mafura e Notsoeng hamonate e Utloisisa Karabelo ea ho Fepa Elic E ngotsoe ke Intra-Acb Shell Muscimol

Ho ja mafura a monate ka linako tsa phepelo ea hoseng ho matlafalitse nakong ea protocol ea matsatsi a 5 [F(4,52) = 13.3; p <.0001; Setšoantšo sa 1A]. Ka letsatsi la bohlano, ho ja lijo tse nang le mafura a mangata e ne e le 4.9 g, e lekanang le 30.4 kcal, ha e bapisoa le tšebeliso ea matla ea 1.8 kcal ea chow sehlopheng sa taolo. Habohlokoa, ho ne ho se na phapang e akaretsang ea boima ba 'mele lipakeng tsa lihlopha tse mafura a tsoekere le a chow nakong ea protocol ea letsatsi ea 5 [F(1,26) = .3; eseng bohlokoa (ns)], 'me ha ho na tšebelisano ea letsatsi le le leng le le leng mabapi le boima ba' mele [F(4,104) = 1.2; ns]. Kahoo, likhoto sehlopheng sa liteko li ile tsa bonahala li koahela tšebeliso ea "caloric" e eketsehileng, mohlomong ka ho fokotsa tšebeliso ea lipapatso tsa bona malapeng (ke hore, likarolo tse khutšoane tsa ho pepesetsoa mafura a monate ha li a ka tsa hlahisa litlamorao tse kang lefu la botena). Bakeng sa mananeo a thapama, moo lihlopha ka bobeli li fuoeng chow, ho ne ho se na phapang pakeng tsa sehlopha sa ho ja le ho se sebelisane ka mokhoa oa ho ja ka letsatsiFs = .2-1.3; ns). Kahoo, ho pepesetsoa mafura a tsoekere a tsoekere ha ho a ka ha susumetsa boemo bo tlase ba phepelo e bonoang mananeong a ho nona a mots'eare.

Setšoantšo sa 1   

Ho ja mafura a natefisitsoeng kapa chowon ka har'a protocol ea matsatsi a 5, moo sehlopha se seng sa likhoto se fumanang mafura a 30 a letsatsi le letsatsi a mafura a monate (sehlopha sa "mafura a monate", n = 14) hoseng (A) le chow thapama (B), 'me ...

Kamora ho phethela protocol ena ea nakoana ea phihlello litheko tsohle li ile tsa qholotsoa ka ho kenella kahare ho Acb ka khubung ea letsoai le muscimol (10 ng). Likhoto tse senotsoeng mafura a natefiloeng ha lia ka tsa bontša karabelo e fetotsoeng ea phepo phephetsong ea letsoai ha e bapisoa le taolo e pepesitsoeng ea chow. Leha ho le joalo, ba bontšitse tšusumetso e matla, e matla haholo ea maikutlo a ts'usumetso ea lijo tse matlafalitsoeng ke muscimol (tšebeliso ea lijo tsa xF(1,26) = 13.6, leq = .001; Setšoantšo sa 2 bakeng sa papiso e khethehileng]. Tšebeliso ea metsi e ne e sa amehe. Joalokaha ho bontšitsoe Setšoantšo sa 2, senscization ea muscimol e ne e ntse e le teng matsatsi a 7 kamora mokhoa o monate oa mafura [F(1,18) = 9.3; p = .007]; Matsatsi a 14 kamora ho pepesetsoa, ​​leha ho le joalo, karabelo ea maikutlo e ne e fokotsehile [F(1,14) = 1.6; ns]. Kamora nako, likhoto tse pepesetsoeng mofuta oa mafura a monate ha lia ka tsa bonts'a karabo ea phepelo e matla ea phepelo ea hora ea 18 ea ho itima lijo ha e bapisoa le balekane ba bona ba pepenene [F(1,19) = .004, ns; Setšoantšo sa 2].

