MAFUNSO: Kuwonanso kwauchidakwa kumatanthawuza njira zowonongeka ndi akatswiri awiri otsogolera a dziko lapansi. Zindikirani kuti Nora Volkow ndi mtsogoleri wa NIDA, ndipo adanena kuti kuledzera kwa makhalidwe kumaphatikizapo njira zofanana komanso ubongo umasinthira monga mankhwala osokoneza bongo.
KUPHUNZIRA KWAMBIRI - Neuropsychopharmacology. 2010 Januware; 35 (1): 217-238.
Yofalitsidwa pa intaneti 2009 Ogasiti 26. doi: 10.1038/npp.2009.110
Kudalirika
Kuledzera ndizovuta zomwe zimabwereranso zomwe zadziwika ndi (1) kukakamizidwa kufunafuna ndikumwa mankhwalawa, (2) kulephera kudziletsa pakuchepetsa kudya, ndi (3) kutuluka kwamalingaliro oyipa (mwachitsanzo, dysphoria, nkhawa, kusakwiya) kuwonetsa chidwi chodziletsa pakutha kwa mankhwalawa. Kugwiritsa ntchito mankhwala osokoneza bongo kumadziwika kuti ndi vuto lomwe limakhudza kusakhudzidwa ndi kukakamizidwa komwe kumapangitsa kuti pakhale chizolowezi chomwa mankhwala osokoneza bongo chopangidwa ndi magawo atatu: 'kumwa mowa mwauchidakwa', 'kusiya / kusokoneza', ndi 'kutanganidwa / kuyembekezera' (kukhumba). Kafukufuku wazinyama ndi umunthu awulula maseketi apadera omwe amalumikizitsa magawo atatu azolowera zosokoneza bongo ndi zinthu zazikulu za ventral tegmental m'dera ndi ventral striatum ngati gawo lofunikira pakumwa mowa mwauchidakwa / kuledzera, gawo lofunikira kwambiri kwa amygdala owonjezera pakutha / zoyipa zimakhudza gawo, komanso gawo lofunikira pakulingalira / kuyembekeza kwa intaneti yomwe imagawidwa kwambiri yokhudza orbitofrontal cortex-dorsal striatum, preortal cortex, basolateral amygdala, hippocampus, ndi insula yomwe imakhudzidwa ndikulakalaka ndi gingasi wa cingate, dorsolateral pre mbeleal, ndi zida zazing'ono zakutsogolo zosokoneza zoletsa. Kusintha kwa chizolowezi kumakhudzanso kutayika kwa thupi m'zinthu zonsezi zomwe zimatha kuyamba ndi kusintha kwa mesolimbic dopamine system ndi kutulutsa kwa neuroadaptations kuchokera ku ventral striatum kupita ku dorsal striatum ndi orbitofrontal cortex ndipo pamapeto pake kuwonongeka kwa preortal cortex, cingate gyrus, ndikulitsa amygdala . Kuwonjezeka kwa ma neurocircuitry of the evolving magawo a matenda osokoneza bongo kumapangitsa kuti pakhale chiyembekezo chofunafuna ma molekyulu, majini, ndi ma neuropharmacological neuroadaptations omwe ali pachiwopsezo chokhala ndi vuto losungulumwa.
ZOKHUDZA KWAMBIRI
Kusokoneza Ubongo Tsankhu: Kugwiritsa Ntchito Mankhwala Osokoneza Bongo, Kugwiritsa Ntchito Mankhwala Osokoneza Bongo, ndi Kugonjetsa Kwadongosolo
Kuledzera ndi mankhwala osokoneza bongo ndi vuto lomwe limabweranso nthawi zonse lomwe limadziwika ndi (1) kukakamizidwa kufunafuna ndi kumwa mankhwalawa, (2) kulephera kudziletsa pa kuchepetsa kumwa mankhwala, ndi (3) kuonekera kwa mkhalidwe woipa wamaganizo (monga dysphoria, nkhawa, kukwiya) komwe kumasonyeza vuto la kusiya kugwiritsa ntchito mankhwala osokoneza bongo pamene mwayi wopeza mankhwalawa waletsedwa (wotanthauzidwa kuti Substance Dependence ndi Diagnostic and Statistical Manual of Mental Disorders [DSM] ya American Psychiatric Association; Koob ndi Le Moal, 1997 ; Table 1 ). Kugwiritsa ntchito mankhwala osokoneza bongo nthawi zina koma pang'ono kumasiyana ndi kugwiritsa ntchito mankhwala osokoneza bongo mopitirira muyeso, kutayika kwa ulamuliro pa kuchepetsa kumwa mankhwala osokoneza bongo, komanso kubuka kwa kufunafuna mankhwala osokoneza bongo kosalekeza komwe kumadziwika ndi kuledzera. Kusiyanitsa kwakukulu pakati pa kugwiritsa ntchito mankhwala osokoneza bongo, nkhanza, ndi kudalira kwawonetsedwa ndi deta yosonyeza kuti pafupifupi 15.6% (29 miliyoni) ya akuluakulu aku US adzapitiriza kugwiritsa ntchito mankhwala osokoneza bongo osagwiritsidwa ntchito kuchipatala kapena osaloledwa nthawi ina m'miyoyo yawo, ndipo pafupifupi 2.9% (5.4 miliyoni) adzayamba kugwiritsa ntchito mankhwala osokoneza bongo osaloledwa ( Grant ndi Dawson, 1998 ; Grant et al , 2004 ). Pa mowa, 51% (120 miliyoni) ya anthu azaka zopitilira 12 anali ogwiritsa ntchito panopa, ndipo mwa ogwiritsa ntchito pano, 7.7% (18 miliyoni) adakwaniritsa zofunikira za Kugwiritsa Ntchito Mankhwala Osokoneza Bongo Kapena Kudalira Mowa. Pa nikotini, mu 2007, pafupifupi 28.6% (70.9 miliyoni) aku America azaka 12 kapena kupitirira anali ogwiritsa ntchito fodya (mwezi watha), ndipo mwa ogwiritsa ntchito pano, 24.2% (60.1 miliyoni) anali osuta fodya pano; 5.4% (13.3 miliyoni) ndudu zosuta; 3.2% (8.1 miliyoni) ankagwiritsa ntchito fodya wopanda utsi; ndipo 0.8% (2.0 miliyoni) ankasuta fodya m'mapaipi ( Substance Abuse and Mental Health Services Administration, 2008 ).
Ngakhale kuti ambiri mwa kafukufuku woyamba wa mankhwala ozunguza bongo amatha kugwiritsira ntchito mankhwala osokoneza bongo (omwe amafanana ndi kuyerekezera kugwiritsa ntchito mankhwala osokoneza bongo), cholinga chake tsopano chikusinthira ku chitukuko chosatha komanso kusintha kwakukulu kwa nthawi yaitali. mu ubongo zomwe zimabweretsa kubwerera. Kafukufuku wa kafukufuku wokhudza kugwiritsa ntchito mankhwala osokoneza bongo amadzimadzi ndikumvetsetsa njira zamagulu / epigenetic, ma cell, ndi maselo omwe amachititsa kusintha kwa nthawi zina, kugwiritsa ntchito mankhwala osokoneza bongo mpaka kutayika kwa khalidwe lofuna kugwiritsira ntchito mankhwala osokoneza bongo komanso kugwiritsa ntchito mankhwala osokoneza bongo. pambuyo posiya kudziletsa kwanthaŵi yaitali kumene kumadziwika kuti ndiledzere.
Njira yolumikizirana maganizo ndi maganizo yomwe imapereka magwero abwino komanso oipa olimbikitsira kumwa mankhwala osokoneza bongo ndi lingaliro lakuti kuledzera ndi mankhwala osokoneza bongo kuli ndi mbali zonse ziwiri za matenda oletsa kutengeka maganizo ndi matenda okakamiza ( Table 1 ). Matenda oletsa kutengeka maganizo amadziwika ndi kupsinjika maganizo kapena kudzuka mtima musanayambe kuchita chinthu chosafuna kutengeka maganizo komanso chisangalalo, kukhutira, kapena mpumulo panthawi yochita chinthucho. Matenda oletsa kutengeka maganizo amagwirizanitsidwa kwambiri ndi njira zabwino zolimbikitsira ( American Psychiatric Association, 1994 ). Mosiyana ndi zimenezi, matenda okakamiza maganizo amadziwika ndi nkhawa ndi kupsinjika maganizo musanayambe kuchita chinthu chosafuna kutengeka maganizo komanso kupumula ku kupsinjika maganizo mwa kuchita khalidwe lokakamiza. Matenda okakamiza maganizo amagwirizanitsidwa kwambiri ndi njira zolimbikitsa zoipa komanso kudzipangitsa kukhala wodzidalira.
Kutha kwa zochitika za kulephera kuchita zinthu mopitirira muyeso ndi kukakamiza kumabweretsa chizolowezi chophatikizana chokhala ndi magawo atatu—kumwa mowa mopitirira muyeso/kuledzera, kusiya/kukhudzidwa ndi zinthu zoipa, kuganizira kwambiri/kuyembekezera—momwe kulephera kuchita zinthu mopitirira muyeso nthawi zambiri kumalamulira pachiyambi ndipo kulephera kuchita zinthu mopitirira muyeso pamodzi ndi kukakamiza kuchita zinthu mopitirira muyeso kumalamulira mtsogolo. Munthu akamachoka pa kulephera kuchita zinthu mopitirira muyeso kupita ku kukakamiza kuchita zinthu mopitirira muyeso, kusintha kumachitika kuchokera pa kulimbitsa thupi kwabwino komwe kumayendetsa khalidwe lolimbikitsidwa kupita ku kulimbitsa thupi koipa ndi kudziyendetsa komwe kumayendetsa khalidwe lolimbikitsidwa ( Koob, 2004 ; Gome 1 ). Magawo atatuwa amaganiziridwa kuti amalumikizana wina ndi mnzake, kukhala amphamvu kwambiri, ndipo pamapeto pake kumabweretsa mkhalidwe wodziwika kuti kuledzera ( Koob ndi Le Moal, 1997 ; Gome 2 ). Kusintha kuchoka pa kugwiritsa ntchito mankhwala nthawi zina kupita ku kuledzera kumakhudza kusokonekera kwa mitsempha m'zinthu zonsezi ndipo kungayambe ndi kugwiritsa ntchito mankhwala koyamba mwa anthu omwe ali pachiwopsezo kapena anthu omwe ali pachiwopsezo chachikulu (monga unyamata; Koob et al , 2008b ). Ndemangayi ikuyang'ana kwambiri za mitsempha ya ubongo yomwe imagwira ntchito pa gawo lililonse la chizolowezi, momwe imasinthira ndikugwiritsa ntchito kwambiri mankhwala osokoneza bongo, komanso momwe imagwirira ntchito kuti ipange mkhalidwe wodziwika kuti chizolowezi.