Setšoantšo sa 2   

Likhoto tse pepesitsoeng protocol ea letsatsi le mafura a 5 e bonts'itseng hypustensitivity ho lethal e le tlase la intra-nucleus accumbens (Acb) shell muscimol, e nkile matsatsi a 7 empa e ne e qalile ho fokotseha ka matsatsi a 14. “Sal” e supa ...

Tšusumetso ea sefapano lipakeng tsa μ-Opioid Receptor le GABA Receptor Stimulation sebakeng sa Acb Shell

Joalokaha ho bontšitsoe ho Setšoantšo sa 3, intra-Acb shell DAMGO e hlahisitse hyperphagia e matla ho le leng la matsatsi a jekeng ea 4 ea karolo ea "DAMGO e pheta-phetoang [F(1,11) = 62.3; p <.0001]. Kamora litlhare tsena tse pheta-phetoang, re ile ra phephetsa likhoto ka letsoai le muscimol; Bakeng sa liphephetso tsena, tlhahlobo ea phapang e hlahisitse litlamorao tse matla tsa nalane ea kalafo e sa foleng [F(1,11) = 7.8; p = .018] le phephetso ea lithethefatsi [F(1,11) = 12.1; p = .005], empa ha ho na tšebelisano [F(1,11) = 1.4; ns]. Leha ho le joalo, lipapiso tse reriloeng lipakeng tsa DAMGO le lihlopha tsa saline bakeng sa ente e 'ngoe le e' ngoe ea phepelo e hlahisitse hore tšebeliso ea lijo ka lebaka la bothata ba intra-Acb shell muscimol e ne e phahame haholo ho likhoto tse tšoaroang ke DAMGO ha li bapisoa le likhoto tse entsoeng ka letsoai le holimo (p <.05) empa karabelo phephetsong ea letsoai e ne e sa fapane lipakeng tsa lihlopha.

Setšoantšo sa 3   

Lits'ila li phekotsoe khafetsa ka li-intra-nucleus accumbens (Acb) maqhubu a khetla ea μ-opioid agonist D- [Ala2, N-MePhe4, Gly-ol] -enkephalin (DAMGO) e bontšitse tšibollo ea maikutlo bakeng sa phephetso e tlase ea muscimol. Saline ea khetla ea intra-Acb ea pele ...

Ho ba sieo ha Muscimol Hypersensitivity Kamora ho Phetoa khafetsa, Phatlalatso ea Khatello ea Khatello ea Kelello kapa Intra-Acb Shell infusions tsa AMPH

Liteko tse peli li ile tsa etsoa ho leka litlamorao tsa ho pepesetsoa ha sebatana le kalafo ea AMPH e phetoang mabapi le karabelo ea morao ea muscimol. Taba ea mantlha, likhoto li ile tsa hlaheloa ke mofuta oa tlhahlobo ea mahlaseli a 5 ea matsatsi a mane tse lateloang ke mathata a intra-Acb shell saline le muscimol (10 ng). Joalokaha ho bontšitsoe Setšoantšo sa 4, nalane ena ea ho pepesoa ha khatello ea maikutlo ha e fetole karabelo ea phepelo phephetsong e ileng ea latela ea muscimol [F(1,19) = 1.1, ns]. Ka mor'a moo, likhoto tse tšoanang li ile tsa beoa khaolong ea matsatsi a 5 ea letsatsi le letsatsi ea li-infusions tsa shell tsa intra-Acb (2 μg). Joalokaha ho ne ho lebelletsoe, AMPH e hlahisitse ts'ebetso ea makoloi a matla joalo ka ha ho bonts'oa "manyalo a mangata a mosebetsi" oa ho tšela likhomo, ho holisa, ho fafatsa, le ho ikoetlisa (bona Mekhoa le Lisebelisoa) ha li bapisoa le likhoto tse tšoeroeng ke letsoai [F(1,22) = 53.9; p <.0001; Setšoantšo sa 5A], ho bonts'a hore tekanyetso e ne e sebetsa ka mokhoa o hlakileng. Phekolo ea Acute ea AMPH ha e-so ka e fetola mekhoa ea ho itšunya-tšunya [tšebelisano ea matsatsi a F(4,76) = .5, ns; ya data e sa bontsweng]. Kamora ho phethela karolo e pheta-phetoang ea AMPH- kapa ea saline-saline, liteko tsohle li ile tsa phephetsoa ka moline-Acb shell saline le muscimol. AMPH ha ea ka ea fetola haholo maikutlo a ho fepa ka tšusumetso ea muscimol (Setšoantšo sa 5B). Ho bile le phello e matla ea kalafo ea kalafong ea kalafo ea kalafo [F(1,19) = 3.6; p = .02]; leha ho le joalo, papiso e reriloeng e senotse hore ts'ebelisano ena e ne e le haholo ka lebaka la phapang e kholo ea kahare ho lithuto ho rarolla mathata a letsoai le mascimol sehlopheng sa AMPH (p = .0009). Leha ho le joalo, ho ne ho se na phapang ea bohlokoa lipakeng tsa lihlopha tsa letsoai le AMPH ho arabela phephetso ea muscimol (p = .11).