Zomwe Zimalimbikitsira: Kulimbikitsa, Njira Yotsutsa, Kulimbikitsana
Kusintha kwa chilimbikitso cha mankhwala osokoneza bongo ndi mphotho zachilengedwe ndi gawo lofunika kwambiri la chizolowezi ( Table 1 ). Ntchito yoyambirira ya Wikler (1952) inagogomezera ntchito ya kusintha kwa machitidwe okhudzana ndi kudalira (apa amatchedwa chizolowezi. Anthu omwe adaphunzira adafotokoza kusintha kwa kusiya kumwa mankhwala ngati 'njala' kapena chosowa chachikulu komanso zotsatira za morphine pa mkhalidwe monga 'kukhuta' kapena kukhutitsa chosowa chachikulu ( Wikler, 1952 ). Ngakhale Wikler adati kulimbikitsa kwabwino kumasungidwa ngakhale kwa anthu omwe amadalira kwambiri mankhwala (monga kusangalala ndi jakisoni wa opioid m'mitsempha), chizolowezicho chinapanga gwero latsopano la kukhutitsidwa, lomwe ndi kulimbitsa thupi koipa ( Table 1 ).
Lingaliro la chilimbikitso linagwirizanitsidwa mosalekeza ndi mkhalidwe wa hedonic, affective, kapena maganizo pakusintha kukhala chizolowezi ndi chiphunzitso cha Solomon cha njira yotsutsa cha chilimbikitso. Solomon ndi Corbit (1974) adanena kuti mkhalidwe wa hedonic, affective, kapena maganizo, ukangoyamba, umasinthidwa zokha ndi dongosolo lapakati la mitsempha ndi njira zomwe zimachepetsa mphamvu ya malingaliro a hedonic. Mayankho abwino a hedonic mukugwiritsa ntchito mankhwala osokoneza bongo amapezeka nthawi yochepa atangowonetsa chilimbikitso, amagwirizana kwambiri ndi mphamvu, khalidwe, ndi nthawi ya cholimbikitsira, ndipo amasonyeza kulolerana ndi kusiya kapena kusiya hedonic (kudziletsa). Mosiyana ndi zimenezi, mayankho oipa a hedonic amatsatira mayankho abwino a hedonic, amayamba pang'onopang'ono, amachedwa kukula kukhala asymptote, amachedwa kuwonongeka, ndipo amakula ndi kuwonetsedwa mobwerezabwereza. Udindo wa njira zotsutsa umayamba koyambirira kwa kumwa mankhwala osokoneza bongo, umasonyeza kusintha kwa machitidwe a mphotho ya ubongo ndi kupsinjika maganizo, ndipo pambuyo pake umapanga chimodzi mwa zifukwa zazikulu zokakamiza kumwa mankhwala osokoneza bongo monga matenda oletsa kukakamizidwa.
Mu njira iyi, kuwonekera kwa matenda odzipatula pambuyo pochotsa mankhwala osatha, kaya owopsa kapena okhalitsa, kumatanthauzidwa malinga ndi zinthu zomwe zimapangitsa munthu kukhala ndi chilakolako chodalira monga kutuluka kwa mkhalidwe woipa wamaganizo (monga dysphoria, nkhawa, kukwiya) pamene kupeza mankhwalawo kwaletsedwa ( Koob ndi Le Moal, 2001 ), osati pa zizindikiro zakuthupi za kudalira, zomwe nthawi zambiri zimakhala zazifupi. Inde, ena anena kuti kukula kwa mkhalidwe woipa woterewu kumatha kufotokozera kudalira poyerekeza ndi chizolowezi ( Russell, 1976 ; Baker et al , 1987 ) ndipo kuti mkhalidwe woipa woterewu umathandizira kukakamiza kudzera mu njira zolimbitsa thupi ( Koob ndi Le Moal, 2005 ).
Kulingalira kwina kwa kusintha kwachisokonezo komwe kumakhudzana ndi kuledzera kumachokera kuntchito yoyamba pa kukhazikitsidwa, kulimbitsa mtima, kulimbikitsa khalidwe, ndi kukhumudwitsa kuphunzirira, zomwe zonsezi zimagwiritsidwa ntchito pothandizira kukondweretsa. Mankhwala amatsitsimutsidwa kuti agwiritse ntchito machitidwe a ubongo omwe amaikidwa kuti atsogolere zinyama kuti zitsimikizire molimba mtima kuti zisungidwe. Kulimbikitsa kuganiza mozama kumakhala kofunika kwambiri ngati chinthu chofala chakumwa mankhwala osokoneza bongo chifukwa chimachepetsanso kufunafuna mankhwala osokoneza bongo pokhapokha mphotho zowonongeka. Kachipatala kowona kuti anthu omwe ali ndi vuto la kugwiritsa ntchito mankhwala ali ndi chidwi chosafunafuna mankhwala osokoneza bongo kuti asapindule ndi masewera achilengedwe akugwirizana ndi malingaliro olimbitsa mtima.
Kuwonjezeka kwa mphamvu ya chilimbikitso yopangidwa ndi mankhwala osokoneza bongo kwayambira kale pakuthandiza kulimbikitsa ndi kufunafuna mankhwala osokoneza bongo ( Robbins, 1976 ; Hill, 1970 ). Pano, kufunafuna mankhwala osokoneza bongo kumayendetsedwa ndi zotsatira za kusokoneza maganizo komwe kumakhudzana ndi mankhwala osokoneza bongo komwe kumathanso kugwira ntchito ngati zolimbikitsa zomwe zimawonetsedwa ngati zotsatira za mayankho a zida ( Everitt et al , 2008 ). Ambiri anena kuti kudzera mu kuphunzira kogwirizana, mphamvu ya chilimbikitso imakhazikika makamaka ku mphamvu zokhudzana ndi mankhwala osokoneza bongo, zomwe zimapangitsa kuti munthu azikakamizika kufunafuna ndi kumwa mankhwala osokoneza bongo ( Hyman et al , 2006 ; Kalivas ndi Volkow, 2005 ). Kuyambitsa kwa mitsempha komwe kumakhudza kusunga mphamvu ya chilimbikitso kumapitirira, zomwe zimapangitsa kuti anthu omwe ali ndi vutoli akhale pachiwopsezo chobwereranso kwa nthawi yayitali.
Lingaliro lina la mphamvu ya chilimbikitso limakhudza kukhudzidwa kwa khalidwe, komwe nthawi zambiri kumayesedwa ngati kuwonjezeka kwa mayankho a locomotor popereka mankhwala mobwerezabwereza. Njira yodziwira khalidwe yapereka chilimbikitso chachikulu pakufufuza osati kokha kayendedwe ka mitsempha ya chizolowezi komanso chitsanzo cha neuroplasticity chomwe chingachitike panthawi yosintha kuchoka pa kugwiritsa ntchito mankhwala osokoneza bongo kupita ku chizolowezi. Pano, kusintha kwa mkhalidwe wa mphamvu ya chilimbikitso, komwe kumafotokozedwa ngati 'kufuna' kolumikizidwa ndi kugwiritsa ntchito mokakamiza, mosiyana ndi 'kukonda' kolumikizidwa ndi mayankho a hedonic, kunaganiziridwa kuti kumawonjezeka pang'onopang'ono chifukwa chogwiritsa ntchito mankhwala osokoneza bongo mobwerezabwereza ( Robinson ndi Berridge, 1993 ).
Kusintha kwa Zolakolako: Zitsanzo za Kugwiritsa Ntchito Mankhwala Osokoneza Bongo, Zinyama Zanyama
Mankhwala osiyana amapanga mitundu yosiyanasiyana ya mankhwala omwe amapezeka ndi mankhwala osokoneza bongo. Mwachitsanzo, maphunziro otupika opioid amatha kupeza njira zambiri zopezera chizoloŵezi choledzera, kuphatikizapo kuvomereza kovuta ndi kuchotsa (zizindikiro zapamwamba zokhudzana ndi kudalira thupi) ndi zizindikiro zambiri zomwe zimakhudzana ndi kuchotsa mtima. Kutengera kusintha kwa mankhwala osokoneza bongo kapena kusuta, kuphatikizapo kuledzera, kulekerera, kuwonjezeka kwa kudya, komanso kuopsa kwa matenda a dysphoria, kukhumudwa, ndi kuwonetsa khungu posiya kudziletsa. Kusamala kwambiri ndi kupeza opioid (chilakolako) kumawonekera zomwe nthawi zambiri zimayambitsanso zizindikiro zowonongeka ndipo zimagwirizanitsidwa osati zokhudzana ndi kupeza mankhwala osokoneza bongo koma komanso zokhudzana ndi kuchotsedwa ndi boma lolimbikitsa. Chitsanzo chimayamba pamene mankhwalawa ayenera kupezeka kuti asapewe matenda oopsa kwambiri okhudzana ndi kudziletsa. Mankhwala osokoneza bongo ena amachitanso chimodzimodzi koma akhoza kuphatikizapo zakumwa zoledzeretsa kapena zoledzeretsa komanso kusokoneza / kusokoneza komanso kuikapo chidwi (nicotine ndi mankhwala osokoneza bongo).
Zambiri mwa kupita patsogolo kwaposachedwa pakumvetsetsa kwa neurobiology ya chizolowezi cha mankhwala osokoneza bongo kwachokera ku kafukufuku wa mitundu ya nyama yomwe imakonda kugwiritsa ntchito mankhwala osokoneza bongo monga zolimbikitsa, ma opioid, mowa, nikotini, ndi Δ9 -tetrahydrocannabinol (Δ9 -THC ). Ngakhale kuti palibe mtundu wa chizolowezi cha nyama womwe umatsanzira bwino momwe munthu alili, mitundu ya nyama imalola kufufuza zinthu zinazake za njira yogwiritsira ntchito mankhwala osokoneza bongo. Zinthu zotere zimatha kufotokozedwa ndi mitundu ya magawo osiyanasiyana a chizolowezi (onani pamwambapa; Gome 2 ).
Kuwonjezeka pang'onopang'ono kwa kuchuluka ndi mphamvu ya kugwiritsa ntchito mankhwala osokoneza bongo ndi chimodzi mwa zinthu zazikulu zomwe zimapangitsa kuti munthu ayambe kugwiritsa ntchito mankhwala osokoneza bongo ndipo zimayenderana ndi mfundo za DSM: 'Mankhwalawa nthawi zambiri amamwedwa mochuluka komanso kwa nthawi yayitali kuposa momwe amafunira' ( American Psychiatric Association, 1994 ). Mitundu iwiri ya nyama, imodzi yokhala ndi mankhwala operekedwa ndi munthu woyesera, ndi inayo yokhala ndi mankhwala odzipangira okha, yagwiritsidwa ntchito kufufuza zotsatira za kuperekedwa mobwerezabwereza kwa mankhwala pa neuroplasticity m'ma neurocircuits omwe atchulidwa pamwambapa. Kuzindikira khalidwe nthawi zambiri kumaphatikizapo kuperekedwa mobwerezabwereza ndi munthu woyesera mankhwala, nthawi zambiri psychostimulant, m'malo enaake ndipo muyeso wodalira nthawi zambiri unali ntchito ya locomotor. Pano, nyama zomwe zidalandira mankhwalawo zidawonetsa kuwonjezeka kwakukulu kwa ntchito ya locomotor kupita ku mlingo wovuta wa mankhwala (sensitization) kuposa zowongolera zomwe zidalandira miyeso mobwerezabwereza ya jakisoni wagalimoto.
Makhalidwe, mwinamwake ali ndi nkhope yowonjezereka yosonyeza kusintha kwa mankhwala osokoneza bongo kupita ku mankhwala osokoneza bongo, angapezeke mwa zitsanzo za nyama zowonjezereka kwa kulandira mankhwala osokoneza bongo. Pano, pogwiritsa ntchito mankhwala osokoneza bongo, kupititsa patsogolo mankhwala osokoneza bongo kumagwirizanitsidwa ndi kuchepa kwa masiku ambiri (Koob, 2009a). Kuwonjezereka kotereku kunayambanso kuledzeredwa ndi mowa momwe makoswe amamwa mopitirira muyeso panthawi yovuta komanso yanthaŵi yaitali kuchoka ku chizolowezi chodalira pogwiritsa ntchito mankhwala osakwanira a madzi kapena mpweya wotentha (Gilpin ndi Koob, 2008). Zinyama zopangidwa mowa mowa mwachidwi zimalandira ma oledzera a magazi mu 100-150
mg%, omwe ali ofanana ndi magulu omwe amachitira nkhanza ndi oledzeretsa mowa kwambiri. Kusintha kwa kuwonjezereka ndi zotsatira zolimbikitsa za mankhwalawa zakhala zikuwonetsedwa potsatira kupititsa patsogolo komanso kudalitsidwa kwa kudalira ndikuphatikizapo kuwonjezeka kwakupititsa patsogolo kuyanjana (Koob, 2009a), kuchulukitsidwa kwa mankhwala osokoneza bongo pambuyo poti kutayika, kuchepa kwa latency ku nthawi yachindunji mu chitsanzo cha msewu wa mphotho ya mankhwala (Deroche-Gamonet Et al, 2004), ndi kuwonjezeka kukana chilango chomwe chiweto chidzapereke chilango chokwanira kuti chipeze mankhwala (Vanderschuren ndi Everitt, 2004). Kaya kulimbikitsa mankhwala osokoneza bongo ndi kupititsa patsogolo kotere kumasonyezera kulimbikitsa mphotho (kapena zolimbikitsa) kapena dziko lopanda malipiro, kapena zonsezi, zikukambiranabe (Vezina, 2004).
NEUROCIRCUITRY OF ADDICTION: NEUROPSYCHOPHARMACOLOGICAL Umboni Wochokera ku Maphunziro A ANIMU
Kumwa mowa mwauchidakwa / kulowerera
Kumvetsetsa kwathu kwa zinthu zomwe zimayambitsa matenda a ubongo chifukwa cha zotsatirapo za kugwiritsa ntchito mankhwala osokoneza bongo kungayambike kuyambira pa ntchito yoyambirira yozindikira njira yopezera mphotho muubongo ndi kupeza mphotho yamagetsi yolimbikitsa ubongo kapena kudzilimbikitsa mkati mwa ubongo ndi Olds ndi Milner (1954) . Mphotho yolimbikitsa ubongo imaphatikizapo ma neurocircuitry ambiri muubongo, koma malo omwe amakhudzidwa kwambiri ndi malire otsika kwambiri amakhudza njira ya medial forebrain bundle yomwe imalumikiza dera la ventral tegmental (VTA) ku basal forebrain ( Olds ndi Milner, 1954 ). Mankhwala onse osokoneza bongo, akaperekedwa mwachangu, amachepetsa malire a mphotho yolimbikitsa ubongo (monga, mphotho yowonjezera; Kornetsky ndi Esposito, 1979 ) ndipo akaperekedwa nthawi zonse amawonjezera malire a mphotho panthawi yochotsa (monga, mphotho yotsika; onani pansipa). Ngakhale kuti poyamba kugogomezera kwakukulu kunayang'ana kwambiri pa ntchito ya machitidwe a monoamine omwe akukwera mu medial forebrain bundle mu mphotho, choyamba norepinephrine ( Stein, 1962 ) kenako dopamine ( Crow, 1973 ; Wise, 1978 ), machitidwe ena osapanga dopamine mu medial forebrain bundle mwachionekere ali ndi gawo lofunika kwambiri pakulimbikitsa mphotho yolimbikitsa ubongo ( Hernandez et al , 2006 ). Zoonadi, ntchito zambiri zikusonyeza kuti kuyambitsa dongosolo la dopamine la midbrain kuli ndi maudindo angapo kuti apereke mphamvu ku zolimbikitsa zomwe zili m'chilengedwe ( Robinson ndi Berridge, 1993 ) kuti alimbikitse magwiridwe antchito a khalidwe lolunjika pa cholinga ( Salamone et al , 2007 ) kapena kuyambitsa kwathunthu ( Le Moal ndi Simon, 1991 ). Posachedwapa, lingaliro lakhala likunenedwa kuti nthawi yogwiritsira ntchito dopamine ndi chinthu chofunikira kwambiri, ndipo nthawi yofulumira kwambiri imakhala ndi gawo lofunika kwambiri pa mphotho ndi kuwerengera zotsatira zomwe zanenedweratu za khalidwe komanso kuyambitsa kutulutsidwa kwa dopamine mosalekeza komwe kumakhala ndi gawo lofunika kwambiri pakupereka zotsatira zolimbikitsa machitidwe enaake okhudzana ndi khalidwe ( Schultz, 2007 ). Ntchito yokhudzana ndi zotsatira zolimbikitsa kwambiri za mankhwala osokoneza bongo imathandizira lingaliro ili momwe mesolimbic dopamine system ndi yofunika kwambiri pa zotsatira zopindulitsa kwambiri za mankhwala osokoneza bongo koma ili ndi ntchito yothandiza kwambiri pa mankhwala onse osokoneza bongo.
Mphamvu yopindulitsa kwambiri ya mankhwala olimbikitsa maganizo yadziwika kale kuti imadalira kuyambika kwa dongosolo la dopamine la mesolimbic, koma kuyambika kwa dongosololi sikofunikira kwenikweni pa zotsatira zolimbikitsa kwambiri za mankhwala ena ozunza ( Koob, 1992 ; Nestler, 2005 ; Hnasko et al , 2005 ). Zilonda zosankhidwa ndi neurotoxin za dongosolo la mesocorticolimbic dopamine zimaletsa zotsatira zolimbikitsa za cocaine ndi -amphetamine ( McGregor ndi Roberts, 1993 ). Mosiyana ndi zimenezi, zilonda za neurochemically za dopamine mu nucleus accumbens yokhala ndi 6-hydroxydopamine sizinalepheretse heroin kapena ethanol kudzilamulira, kuthandizira lingaliro ili ( Koob ndi Le Moal, 2006 ).
Pogwiritsa ntchito njira yodzipangira yokha mkati mwa mutu ( Table 1 ) ndi kukonza malo mkati mwa mutu ( Table 1 ), ma opioid ndi mowa zawonetsedwa kuti zimaperekedwa zokha mwachindunji mu VTA. Ma opioid amapanganso kukonda malo komwe kumakonzedwa akaikidwa mu VTA. Ma opioid, phencyclidine, ndi ma psychostimulants amaperekedwa okha mwachindunji mu nucleus accumbens, ndipo ma psychostimulants amapanga kukonda malo komwe kumakonzedwa akaikidwa mu nucleus accumbens. Cocaine ndi phencyclidine zimaperekedwa zokha mwachindunji mu frontal cortex ( McBride et al , 1999 ). Dongosolo la dopamine la mesolimbic limayatsidwa ndi kuperekedwa mwachangu kwa ma opioid, ethanol, nikotini, ndi Δ 9 -THC ( Di Chiara ndi Imperato, 1988 ).
Kudzipatsa wekha nikotini m'mitsempha kumatsekedwa ndi zilonda za neurotoxin za mesocorticolimbic dopamine system, ndipo ntchito ya neuropharmacological yaganiziridwa kuti imachitika kudzera mu nicotinic receptor activation yotulutsa dopamine makamaka mu VTA komanso presynaptically mu nucleus accumbens ( Watkins et al , 2000 ). Komabe, mphotho ya nikotini yomwe imayesedwa ndi malo omwe amakonda ikuwoneka kuti siili yodziyimira payokha pa mesocorticolimbic dopamine system ( Laviolette et al , 2002 ). Ma substrates ena omwe amakhudzidwa ndi mphotho ya nikotini akuphatikizapo cholinergic inputs ku pedunculopontine nucleus ( Yeomans ndi Baptista, 1997 ). Mu VTA, kuyambika kwa β 2 subunit ya nicotinic receptors kumawoneka kuti ndikofunikira kwambiri pakuyambika kwa nikotini kwa dopamine neurons ( Mameli-Engvall et al , 2006 ). Maphunziro a neuropharmacological pa cannabinoids akhudza njira zonse za cannabinoid ndi opioid. Opioid ndi cannabinoid CB1 antagonists amaletsa kudzipatsa Δ9 - THC m'mitsempha mwa anyani agologolo ( Justinova et al , 2003 ). Mofanana ndi mankhwala ena ogwiritsidwa ntchito molakwika, kupereka Δ9 - THC kumayatsa kutulutsidwa kwa dopamine mu chipolopolo cha nucleus accumbens ( Tanda et al , 1997 ).
Motero, mankhwala onse osokoneza bongo amachititsa kuti dopamine ya mesolimbic iyambe kugwira ntchito, koma umboni wambiri umasonyeza kuti dopamine-independent reinforcement imachitika pamlingo wa nucleus accumbens, zomwe zikusonyeza kuti pali zinthu zambiri zomwe zimapangitsa kuti ma circuitry a reinforcement circuitry ayambe kugwira ntchito m'madera awa a ubongo ( Koob, 1992 ; Nestler, 2005 ).
Pakatikati pa amygdala (CeA) palinso ntchito yofunika kwambiri pakuchita zinthu zolimbitsa thupi kwambiri pogwiritsa ntchito mankhwala osokoneza bongo. Kuika mankhwala oletsa kutupa a dopamine D1 receptor antagonists mu CeA block cocaine self-administration ( Caine et al , 1995 ; McGregor ndi Roberts, 1993 ). Malo ofunikira kwambiri a γ -aminobutyric acid (GABA) ndi opioid antagonism ya kumwa mowa wodziyimira pawokha m'makoswe osadalira anali CeA ( Hyytia ndi Koob, 1995 ; Heyser et al , 1999 ). Zilonda za CeA zimaletsa kumwa mowa wodziyimira pawokha ( Moller et al , 1997 ). Serotonin-3 antagonists yomwe imalowetsedwa mu CeA block oral ethanol self-administration m'makoswe osadalira, zomwe zimaganiziridwa kuti zingakhudze kuthekera kwa serotonin-3 receptor antagonists kuletsa kutulutsidwa kwa dopamine komwe kumayambitsa mankhwala ( Dyr ndi Kostowski, 1995 ).