Setšoantšo sa 4   

Likhoto tse pepesitsoeng ha nakoana, liketsahalo tse khutšoane tsa khatello ea likhathatso ka matsatsi a 5 (bona Mekhoa) ha lia ka tsa bonts'a phetoho efe kapa efe ea maikutlo a phetoho ea intra-nucleus accumbens (Acb) shell muscimol. Mefuta e mengata ea sehlopha e ne e le likhoto tsa 11 bakeng sa sehlopha sa khatello ea maikutlo, 10 ea ...
Setšoantšo sa 5   

Litlhare tse phetoang khafetsa ka li-infra-nucleus accumbens (Acb) shell d-amphetamine (AMPH, 2 μg) infusions ha lia ka tsa hlahisa hypersensitivity ho phello ea ho fepa ea lethalinyana le tlase la intra-Acb shell muscimol. (A) Acute AMPH e hlahisitse motor bohlokoa ...

Ho hlahloba ka ho eketsehileng litlamorao tsa infusions tse ngata tsa AMPH ho sensitivity ea muscimol (ho nka hore likhoto tse hatisitsoeng li sebelisitsoe bakeng sa liteko tsa AMPH mme boiphihlelo bona ba khatello ea morao-rao bo ka be bo fetotse likarabo tsa bona tsa AMPH), tlhahlobo ea bobeli e ile ea etsoa sehlopheng se arohaneng sa likhoto tseo e seng tsa nnete moo lithuto li ile tsa ngoloa khafetsa matsatsing a 5 ea infra-Acb shell infusions ea lethal e phahameng ea AMPH (10 μg), ea lateloa ke mathata a kokelo ea shell ea intra-Acb ka saline le litekanyetso tse peli tsa muscimol (10 le 50 ng). Hape, re hlokometse ts'ebetso e matla ea koloi e matla ho arabela matseng a AMPH [F(1,22) = 83.7; p <.0001; Setšoantšo sa 6], empa ha ho litlamorao ho fepa [F(4,76) = 1.7, ns]. Ha likhoto tsena li ne li qholotsoa ka 10-ng kapa 50-ng intra-Acb shell muscimol, li ile tsa sitoa ho bonts'a likarabo tse khothatsang tsa ho fepa [F(2,38) = 1.4; ns]. E le taolo e ntle, likhoto sehlopheng sa AMPH li ne li se li pepesoa mofuta oa 5 o monate oa letsatsi le mafura (le likhoto sehlopheng sa letsoai ho ea regimen ea chow); likhoto tsohle li ile tsa qholotsoa ka ho kenella kahare ho 10-ng muscimol. Re hlokometse karabelo ea maikutlo a phepelo ea muscimol likotong tsena kamora ho pepesetsoa hoa mafura a monate [F(1,19) = 5.8; p = .027; inset, Setšoantšo sa 6], ho bontša hore likhoto tse tšoanang tse sa kang tsa bonts'a maikutlo kamora ho pheta-pheta ha AMPH li ne li khona ho nts'etsapele le ho hlahisa maikutlo a muscimol ha a arabela ho pepesetsoa hoa mafura a monate.