Chotuluka chachikulu kuchokera ku nucleus accumbens ndi ventral pallidum/substantia innominata. Mogwirizana ndi nucleus accumbens ngati gawo lofunikira la mphotho ya mankhwala osokoneza bongo, zilonda za ventral pallidum zimathandiza kwambiri poletsa chilimbikitso chogwira ntchito ya cocaine yolowetsedwa m'mitsempha ndi heroin yolowetsedwa m'mitsempha ( Hubner ndi Koob, 1990 ; Robledo ndi Koob, 1993 ). Kuphatikiza apo, kutsekeka kwa dopamine ndi GABA A receptors mu ventral pallidum kumaletsa mphamvu ya mowa ( Melendez et al , 2004 ; June et al , 2003 ). Chifukwa chake, zinthu za ventral pallidum sizingakhale zofunikira kokha pakukonzanso chizindikiro cha mphotho ya mankhwala osokoneza bongo komanso zitha kusinthidwa mwachindunji ndi mankhwala osokoneza bongo.
Kutupa kwa dorsal striatum sikukuwoneka kuti kuli ndi gawo lalikulu pa zotsatira zolimbikitsa kwambiri za kugwiritsa ntchito mankhwala osokoneza bongo koma zikuwoneka kuti zimayamba panthawi yopanga kufunafuna mankhwala osokoneza bongo mokakamiza ( Everitt et al , 2008 ). 6-Kutupa kwa Hydroxydopamine kwa dorsal striatum sikuletsa ntchito ya locomotor yomwe imabwera chifukwa cha cocaine kapena kudzipangira cocaine ( Roberts, 1992 ) koma kumaletsa khalidwe losazolowereka lomwe limabwera chifukwa cha amphetamine ( Kelly ndi Iversen, 1976 ; Creese ndi Iversen, 1974 ). Pogwiritsa ntchito ndondomeko yachiwiri ( Table 1 ), zilonda za nucleus accumbens ndi basolateral amygdala zinaletsa kupeza cocaine-searching ( Whitelaw et al , 1996 ). Mofananamo, pamene nucleus accumbens core inavulazidwa mbali imodzi ya ubongo ndikuphatikizidwa ndi dopamine receptor blockade mu contralateral dorsal striatum, palibe chomwe chinawoneka mwa nyama nthawi yomweyo atangotenga, koma kuchepa kwakukulu kwa cocaine-searching kunawonedwa mwa makoswe omwe amayankha bwino pa ndondomeko yachiwiri ( Belin ndi Everitt, 2008 ). Zotsatirazi zikusonyeza kuti dorsal striatum ikhoza kukhala ndi gawo laling'ono pa zotsatira zolimbikitsa kwambiri za mankhwala osokoneza bongo koma gawo lofunika kwambiri pakusintha kupita ku kugwiritsa ntchito mokakamiza ( Everitt et al , 2008 ).
Deta yokhala ndi mbewa zogundana imaperekanso chidziwitso chofunikira pa ntchito ya dopamine mu zotsatira zabwino za mankhwala osokoneza bongo. Mbewa zosinthidwa majini zomwe zimakhala ndi homozygous komanso kusowa kwa dopamine D1 receptor sizimadzipatsa cocaine zokha ( Caine et al , 2007 ). Ngakhale lipoti loyambirira loti mbewa zonyamula dopamine (DAT) zogundana zinapitiliza kudzipatsa cocaine ( Rocha et al , 1998 ) zinakayikira ntchito ya DAT mu mphamvu ya cocaine, kafukufuku waposachedwapa wasonyeza kuti nyama zosinthika zomwe zimasonyeza DAT zomwe sizimangirira cocaine koma zomwe zimagwira ntchito ngati chonyamulira dopamine sizinawonetse mphotho ya cocaine yomwe imayesedwa ndi malo omwe amakonda ( Chen et al , 2006a ). Zotsatirazi zikuthandizira lingaliro la gawo lofunika kwambiri la DAT mu mphamvu ya cocaine.
Pamaziko a kapangidwe kameneka, njira yoyambirira ya neurobiological yopezera mphotho ya mankhwala inaperekedwa ( Koob, 1992 ) yomwe yafotokozedwa bwino ndikukulitsidwa ( Koob ndi Nestler, 1997 ; Chithunzi 1 ). Poyambira njira yopezera mphotho inali mtolo wa medial forebrain, wopangidwa ndi ulusi wa myelinated womwe umalumikiza mbali ziwiri za tubercle ya olfactory ndi nucleus accumbens ndi hypothalamus ndi VTA ( Nauta ndi Haymaker, 1969 ) komanso kuphatikiza njira zokwera za monoamine monga mesocorticolimbic dopamine system.
Kuyamba kwa ntchito ya mankhwala osokoneza bongo kunaganiziridwa kuti kumadalira kutulutsidwa kwa dopamine mu nucleus accumbens ya cocaine, amphetamine, ndi nikotini; kuyambitsa kwa opioid peptide receptor mu VTA (kuyambitsa dopamine) ndi nucleus accumbens (popanda kuyambitsa dopamine) ya opiates; ndi machitidwe a GABA A mu nucleus accumbens ndi amygdala ya mowa. Nucleus accumbens ili pamalo abwino kuti ilandire chidziwitso chofunikira cha limbic kuchokera ku amygdala, frontal cortex, ndi hippocampus chomwe chingasinthidwe kukhala cholimbikitsa kudzera mu kulumikizana kwake ndi extrapyramidal motor system. Chifukwa chake, gawo loyambirira lofunikira la nucleus accumbens linakhazikitsidwa pa zotsatira zolimba za mankhwala, ndi gawo lothandizira la CeA ndi ventral pallidum ( Zithunzi 1 ndi and2a 2a ).
Kuchotsa / Kusokoneza Mkhalidwe
Chiwalo cha neuroanatomical chotchedwa amygdala yowonjezereka ( Heimer ndi Alheid, 1991 ) chikhoza kuyimira gawo lodziwika bwino la anatomical lomwe limaphatikiza machitidwe a ubongo olimbikitsa kupsinjika ndi machitidwe opangira hedonic kuti apange malingaliro oipa omwe amalimbikitsa njira zolimbitsa zoyipa zomwe zimagwirizanitsidwa ndi kukula kwa chizolowezi. Amygdala yowonjezereka imapangidwa ndi CeA, nucleus ya stria terminalis (BNST), ndi malo osinthira m'chigawo cha medial (shell) cha nucleus accumbens ( Chithunzi 2b ). Chigawo chilichonse chili ndi kufanana kwa cytoarchitectural ndi circuitry ( Heimer ndi Alheid, 1991 ). Amygdala yowonjezereka imalandira ma afferent ambiri kuchokera ku mapangidwe a limbic monga basolateral amygdala ndi hippocampus ndipo imatumiza ma efferents ku gawo lapakati la ventral pallidum ndi chiwonetsero chachikulu ku lateral hypothalamus, motero imafotokoza bwino madera enieni a ubongo omwe amalumikiza mapangidwe a limbic (maganizo) ndi zotsatira za extrapyramidal motor system ( Alheid et al , 1995 ). Kwa nthawi yayitali, amygdala yowonjezereka yakhala ikuganiziridwa kuti ili ndi gawo lofunika kwambiri osati kokha pakuchepetsa mantha ( Le Doux, 2000 ) komanso mu gawo la malingaliro la kukonza ululu ( Neugebauer et al , 2004 ).
Kusinthasintha kwa mitsempha mkati mwa dongosolo kuti munthu azitha kugwiritsa ntchito mankhwala osokoneza bongo nthawi yayitali kumaphatikizapo kuchepa kwa magwiridwe antchito a ma neurotransmitter systems m'ma neurocircuits omwe amakhudzidwa ndi zotsatirapo zolimbikitsa kwambiri za kugwiritsa ntchito mankhwala osokoneza bongo. Lingaliro limodzi lodziwika bwino ndilakuti ma dopamine system amawonongeka m'magawo ofunikira kwambiri a chizolowezi, monga kusiya, ndipo kumabweretsa kuchepa kwa chilimbikitso cha zinthu zosakhudzana ndi mankhwala osokoneza bongo komanso kuwonjezeka kwa chidwi cha mankhwala osokoneza bongo ( Melis et al , 2005 ; onani maphunziro a ubongo pansipa). Kusiya psychostimulant mwa anthu kumalumikizidwa ndi kutopa, kuchepa kwa malingaliro ndi kuchedwa kwa psychomotor, ndipo mwa nyama kumalumikizidwa ndi kuchepa kwa chilimbikitso chogwirira ntchito kuti apeze mphotho zachilengedwe ( Barr ndi Phillips, 1999 ) ndi kuchepa kwa ntchito ya locomotor ( Pulvirenti ndi Koob, 1993 ), zotsatira za khalidwe zomwe zingaphatikizepo kuchepa kwa ntchito ya dopaminergic. Nyama panthawi yosiya amphetamine zimasonyeza kuchepa kwa kuyankha pa ndondomeko yowonjezereka ya yankho lokoma, ndipo kuchepa kwa kuyankha kumeneku kunasinthidwa ndi dopamine partial agonist terguride ( Orsini et al , 2001 ), zomwe zikusonyeza kuti dopamine yochepa imathandizira kufooka kwa chilimbikitso chokhudzana ndi kusiya psychostimulant. Kuchepa kwa ntchito ya mesolimbic dopamine system ndi kuchepa kwa serotonergic neurotransmission mu nucleus accumbens kumachitika panthawi yochotsa mankhwala mwachangu kuchokera ku mankhwala onse akuluakulu ogwiritsidwa ntchito molakwika mu maphunziro a nyama ( Rossetti et al , 1992 ; Weiss et al , 1992 , 1996 ).
Gawo lachiwiri la gawo la kuchotsedwa/kukhudzidwa ndi negative ndi neuroadaptation pakati pa dongosolo pomwe machitidwe osiyanasiyana a neurochemical omwe amagwira ntchito mu kusintha kwa kupsinjika amathanso kugwira ntchito mkati mwa mitsempha ya kupsinjika kwa ubongo ndi machitidwe otsutsa pofuna kuthana ndi kupezeka kosatha kwa mankhwala osokoneza bongo kuti abwezeretse ntchito yachibadwa ngakhale kuti mankhwalawo alipo. Hypothalamic-pituitary-adrenal axis ndi ubongo stress/aversive system zomwe zimayendetsedwa ndi corticotropin-releasing factor (CRF) zimayatsidwa panthawi yosiya kugwiritsa ntchito mankhwala onse akuluakulu omwe ali ndi mphamvu yogwiritsa ntchito molakwika, ndi yankho lofala la adrenocorticotropic hormone, corticosterone, ndi amygdala CRF panthawi yosiya kugwiritsa ntchito mankhwala mwachangu ( Koob, 2008 ; Koob ndi Kreek, 2007 ). Kusiya kugwiritsa ntchito mankhwala onse ozunza kumabweretsanso mkhalidwe wotsutsa kapena wofanana ndi nkhawa momwe CRF ndi machitidwe ena okhudzana ndi kupsinjika (kuphatikiza njira za noradrenergic) ali ndi maudindo ofunikira.
Zotsatira zoyambitsa kusokonezeka kwa mankhwala osokoneza bongo zitha kuyezedwa pogwiritsa ntchito kukana mankhwala osokoneza bongo ( Hand et al , 1988 ), ndipo mlingo wa opioid partial agonist buprenorphine modalira unachepetsa kukana mankhwala osokoneza bongo komwe kumachitika chifukwa cha kukana mankhwala osokoneza bongo. Kupereka mankhwala osokoneza bongo a CRF 1 receptor antagonist ndi peptide CRF 1 /CRF 2 antagonist mwachindunji mkati mwa ubongo kunachepetsanso kukana mankhwala osokoneza bongo komwe kumachitika chifukwa cha kukana mankhwala osokoneza bongo ( Stinus et al , 2005 ; Heinrichs et al , 1995 ). Mankhwala othandiza a noradrenergic omwe amaperekedwa mwachindunji mu BNST analetsa kukana mankhwala osokoneza bongo, zomwe zikusonyeza kufunika kwa kukakamiza kwa noradrenergic m'mayankho opsinjika omwe amatsatira kusiya mankhwala mwachangu ( Delfs et al , 2000 ). Zoonadi, mankhwala akale omwe amagwiritsidwa ntchito pochiza kusiya mankhwala osokoneza bongo mwa anthu omwe amagwiritsa ntchito mankhwala osokoneza bongo a heroin ndi zidakwa amaphatikizapo mankhwala a α -adrenergic (monga clonidine) omwe amaletsa kutulutsidwa kwa noradrenergic ndikuchepetsa zizindikiro zina za kusiya mowa ndi heroin.
Wina amene ali ndi vuto la kusiya mankhwala osokoneza bongo ndi dynorphin. Umboni wambiri umasonyeza kuti dynorphin imawonjezeka mu nucleus accumbens poyankha kuyambitsidwa kwa dopaminergic ndipo, motero, kuti kugwira ntchito mopitirira muyeso kwa machitidwe a dynorphin kungachepetse ntchito ya dopaminergic. κ -Opioid agonists ndi otsutsa, ndipo cocaine, opioid, ndi ethanol kuchotsa zimagwirizanitsidwa ndi kuwonjezeka kwa dynorphin mu nucleus accumbens ndi/kapena amygdala ( Koob, 2008 ). Chosiyana ndi salvidorin A, yomwe ndi κ -agonist yomwe imagwiridwa ntchito ndi anthu, koma izi zitha kuwonetsa zotsatira zake za hallucinogenic m'malo mwa zinthu zilizonse zosangalatsa ( Gonzalez et al , 2006 ).
Yankho lina lofala pakati pa machitidwe pakusiya mwachangu komanso kusiya kugwiritsa ntchito mankhwala osokoneza bongo kwa nthawi yayitali ndi kuwonetsa mayankho ofanana ndi nkhawa. Mwachitsanzo, kusiya kumwa cocaine mobwerezabwereza kumabweretsa yankho lofanana ndi nkhawa mu mayeso okwera komanso oteteza, omwe onse amasinthidwa ndi otsutsana ndi CRF. Mofananamo, kusiya ethanol kumabweretsa khalidwe lofanana ndi nkhawa lomwe limasinthidwa ndi kuperekedwa kwa otsutsana ndi CRF 1 /CRF 2 mkati mwa ubongo , kuperekedwa kwa molekyulu yaying'ono ya CRF 1 , ndi kuperekedwa kwa otsutsana ndi peptidergic CRF 1 /CRF 2 mu amygdala ( Funk et al , 2006 ; Koob, 2008 ). Otsutsana ndi CRF omwe amalowetsedwa mkati mwa ubongo kapena m'thupi amalepheretsanso mayankho ofanana ndi nkhawa ku zopsinjika zomwe zimawonedwa panthawi yosiya kumwa ethanol nthawi yayitali, ndipo zotsatira za otsutsana ndi CRF zakhala zikuchitika ku CeA ( Koob, 2008 ). Kusiya mwachangu nikotini kumabweretsa mayankho ofanana ndi nkhawa omwe amasinthidwanso ndi otsutsa a CRF ( Tucci et al , 2003 ; George et al , 2007 ).
Motero, kusiya mwachangu kumagwirizanitsidwa ndi kusintha kwa mkati mwa dongosolo komwe kumawonetsedwa ndi kuchepa kwa ntchito ya dopamine mu mesolimbic dopamine system komanso ndi kusonkhanitsa pakati pa dongosolo kwa ma neurotransmitter system omwe amapereka kupsinjika ndi zotsatira zofanana ndi nkhawa monga CRF ndi dynorphin. Ma neurotransmitter ena omwe amadziwika kuti amakhudzidwa ndi kusokonezeka kwa malingaliro kwa zotsatira zolimbikitsa za kusiya mankhwala ndi monga norepinephrine, substance P, vasopressin, neuropeptide Y (NPY), endocannabinoids, ndi nociceptin ( Koob, 2008 ).
Kutanganidwa / Kuyembekezera (Kukhumba) Gawo
Gawo loganizira kwambiri/kuyembekezera kapena chilakolako cha chizolowezi choledzera lakhala likuganiziridwa kwa nthawi yayitali kuti ndi gawo lofunika kwambiri la kubwereranso kwa anthu ndipo limafotokoza kuti chizolowezicho ndi vuto lobwereranso kwa nthawi yayitali. Ngakhale kuti nthawi zambiri limagwirizanitsidwa ndi kapangidwe ka chilakolako, chilakolako chokhacho chakhala chovuta kuchiyesa kuchipatala ( Tiffany et al , 2000 ) ndipo nthawi zambiri sichigwirizana bwino ndi kubwereranso. Komabe, gawo la chizolowezi chomwe munthu amabwezeretsa khalidwe lofunafuna mankhwala osokoneza bongo atasiya kusiya limakhalabe lovuta kwambiri pa njira za ubongo ndi chitukuko cha mankhwala kuti alandire chithandizo. Mitundu ya ziweto ya chilakolako ikhoza kugawidwa m'magawo awiri: kufunafuna mankhwala osokoneza bongo chifukwa cha mankhwala osokoneza bongo kapena zolimbikitsa zomwe zimagwirizanitsidwa ndi kumwa mankhwala osokoneza bongo, ndi kufunafuna mankhwala osokoneza bongo chifukwa cha kupsinjika maganizo kapena mkhalidwe wotsalira wamaganizo oipa, nthawi zambiri mkhalidwe wa nkhawa, wotchedwa kudziletsa kwa nthawi yayitali (onani Kusintha ku chizolowezi: machitidwe ogwiritsira ntchito mankhwala osokoneza bongo, gawo la zitsanzo za ziweto).
Umboni wambiri wochokera ku kafukufuku wa zinyama umasonyeza kuti kubwezeretsa kwa mankhwala osokoneza bongo kumachitika ku dera la medial prefrontal cortex/nucleus accumbens/ventral pallidum lomwe limayendetsedwa ndi neurotransmitter glutamate ( McFarland ndi Kalivas, 2001 ). Mosiyana ndi zimenezi, kubwezeretsa kwa mankhwala osokoneza bongo kumawoneka kuti kumakhudza amygdala ya basolateral ngati substrate yofunika kwambiri yokhala ndi njira yopezera mphamvu kudzera mu dongosolo la prefrontal cortex lomwe limakhudzidwa ndi kubwezeretsa kwa mankhwala osokoneza bongo ( Everitt ndi Wolf, 2002 ; Weiss et al , 2001 ). Kugwirizana kwa zinthu zomwe sizinali zandale zomwe zimagwirizanitsidwa ndi kuchotsa opioid (kuchotsa mankhwala osokoneza bongo) kumadaliranso kwambiri pa amygdala ya basolateral ( Schulteis et al , 2000 ), ndipo zinthu zoterezi zingakhale ndi tanthauzo lolimbikitsa ( Kenny et al , 2006 ). Kusintha kwa mitsempha yokhudzana ndi kubwezeretsa kwa mankhwala ndi zizindikiro pambuyo poti zatha kwalumikizidwa ndi njira ya glutamatergic kuchokera ku prefrontal cortex kupita ku nucleus accumbens core, dopamine projection kuchokera ku VTA kupita ku medial prefrontal cortex, ndi GABA projection kuchokera ku nucleus accumbens kupita ku ventral pallidum ( Kalivas ndi O'Brien, 2008 ).
Mosiyana ndi zimenezi, kubwezeretsedwa kwa kuyankha kwa mankhwala m'zitsanzo za nyama chifukwa cha kupsinjika maganizo kumadalira kuyambika kwa CRF ndi norepinephrine m'zinthu za amygdala yotalikirapo (onse a CeA ndi BNST; kuti muwone ndemanga, onani Shaham et al , 2003 ; Shalev et al , 2002 ). Kusiya kumwa mowa kwa nthawi yayitali, komwe kumafotokozedwa kwambiri m'zitsanzo zodalira mowa, kumawoneka kuti kumaphatikizapo machitidwe a glutamatergic ndi CRF ochulukirapo, mwina m'ma amygdala otalikirapo, ngakhale kuti izi zikadali zofunika kuzifufuza ( de Witte et al , 2005 ; Valdez et al , 2002 ).
Anthu omwe ali ndi chizolowezi cha cocaine amawonetsa kusagwira bwino ntchito m'magawo okhudzana ndi chidwi, kusinthasintha kwa chidziwitso, komanso kuchepetsedwa kwa mphotho komwe kumayendetsedwa ndi ma cortices apakati ndi a orbital prefrontal, komanso kuwonongeka kwa kukumbukira kwa malo, mawu, ndi kuzindikira komwe kumayendetsedwa ndi hippocampus, ndipo zoperewerazi zimatha kulosera zotsatira zoyipa za chithandizo ( Aharonovich et al , 2006 ; Bolla et al , 2003 ). Kafukufuku wofanana wa nyama wa orbitofrontal, prefrontal cortex, ndi hippocampus mu chizolowezi chogwiritsa ntchito mitundu ya nyama wayamba kuwonetsa zofooka zina zomwe zikuwonetsedwa mu maphunziro a anthu. Cocaine yoperekedwa ndi anthu omwe amayesa idabweretsa zovuta mu kuphunzira kobwerera m'mbuyo (ntchito ya orbital frontal) mwa makoswe ndi anyani ( Jentsch et al , 2002 ; Schoenbaum et al , 2004 ; Calu et al , 2007 ). Mwina chochititsa chidwi kwambiri, nyama zinalola mwayi wochuluka, koma osati wochepa, wopeza cocaine, zinawonetsa zoperewera mu kukumbukira ntchito (ntchito yodalira prefrontal-cortex), ntchito yosamalira mosamala (ntchito yodalira prefrontal-cortex), ndi ntchito yozindikira chinthu (ntchito yodalira hippocampus; Briand et al , 2008a , 2008b ; George et al , 2008 ). Mu kafukufuku wina ( Briand et al , 2008a ), zoperewerazi zinagwirizanitsidwa ndi kuchepa kwakukulu kwa dopamine D2 receptor mRNA mu medial ndi orbital prefrontal cortices, zomwe zikugwirizananso ndi maphunziro a anthu. Chifukwa chake, maphunziro a nyama pogwiritsa ntchito mitundu ya compulsive stimulant administration akuyamba kuwonetsa zoperewera zomwe zimagwirizanitsidwa ndi chizolowezi cha cocaine mwa anthu (onani Maphunziro a Anthu: kujambula zithunzi ndi neuropsychopharmacology).