Setšoantšo sa 6   

Litlhare tse phetoang khafetsa ka li-infra-nucleus accumbens (Acb) shell d-amphetamine (AMPH, 10 μg) infusions ha lia ka tsa tlisetsa hypersensitivity litlamorao tsa ho fepa ka tekanyo e tlase ea intra-Acb shell muscimol (Musc). Moralo o akaretsang oa teko ena ...

Sebaka sa Plannulae

Setšoantšo sa 7 e bonts'a 'mapa oa merero ea ho bea li-cannulae ho tsoa liteko tsohle tsa thuto ena. Joalokaha ho ka bonoa setšoantšong, boholo ba lipehelo (95%) li ile tsa oela kahare ho halofo e kantle ea khetla ea medb Acb, ho kenyeletsoa le lekala le hole haholo. Liperesente tse hlano tsa ho beoa li oetse hantle feela bohareng ba bophahamo ba anteroposterior, ka hara lekala le fanang ka likarabo tse nang le takatso empa e le sebaka sa ts'ebetso se fanang ka boits'oaro bo ts'oanang le boits'ireletso (). Ho beoa kahara libaka tsena ho ne ho emeloa ka mokhoa o tšoanang litekong tsohle, 'me ho ne ho se na phapang e fapaneng litabeng tsa boitšoaro kapa litlamorao tsa karohano ka har'a axis ea anteroposterior.

Setšoantšo sa 7   

Litšoantšo tse mola tse bontšang ho kenella ka sejoeng sa nucleus li bokella likhetla ho tsoa liteko tsohle. Libaka tse nang le tšenyo e kholo li bonts'a libaka tseo 95% ea lipehelo li oeleng ho eona; libaka tse hloahloa li bonts'a ho beha ha 5% e setseng. Ho ne ho se na tsamaiso ...

Puisano

Thutong ena, re bontša mofuta o mocha oa tloaelo ea ho iphepa e khothatsang bokong. Litlamorao tse matla tsa tšebeliso ea mafura a tsoekere a ile a hlasimolla matla a ho fepa a hlahisoang ke phephetso ea tekanyo e tlase ea muscimol khetla ea Acb; phello e matlafalitsoeng e ne e batla e lekana le e hlahisoang ke tekanyo e phahameng ka makhetlo a mahlano ea muscimol ho litoeba tse se nang thuso. Ts'ebetso ena ea hypersensitivity e ne e sa bonahale e le phello e sa utloahaleng ea ho kopanya hoa tlhaho e fapaneng le tikoloho e amanang le ho pepeseha hoa mafura a monate. Ka hona, ho pepesetsoa khafetsa ho susumetsang ho susumetsang haholo (ho pepeseha khatello ea khatello ea maikutlo), esita le tse nang le tšusumetso e ntle ea moea (intra-Acb shell AMPH) (-), li ne li sa lekana ho susumetsa ho feptjoa ha muscimol. Ho fapana le moo, infra-Acb shell infusions ea DAMGO, e ileng ea phahamisa ho fepa nakong ea ts'ebetso ea boiphetetso ea teko, e hlahisitse maikutlo a matla a ho sisinyeha ho muscimol. Ka hona, thepa e tloaelehileng ea ho ja mafura a monate le ho tsamaisoa ke μ-opioid e tsamaeang le chow, ntle le ntlafatso ea bona ea mohopolo o akaretsang, e hlokahala bakeng sa ho kenyelletsa maikutlo a GABA. Ka botlalo sena se bonts'a hore thepa ea orosensory kapa postingestive e ikhethang ho tsoekere kapa mafura ha e tlangoe ho nts'etsopele ea muscimol sensitization. Sebakeng seo, mochine o tloaelehileng oa ho hohela o ka pheta-pheta ho tšoaea ha op-opioid ka har'a khetla ea Acb, e hlahisoang ke tsamaiso ea DAMGO ea kantle kapa tlhahiso ea peptide ea μ-opioid ea khale e ts'oeroeng e khopisitsoe ke ho tsikinyeha hoa mafura.