KUPHUNZITSA ANTHU: KUCHITA NDI NEUROPSYCHOPHARMACOLOGY
Monga tafotokozera pamwambapa, umboni wochokera kuzinthu zozizwitsa komanso zamakono umasonyeza kuti kumwa mowa kumayimira matenda osokoneza bongo. Chotsatira chake, chiyeso choyambirira chimangokhala chokakamiza ndipo chimakhala (potsiriza) chosachiritsika ndi kubwereranso. Ntchito kuchokera kufukufuku wogwiritsa ntchito mafano yatsimikizira kuti kusinthaku kumaphatikizapo kubwezeretsanso maulendo a neuronal omwe amapanga (1) mphotho ndi zolinga; (2) chikumbutso, chikhalidwe, ndi habituation; (3) ntchito yayikulu ndi kuletsa zoletsa; (4) kutengapo mbali ndi kudzidziwitsa; ndi (5) kukhumudwitsidwa. Kusintha kumeneku kumakhudzidwa kwambiri ndi zamoyo, zotsitsimutsa, ndi zachilengedwe komanso zochitika zogwirizana, zomwe zidzatsimikiziranso kuopsa kwa chizolowezi choledzeretsa.
Zofanana ndi kufufuza kwapadera, kusiyanitsa magawo atatu muzoledzeretsa mwa anthu (kumwa mowa, kuchotsa, ndi kukhumba / kubwerera) kwakhala kopindulitsa. Zigawo zotsatirazi zikulongosola magawo awa ndi maulendo ena omwe amawatsata.
Kumwa mowa mwauchidakwa / kulowerera
Nthawi zambiri anthu amamwa mankhwala osokoneza bongo chifukwa cha zinthu zomwe zimafunidwa chifukwa cha mphamvu zawo za hedonic. Komabe, kuyesa mankhwala osokoneza bongo kumabweranso chifukwa cha zotsatira zolimbikitsa kutsatira magulu a anthu (kukakamizidwa ndi anzawo) zomwe zimapangitsa kuti munthu ayambe kugwiritsa ntchito mankhwalawa kuti awonjezere mphamvu zake. Nthawi zambiri, kugwiritsa ntchito koyamba mankhwala kungakhale kogwirizana ndi mphamvu zake zochiritsira (monga mankhwala ochepetsa ululu kapena zolimbikitsa matenda a kusowa chidwi). Monga momwe maphunziro asanachitike, chinthu chofunikira kwambiri pa mphamvu zolimbikitsira mankhwala chimavomerezedwa kuti chikuphatikizapo kuthekera kwawo kuyambitsa kuchuluka kwakukulu kwa dopamine yakunja m'malo a limbic (kuphatikiza nucleus accumbens). Ngakhale kudzipatsa mankhwala mwachangu ndi chitsanzo chabwino cha nyama choledzeretsa mankhwala osokoneza bongo, kugwiritsa ntchito zitsanzo za nyama kuti muyese kugwirizana kwa dopamine yoyambitsidwa ndi mankhwala ndi kovuta. Maphunziro a ubongo mwa anthu akhala othandiza kwambiri posonyeza kuti kuwonjezeka kwa dopamine yoyambitsidwa ndi mankhwala mu striatum (kuphatikiza ventral striatum komwe nucleus accumbens ili) kumagwirizanitsidwa ndi mafotokozedwe a mphotho (monga chisangalalo, kukwera, kusangalala; Volkow et al , 1996b ). Komanso, maphunzirowa asonyeza kuti kusintha kwa dopamine mwachangu kumagwirizanitsidwa ndi malingaliro aumwini a mphotho, pomwe kuwonjezeka kwa dopamine pang'onopang'ono komanso kokhazikika sikuyambitsa mayankho aumwini awa ( Grace, 2000 ; Volkow ndi Swanson, 2003 ).
Mankhwala a mankhwala osokoneza bongo, omwe amachititsa kuti liwiro la ubweredwe mu ubongo komanso nthawi ya zochita zawo, ndizofunikira kwambiri pa chizoloŵezi chawo choledzera. Ma pharmacokinetic imapanga mlingo, njira zogwiritsira ntchito, komanso nthawi zambiri kugwiritsa ntchito mankhwala osokoneza bongo m'magawo omwe amapatsidwa. Mwachitsanzo, kuyerekezera ubongo wa pharmacokinetics wa cocaine ndi methamphetamine kumasonyeza kuti zonse zimafikira ubongo mofulumira (ngakhale kuti cocaine imakhala mofulumira kuposa methamphetamine) koma cocaine imachoka mu ubongo mofulumira kuposa methamphetamine (Chithunzi 3). Kusiyana kumeneku kumathandiza kumvetsa chifukwa chake cocaine imatengedwa kulikonse 30-60min pakamwa, pamene methamphetamine imatengedwa maola angapo (Fowler Et al, 2008). Kufunika kwa pharmacokinetics kumathandizanso kufotokoza chifukwa chomwe anthu ambiri amachitira nkhanza mankhwala osokoneza bongo (kupatulapo mowa) ali jekeseni, akusuta, kapena amawotcha. Njirazi zimapangitsa kuti mankhwala obwera mofulumira kwambiri apite ku ubongo kusiyana ndi pamene amwedwa pamlomo (Volkow Et al, 2000). Pharmacokinetics imathandizanso kufotokoza chifukwa chake mankhwala osokoneza bongo monga methylphenidate kapena amphetamine, omwe amachulukitsanso dopamine, siwomwe amadziwika kuti akulimbikitsana pamene amatengedwa mwachindunji monga momwe analembera therapeutically (Sungani, 1994; Volkow Et al, 2001b).
Kafukufuku wazachipatala wasonyezanso kuti kuyembekezera zotsatira za mankhwalawa kumakhudza kwambiri mayankho opindulitsa ku mankhwala osokoneza bongo, kotero kuti momwe ubongo umayankhira machitidwe komanso momwe ubongo umayankhira mankhwala osokoneza bongo m'deralo zimakhala zolimba kwambiri pamene mankhwala opindulitsa akuyembekezeka poyerekeza ndi pamene mankhwala omwewo alandiridwa mosayembekezereka ( Volkow et al , 2003 ). Kudalira kwa zotsatira zabwino za mankhwalawa pazochitika ndi chiyembekezo kukuwonetsa kufunika kwa ma neurotransmitters ena monga glutamate, omwe amasintha momwe maselo a dopamine amagwirira ntchito komanso kutulutsidwa kwa dopamine mu nucleus accumbens, mu zotsatira zabwino za mankhwala osokoneza bongo ( Kalivas ndi Volkow, 2005 ).
Kuchotsa / Kusokoneza Mkhalidwe
Yankho lomwe limatsatira gawo la kuledzera kwa mankhwala limasiyana kwambiri pa mankhwala ndipo limakhudzidwa ndi nthawi yayitali komanso kuchuluka kwa kugwiritsa ntchito molakwika. Kwa mankhwala ena monga opiates, mowa, ndi sedative hypnotics, kusiya kugwiritsa ntchito mankhwala mwa ogwiritsa ntchito mankhwala osokoneza bongo nthawi yayitali kungayambitse matenda oopsa komanso opweteka omwe, ngati sakuyendetsedwa bwino komanso akakula, nthawi zina amatha kupha. Mankhwala onse osokoneza bongo amagwirizanitsidwa ndi matenda oletsa kukakamiza omwe amadziwika ndi dysphoria, kukwiya, kuvutika maganizo, ndi kusokonezeka kwa tulo komwe kumapitirira ngakhale atasiya nthawi yayitali. Neurobiology ya kusiya nthawi yayitali ndi yosiyana ndi kusiya nthawi yayitali kapena kukakamiza, ndipo zonsezi zimathandiza kubwereranso. Kafukufuku wochepa wojambulidwa wachitika panthawi yosiya nthawi yayitali. Kafukufuku wina wotere womwe unayesa kusintha kwa dopamine panthawi yosiya heroin sanathe kulemba kuchepa kwa dopamine mu nucleus accumbens komwe kudanenedwa kale ndi microdialysis mu ubongo wa makoswe ( Wang et al , 1997 ). Kuchokera mu kafukufukuyu, sizikudziwika ngati zotsatira zake zikuwonetsa kusakhudzidwa kwa dopamine yoyambira panthawi yosiya nthawi yayitali mwa ogwiritsa ntchito heroin kapena kukhudzidwa kochepa kwa ukadaulo wa positron emission tomography (PET).
Njira zomwe zimayambitsa kusiya mankhwala mwachangu zimatha kukhala zogwirizana ndi mankhwala ndipo zimasonyeza kusintha kwa mamolekyu a mankhwala awa. Mwachitsanzo, m'masiku oyamba osiya kugwiritsa ntchito cocaine, ubongo umakhudzidwa kwambiri ndi zotsatira za mankhwala owonjezera GABA zomwe zingasonyeze kuchepa kwa neurotransmitter iyi pogwiritsa ntchito cocaine nthawi zonse ( Volkow et al , 1998 ). Mofananamo, maphunziro okhudza ubongo awonetsanso kuchepa kwa ma opioid achilengedwe panthawi yosiya cocaine, zomwe zingayambitse kukwiya, kusakhala bwino, ndi dysphoria zomwe zimachitika panthawiyi yosiya kugwiritsa ntchito mankhwala ( Zubieta et al , 1996 ).
Pa nthawi yopuma nthawi yayitali, zizindikiro ndi zizindikiro za kusiya mwachangu zikatha, maphunziro ojambula zithunzi awonetsa hypofunction mu njira za dopamine, zomwe zawonetsedwa ndi kuchepa kwa D2 receptor expression ndi kuchepa kwa dopamine release, zomwe zingathandize anhedonia (mwachitsanzo, kuchepa kwa chidwi ndi zinthu zabwino) ndi chisangalalo chomwe chanenedwa ndi anthu omwe ali ndi vuto la mankhwala osokoneza bongo panthawi yopuma nthawi yayitali ( Volkow et al , 1997b , 2007 ; Martinez et al , 2004 , 2005 ). Kuchepa kwa dopamine reactivity kuzinthu zowonjezera kumapezekanso pambuyo posiya mowa nthawi yayitali pamene kusiya mwachangu kwatha. Mosiyana ndi kuchepa kwa chidwi ndi mphotho (kuphatikiza mphotho za mankhwala), maphunziro ojambula zithunzi awonetsa kuti panthawi yochotsa poizoni m'thupi, kukhudzidwa kwambiri ndi zizindikiro zokhazikika kumachitikanso. Kusiya kusuta, mwachitsanzo, kungayambitse kwambiri mayankho a mitsempha ku zizindikiro zokhudzana ndi kusuta ( McClernon et al , 2009 ). Mayankho okhazikika awa amasunga kuzungulira kwa kudziletsa ndi kubwereranso komwe kumawonetsa matenda ogwiritsa ntchito mankhwala osokoneza bongo ( Childress et al , 1988 ).