Mabapi le sena, ho bontšitsoe hore ho ts'oaroa ha li-receptor tsa intra-Acb μ-opioid maemong a Acb ho hlahisa sensio ea opioid le karabelo ea boemo ba ho fepa phephetso e latelang ea saline (). Litholoana tsena li ikemetse ka mokhoa oa dopamine (), joalo ka lits'ebetso tse ling tsa Acb-localized, μ-opioid-Mediated tse kang ntlafatso ea tatso ea tatso ea hedonic (,,). Ka mokhoa o akaretsang, ho se atlehe ha infusions ea AMPH e phetoang ho fepela maikutlo a susumetsang a muscimol a lumellanang le liphumano tsena; ka hona, opioid-GABA-sensitization ea sefapano e ka emela mofuta oa neuroadaptation e ikemetseng ea dopamine ho Acb. Ho khahlisang, ha rea ​​ka ra bona karabelo ea boemo ba phepo phephetso ea letsoai ho litoeba tse tšoaroang ke DAMGO. Hlokomela, leha ho le joalo, hore ho kenyelletsa phello ea phepo e nang le opioid e ka feto-fetoha 'me ho hloka kalafo e phetoang makhetlo a mane (V. Bakshi, puisano ea motho, June 2012). Ho sa tsotelehe, liphetho tsena li bonts'a hore phello ea phepo e phetseng hantle (bonyane, e nang le bokhoni ba ho senoloa ka phephetso ea saline) ha e hlokehe bakeng sa tlhahiso ea maikutlo a matla a sefapano sa opioid-GABA. Ntle le moo, ha re so ka ra bona likarabo tse matlafatsoang ke likhoto tse senotsoeng mafura mantsiboea a kopor, kapa karabelo mathateng a letsoai kapa tlala, ho bonts'a ho hlaka ho itseng mochineng o hapang maikutlo bakeng sa karabelo e khothatsang ea ho fepa.

Mokhoa oa neural oa ho fepa o hlahisoang ke muscimol le li-amino acid tse ling ka har'a khetla ea Acb e bonahala e le tšitiso ea tekano ea li-activation tsa AMPA-Mediated le GABA-Mediated inhibitory signaling ho li-neuron tse bohareng. Ha ts'ebetso ea ts'ebetso e le phokotso ts'ebetsong ea li-neuron tsena, ekaba ka GABA-Mediated inhibition kapa ka blockade ea AMPA-mofuta glutamate receptors, robust hyperphagia e bakoa (,,,). Kahoo, tlhaloso e hlakileng ea sephetho sa rona ke hore ts'ebetso e phetoang ea li-receptor tsa μ-opioid (e laetsoeng ka mokhoa o tsoileng matsoho DAMGO kapa tokollo ea peptide ea opioid peptide e hlahisitsoeng ke mafura a monate) e khothaletsa phetoho e tobileng ho GABAA sensitivity sensiti ka se, kapa phetoho e akaretsang ho tekano ea phetiso / e thibelang maikutlo e le hore ho ka ba bonolo ho fihlella mokhoa oa ho thibela ts'ebetso ea GABA-Mediated inhibition.. Phekolo e phetoang khafetsa ea opioid agonist (morphine) e hlahisa litlamorao ho ena, joalo ka Gaba ea ho eketsehaA libaka tsa marang-rang tse bokelletsoeng le tšebetso ea chloride e khothalletsoang ke muscimol ka li-synaptosomes (), molemong oa GABAA expression-subunit expression in b inb), le ho kenella kahare ha GluR1 subunit ea li-receptor tsa AMPA khetla ea Acb (). Mang kapa mang a mekhoa ena (kapa motsoako oa 'ona) ka har'a khetla ea Acb a ka khona ho hlahisa hypersensitivity ho ea ka muscimol-induction neural inhibition. Leha ho le joalo, litlhaloso tse ling lia khoneha; mohlala, ho kanna ha ba le neuroadaptations kahare ho "tlhahiso" ea marang-rang eo ho eona ho buuoang ka Acb-shell-Mediated tabia ea ho fepa (joalo ka lateral hypothalamus). Ho hlokahala lithuto tse ling ho leka monyetla ona.