Kuonjezera apo, kufufuza zofufuza zofufuza zizindikiro za ubongo zimasonyeza kuti anthu ogwiritsa ntchito mankhwala osokoneza bongo amayesedwa panthawi yomwe amatha kusokoneza chiwonetsero cha umboni wa kusokoneza ntchito za m'madera akumidzi, kuphatikizapo dorsolateral prefrontal, zigawo zagyrus, ndi orbitofrontal cortex, zomwe zimagwiritsidwa ntchito kuti zisawonongeke. kukhudzidwa mtima komanso kuthandizira kubwerera m'mbuyo (onani gawo lotsatirali kuti mukambirane).
Kutanganidwa / Kuyembekezera (Kukhumba) Gawo
Kuzindikira kwambiri zizindikiro zokhazikika, zomwe zimaphatikizapo momwe munthu akumvera, kumayambitsa gawo lobisika la chidwi/kuyembekezera (chilakolako), lomwe limadziwika ndi kuwonjezeka kwa chilakolako cha mankhwala osokoneza bongo. Zoonadi, kupsinjika maganizo ndi chifukwa champhamvu chobwezera machitidwe ogwiritsira ntchito mankhwala osokoneza bongo kudzera mu kuyambitsa ma circuits a ubongo omwe amakhudzidwa ndi kukonza mphotho komanso kukondera ndi kukumbukira kukumbukira kugwiritsa ntchito mankhwala osokoneza bongo ( Duncan et al , 2007 ). Vutoli losatha la kubwereranso limadziwika kuti ndi limodzi mwa mavuto ovuta kwambiri polimbana ndi chizolowezi cha mankhwala osokoneza bongo. Anthu omwe ali ndi vutoli amatha kubwerera ku kumwa mankhwala osokoneza bongo nthawi yayitali atakhala ndi zizindikiro zosiya kumwa mankhwala osokoneza bongo ( Langleben et al , 2008 ). Kukonzanso pang'onopang'ono kwa ma circuits a mphotho ndi kukumbukira, komwe kumachitika chifukwa cha kugwiritsa ntchito mankhwala osokoneza bongo nthawi yayitali, akuti ndikofunikira kwambiri pakukweza mayankho awa. Dopamine ndi glutamate zonse zapezeka m'maphunziro a preclinical kuti zimathandizira kusintha kwa mitsempha yokhudzana ndi mayankho okhazikika. Kuphatikiza apo, kusintha kwa pulasitiki mu CRF ndi glucocorticoid receptors mwina kumatenga nawo mbali pakukulitsa chidwi cha kupsinjika. Mwa anthu, kusowa kwa ma radiotracer oyenera kuti aone ngati glutamate neurotransmission ndi kusowa kwa ma ligand a CRF kapena glucocorticoid receptors kwachepetsa maphunziro a chilakolako makamaka ku dopamine system.
NEUROCIRCUITRY DYNAMICS M'CHIFUKWA CHOCHITIKA KUCHITA
Ma neurocircuitry omwe afotokozedwa pamwambapa ndi omwe amapanga maziko a neuroplasticity yogwirizana ndi kukula kwa chizolowezi. Mwachidule pansipa pali kusintha kwa neuroadaptive komwe kumachitika mkati mwa ma circuits omwe akuyimira magawo a chizolowezi chomwe chafotokozedwa pamwambapa. Ma circuits asanu akuganiziridwa kuti amachitika motsatizana, kuphatikiza (1) mesolimbic dopamine system, (2) ventral striatum, (3) ventral striatum/dorsal striatum/thalamus circuits, (4) dorsolateral frontal cortex/inferior frontal cortex/hippocampus circuits, ndi (5) extended amygdala ( Chithunzi 4 ). Kulemera ndi malangizo a kusintha kwa neuroadaptive kumeneku kukuwonetsedwa mu chithunzi cha circuit cha addicted state ( Chithunzi 5 ).
Mesolimbic Dopamine System: Kulimbikitsana Pakati, Kukhala Wokhulupirika
Lingaliro limodzi lalikulu lomwe likutsogolera kusokonekera kwa mitsempha yokhudzana ndi chizolowezi likuyang'ana kwambiri pa dongosolo la dopamine la mesolimbic. Lingaliro ndilakuti mankhwala osokoneza bongo, makamaka cocaine ndi amphetamine, amawonjezera kutulutsidwa kwa dopamine m'njira yayitali komanso yosalamulirika kuposa zoyambitsa zachilengedwe, zomwe zimapangitsa kusintha kwa synaptic plasticity mkati mwa dongosolo la dopamine komanso mu ma neuron olandila dopamine ( Wolf, 2002 ). Kusintha kumeneku pamapeto pake kumagwiritsa ntchito njira zophunzirira wamba kuti zisinthe ma neurocircuitry kukhala mayanjano kapena mtundu wa kuphunzira chizolowezi komwe kumapitilira ngakhale pali zotsatirapo zoyipa (gawo la kukakamizidwa; Everitt ndi Wolf, 2002 ; Hyman et al , 2006 ).
Zitsanzo za nyama zolimbikitsa khalidwe labwino zakhala zikuyang'ana kwambiri pa zotsatira zowonjezera zoyambitsa locomotor za mankhwala olimbikitsa psychomotor mwa nyama zomwe zili ndi mbiri ya stimulant. Kafukufuku woterewu wavumbula neuroplasticity wochuluka wogwirizana ndi mesolimbic dopamine systems ndi terminal projection yake ku ventral striatum (kumene nucleus accumbens ili). Mankhwala osokoneza bongo amachititsa kusintha kwa kanthawi kochepa komanso kwanthawi yayitali kwa kuwombera ma dopamine neurons mu VTA ( Bonci et al , 2003 ). Kafukufuku wasonyeza kuti kuwombera ma dopamine neurons mu VTA kumawoneka kuti kukugwirizana ndi yankho lolunjika ku sensory stimulus ( Freeman et al , 1985 ). Kupezeka kamodzi mu vivo ku cocaine kapena amphetamine kumayambitsa long-term potentiation (LTP) ya AMPA-mediated excitatory neurotransmission mu dopamine neurons ( Ungless et al , 2001 ). Kuwongolera kwa mayankho a synaptic AMPA kwaganiziridwa kuti kuonjezera kuchuluka kwa kuwombera kwa burst ( Jones ndi Bonci, 2005 ). Kusagwiritsa ntchito mankhwala osokoneza bongo kwa miyezi itatu kunayambitsidwa mu VTA mwa makoswe omwe ankadzipatsa okha cocaine koma osati mwa makoswe omwe ankadzibaya okha ( Chen et al , 2008 ). Zotsatira zofanana za kuyambitsa kwa LTP ya kufalikira kwa glutamate pa ma neuron a dopamine zawonedwa ndi morphine ndi nikotini ( Saal et al , 2003 ).
Komabe, kupereka mankhwala olimbikitsa mobwerezabwereza kwa psychostimulants kunalephera kuyambitsa chidwi cha ntchito ya dopamine ya mesolimbic monga momwe zimayesedwera ndi microdialysis ya in vivo ( Maisonneuve et al , 1995 ). Kuphatikiza apo, mwayi wopeza cocaine nthawi yayitali sungapangitse chidwi cha locomotor ( Ben-Shahar et al , 2004 ) koma umabweretsa yankho lodziwika bwino la khalidwe ( Ferrario et al , 2005 ). Kuphatikiza apo, anthu omwe amagwiritsa ntchito cocaine molakwika adawonetsa mayankho a dopamine atatsutsidwa ndi mankhwala olimbikitsa, zomwe zimasiyana ndi zomwe zidanenedweratu ndi chidwi chowonjezereka cha ntchito ya dopamine ya mesolimbic ( Volkow et al , 1997b ; Martinez et al , 2007 ).
Ventral Striatum: Kulimbikitsa Mphamvu, Njira Yopatsa Mphamvu
Kusinthasintha kwina komwe kumagwirizanitsidwa ndi kukhudzidwa kwa khalidwe ndi kuwonjezereka kosalekeza kwa ma synapses otulutsa nucleus accumbens omwe amawonedwa pambuyo pogwiritsidwa ntchito mobwerezabwereza ndi mankhwala otsatiridwa ndi nthawi yayitali yopanda mankhwala ( Kourrich et al , 2007 ). Kuperekedwa mobwerezabwereza kwa cocaine kumawonjezera kufalikira kwa glutamate mu mitsempha yokha mwa makoswe omwe adawonetsa kukhudzidwa kwa khalidwe ( Pierce et al , 1996 ). Kuphatikiza apo, mbewa zomwe zimakhudzidwa ndi cocaine zidawonetsa kuwonjezeka kwa LTP mu magawo a nucleus accumbens panthawi yopuma, zomwe mwina zikuwonetsa kuwonjezeka kwa ntchito ya glutamatergic ( Yao et al , 2004 ). Kuwonjezeka kwa chiŵerengero cha pamwamba pa maselo cha glutamate-1 receptors (GluR1) kwawonedwa masiku 21 pambuyo pa jekeseni yomaliza ya cocaine, zomwe zikusonyeza kufalikira pang'onopang'ono kwa ma receptors a AMPA pamwamba pa ma neuron a nucleus accumbens, makamaka kwa omwe alibe GluR2 ( Boudreau ndi Wolf, 2005 ; Conrad et al , 2008 ). Kuwonjezeka kwa ma AMPA receptors a pamwamba pa maselo kumadalira kuyambika kwa dopamine D1 receptors ndi protein kinase A signaling yotsatira ( Chao et al , 2002 ). Mwa kugwira ntchito, kuwonetsa kwambiri GluR1 mu nucleus accumbens kunathandizira kutha kwa mayankho ofuna cocaine ( Sutton et al , 2003 ) ndikuwonjezera malire a mphotho yolimbikitsa ubongo, kuwonetsa kuchepa kwa mphotho komanso mwina kuchepa kwa khalidwe lolimbikitsa ( Todtenkopf et al , 2006 ). Komabe, kuwonetsanso kamodzi ku cocaine panthawi yopuma kwa nthawi yayitali kunapangitsa kuti synaptic depression, yomwe ingawonetse kutulutsidwa kwa glutamate panthawi yopuma kwa cocaine ( Kourrich et al , 2007 ). Chodabwitsa n'chakuti, kuwonjezeka kwa AMPA receptor expression yomwe imapezeka ndi cocaine sikuchitika m'makoswe omwe ali ndi amphetamine, zomwe zimapangitsa kuti pakhale lingaliro la zotsatira zosiyanasiyana za ntchito za glutamate zomwe zimawonetsedwa ku nucleus accumbens panthawi yopuma kwa cocaine vs amphetamine ( Nelson et al , 2009 ).