Mabapi le bohlokoa ba bongaka ba liphumano tsena, monyetla o khahlisang ke hore GABA hypersensitivity khetla ea Acb e hlaha ho arabela maemong a tšohanyetso a sitisang nako e telele, maemo a phahameng a phasic ho saenaeng ea μ-opioid, joalo ka "phephetso" ea phepo e ntle.. kentlheng ena, phetoho ea GABA e ka emela mokhoa oa phepelo bakeng sa boits'ebetso bo sa khaotseng ba takatso ea lijo. Liphetho tsa rona li kanna tsa ba le kutloisiso ho utloisiseng litlamorao tsa "crossover" lipakeng tsa moputso oa lijo le lithethefatsi tse ling tsa tlhekefetso. Moemeli a le mong ea hlakileng ke joala (EtOH), litlamorao tsa tsona tse fetotsoeng ke litsamaiso tsa μ-opioid le GABA ka bobeli ho Acb (-). Ho khahlisang, liphuputso tse ling li tlalehile setsoalle lipakeng tsa litakatso tsa lijo, ho itlopa joala le tšebeliso ea lino tse tahang bathong (,). Lithutong tsa liphoofolo, ebang ke GABA kapa opioid receptor blockade khetla ea Acb e fokotsa ho kenella ha EtOH [(,), empa bona Stratford le Wirtshafter ()], hape, ka mokhoa o makatsang, EtOH e ipehile ka kotloloho ho khetla ea Acb (). Ntle le moo, boithuto ba morao-rao ba positron emission tomography bo bontšitse hore ho tšoaea μ-opioid ho Acb ho tsamaisana le seno se tahang se nooang se monate (). Boemong ba cellular, ho bontšitsoe hore Acb shell-localized GABAA li-receptors tse nang le δ subunit li fetola litla-morao tsa boits'oaro ba tšebeliso ea li-EtOH tsa boleng bo tlase (); joalo ka ha ho boletsoe pejana, polelo ea mofuta oa subunit ena e kenelletsoa hape ka har'a khetla ea Acb ka ho hlohlelletsa hangata ha μ-opioid receptor (). Kahoo, ho ka etsahala hore tokollo ea "li-peptide" tsa "oproid" ka lijo tse fumanehang habonolo molemong oa ho nooa oa EtOH kapa lino tse nooang tse natefiloeng (joalo ka tse rekisoang ho ba noang bongoana) li ka kenya letsoho li-neuroadaptations tse potlakileng. liseketeng tsa Acb shell amino acid-li-coded. Khopolo-taba ena, leha e le e inahaneloang, e lebisa ponong e lekiloeng mabapi le moelelo o ka bang teng moo maikutlo a GABA a liphatlalatso tsa meputso ea kelello ea batho ba tlokotsing a ka etsang hore lijo tse fumanehang habonolo li "sebelisoe ka lithethefatsi" bakeng sa ho phahama ha methapo ea lijo le tšebeliso ea EtOH.

Boitsebiso bo Eketsehileng

Faele ea tlatsetso

lumela hore baa fokola

Mosebetsi ona o tšehelitsoe ke National Institutes of Health Grant Nos. DA 009311 le MH 074723. Tlhahiso-leseling ea lintlha tsena e hlahisitsoe e le sebopeho sebokeng sa 2009 sa Mokhatlo bakeng sa Seboka sa Study of Ingestive Behaeve in Portland, Oregon.

Mongolo o botlaaseng ba leqephe

Bangoli ha ba tlalehe litabeng tsa lichelete kapa litabeng tse ka 'nang tsa e-ba le thahasello.

Lintho tse ling tse eketsehileng e boletsoeng sengoliloeng sena e fumaneha inthaneteng.

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