Mogwirizana ndi zotsatira za kusintha kwa glutamate neurotransmission m'makoswe omwe ali ndi vuto la cocaine, maphunziro a microdialysis ndi microinjection awonetsa kuti pambuyo pa cocaine yosatha, kuchepa kwa basal release ya glutamate kumachitika koma kumachepetsa kutulutsidwa kwa synaptic glutamate panthawi yobwezeretsa kufunafuna mankhwala osokoneza bongo m'makoswe ( Kalivas ndi O'Brien, 2008 ; McFarland et al , 2003 ). Kusokonekera kwa glutamate kumeneku kwaganiziridwa kuti kumachitika chifukwa cha kuchepa kwa ntchito ya cystine-glutamate exchanger ( Baker et al , 2003 ) komanso kuchepa kwa metabotropic glutamate mGlu2/3 receptor. Kutsika kwa basal glutamate, kuphatikiza ndi kuwonjezeka kwa kutulutsidwa kwa synaptic glutamate kuchokera ku kuyambitsa kwa prefrontal cortex afferents kupita ku nucleus accumbens, kukuyembekezeka kuti kumabweretsa chikhumbo chofuna mankhwala osokoneza bongo ( Kalivas, 2004 ).
Zotsatira za synaptic izi zomwe zimakhalapo kwa nthawi yayitali zimapangitsa kuchepa kwa glutamate neurotransmission panthawi yopereka mankhwala nthawi yayitali komanso kuwonjezeka kosalekeza kwa mphamvu ya glutamatergic synapse neurotransmission panthawi yobwezeretsa pambuyo posiya kugwiritsa ntchito. Kusintha kwamphamvu kumeneku kungayambitse kusangalatsa kwa maselo, komwe kwaganiziridwa kuti ndi gawo lofunikira pakulimbikitsa chidwi ndi kuphunzira zokhudzana ndi mankhwala osokoneza bongo mu mkhalidwe woledzera ( Kauer ndi Malenka, 2007 ; Wolf et al , 2004 ).
Monga momwe zitsanzo za nyama zinanenera kale, kukula kwa kutulutsidwa kwa dopamine m'thupi (makamaka m'mimba mwake) mwa anthu kumagwirizana bwino ndi momwe hedonic imayankhira ku mankhwala ambiri ogwiritsidwa ntchito molakwika, kuphatikizapo amphetamine ( Drevets et al , 2001 ), cocaine ( Volkow et al , 1997a ), methylphenidate ( Volkow et al , 2002 ), ndi nicotine ( Sharma ndi Brody, 2009 ). Kuwonjezeka kwa dopamine komwe kumadalira mankhwala osokoneza bongo, mwachangu, komanso kwapamwamba kwambiri kumatha kutsanzira kusintha kwa dopamine komwe kumachitika chifukwa cha kuphulika kwa maselo a dopamine omwe amachitika poyankha zoyambitsa, motero kugawa zomwe zimachitika ndi mankhwala ngati zomwe zimakhala zodziwika bwino, zotsatira zomwe zimapangitsa chidwi ndikulimbikitsa kuphunzira kosangalatsa, komanso chilimbikitso ( Volkow et al , 2004b ). Kutengera zomwe zapezeka mu nyama za labotale, kuwonetsedwa pafupipafupi ndi mayankho a mankhwalawa mwa ogwiritsa ntchito mankhwala osokoneza bongo kumaganiziridwa kuti kumabweretsa kubwezeretsanso kwa dopamine-activating (mphoto) malire azinthu zachilengedwe zolimbitsa thupi.
Motero, munthu akhoza kuganiza za kusintha kwa kufalikira kwa ma neuron a dopamine a mesolimbic komwe kumayamba ndi kuperekedwa kwa mankhwala, kumakula kukhala LTP poyamba mu VTA kenako nucleus accumbens, ndipo kudzera mu feedback loops pambuyo pake kumakhudza dorsal striatum. Kuphatikiza apo, kusintha kwa nthawi yayitali mu CeA ndi medial prefrontal cortex kumatha kutsatiridwa, komanso kuphatikiza ndi kusokonekera kwa machitidwe opsinjika kwa ubongo (onani pansipa) kungapereke chilimbikitso champhamvu cha khalidwe lofunafuna mankhwala osokoneza bongo ngakhale miyezi ingapo mutasiya kugwiritsa ntchito mankhwala osokoneza bongo ( Chithunzi 4 ndi ndi5 5 ).
Ventral Striatum / Dorsal Striatum / Thalamus: Mwaufulu kwa Kufunafuna Mankhwala Osokoneza Bongo
Lingaliro lakuti dorsal striatal circuitry ili ndi gawo lofunika kwambiri pakukula kwa kugwiritsa ntchito cocaine mwachizolowezi limathandizidwa ndi deta yosonyeza kufunika kwa dorsal striatum mu kuphunzira kwa stimulus-response habit learning ( Yin et al , 2005 ) ndi maphunziro a microdialysis omwe akusonyeza kuti kufunafuna cocaine kwa nthawi yayitali kunawonjezera kutulutsidwa kwa dopamine mu dorsal striatum koma osati ventral striatum ( Ito et al , 2002 ). Kulekanitsidwa kwa ventral striatum kuchokera ku dorsal striatum m'makoswe omwe amadzipatsa okha cocaine pa second-order schedule kunangowonetsa kusowa kwa nyama zomwe zili ndi 'compulsive' intake yokhazikika koma osati mwa nyama zomwe zangopeza second-order schedule ( Belin ndi Everitt, 2008 ). Chifukwa chake, lingaliro ndilakuti kuledzera ndi mankhwala osokoneza bongo kumayimira kusintha kwa kapangidwe ka associative kuti kakhale kodziyimira pawokha kapena kachizolowezi ndipo kumaphatikizapo kulowerera pang'onopang'ono kwa njira za dorsal striatal.
Kafukufuku wa zinyama wasonyeza kuti ngati munthu akumwa mankhwala osokoneza bongo mobwerezabwereza, zinthu zosakhudzana ndi mankhwala osokoneza bongo zimatha kukhala ndi mphamvu yowonjezera dopamine yokha. Kafukufuku wokhudza ubongo watsimikizira izi mwa anthu omwe ali ndi vutoli ( Volkow et al , 2008a ; Heinz et al , 2004 ). Kafukufukuyu adawonetsa kuti zizindikiro zokhudzana ndi mankhwala osokoneza bongo zimayambitsa kuchuluka kwa dopamine mu dorsal striatum (caudate ndi putamen), zomwe zimagwirizana ndi malipoti a chilakolako. Kuchuluka kwa dopamine komwe kumayambitsidwa ndi zizindikirozi kunagwirizanitsidwa ndi kuchuluka kwa chizolowezi choledzera kukuwonetsa kufunika kwa mayankho a dopamine omwe ali ndi vutoli pakuledzera kwa mankhwala osokoneza bongo mwa anthu.
Kafukufuku wazachipatala wasonyezanso kuti kuchuluka kwa dopamine pang'onopang'ono komwe kumachitika chifukwa cha kumwa mankhwala a methylphenidate pakamwa sikubweretsa chilakolako mwa ogwiritsa ntchito mankhwala osokoneza bongo a cocaine pokhapokha ngati agwirizanitsidwa ndi zizindikiro zokhudzana ndi mankhwala osokoneza bongo ( Volkow et al , 2008a ). Izi mwina zikuwonetsa kuti chilakolakocho chimachokera ku kuwonjezeka kwa dopamine mwachangu komwe kumachitika ndi phasic dopamine firing, mosiyana ndi kuwonjezeka kwa dopamine pang'onopang'ono komwe kumachitika ndi tonic dopamine firing komanso poyesa kugwiritsa ntchito methylphenidate pakamwa. Ndipotu, kupereka methylphenidate m'mitsempha, komwe kumabweretsa kuwonjezeka kwa dopamine mwachangu, kumayambitsa chilakolako chachikulu.
Kafukufuku wokhudza ubongo wasonyezanso kuti, mwa anthu omwe ali ndi vuto la kugwiritsa ntchito mankhwala osokoneza bongo, njirazi zimakhudza orbitofrontal cortex, dera la ubongo lomwe limakhudzidwa ndi kusinthasintha kwa mphamvu ya ubongo komanso chilimbikitso, kusokonezeka komwe kumabweretsa kukakamizidwa, ndipo ndi dera la ubongo lomwe lili ndi ziwonetsero zazikulu ku dorsal striatum. Cingulate gyrus imakhudzidwanso ndipo ndi dera la ubongo lomwe limakhudzidwa ndi kuletsa kulamulira ndi kuthetsa mikangano, kusokonezeka komwe kumabweretsa kulakalaka ( Volkow et al , 2004b ). Komanso, mwa anthu omwe ali ndi vuto la kugwiritsa ntchito cocaine, koma osati omwe ali ndi vuto la kugwiritsa ntchito cocaine, kuperekedwa kwa methylphenidate kudzera m'mitsempha, komwe ogwiritsira ntchito cocaine amanena kuti kuli ndi zotsatira zofanana ndi za cocaine, kuyambitsa orbital ndi medial prefrontal cortices, ndipo kuyambitsa kumeneku kunagwirizanitsidwa ndi chilakolako cha cocaine ( Volkow et al , 2005 ). Mofananamo, mwa anthu omwe ali ndi vuto la kugwiritsa ntchito chamba, koma osati mwa anthu omwe alibe vuto la kugwiritsa ntchito cocaine, kupereka mwachangu Δ9 -THC kunayambitsa obitofrontal cortex ( Volkow et al , 1996a ). Kuyambitsa kwa obitofrontal cortex ndi cingulate gyrus kumayambitsidwanso ndi zizindikiro zokhazikika zomwe zimaneneratu mphotho ndi kuyambitsa chilakolako ( McClernon et al , 2009 ). Chosangalatsa n'chakuti, awa ndi madera omwe amalamulira kutulutsa ndi kutulutsa kwa maselo a dopamine, omwe aganiziridwa kuti ndi ofunikira pakulimbikitsa kulimbikitsa kwa mankhwala osokoneza bongo mwa anthu omwe ali ndi vuto la kugwiritsa ntchito mankhwala osokoneza bongo (monga lingaliro lochokera ku maphunziro a nyama; Volkow et al , 1999 ). Zikaphatikizidwa, zomwe zawonedwazi zikusonyeza kuti kuwonjezeka kwa dopamine komwe kumagwirizanitsidwa ndi zizindikiro zokhazikika sikoyankho loyambirira, koma chifukwa cha kukondoweza kwa maselo a dopamine, omwe mwina ndi glutamatergic afferents ochokera ku prefrontal cortex ndi / kapena amygdala. Potengera zomwe zapezekazi, kuyambitsa kwa obitofrontal cortex, ndi kuwonjezeka kwa dopamine komwe kumapangidwa ndi mankhwalawa, kwaganiziridwa kuti kumathandizira kumwa mankhwala osokoneza bongo omwe amadziwika ndi kumwa mankhwala osokoneza bongo mwa anthu omwe ali ndi vuto la kugwiritsa ntchito mankhwala osokoneza bongo ( Volkow et al , 2007 ).
Zoonadi, kafukufuku wa ubongo wa anthu akuwonetsa kuti prefrontal cortex (orbitofrontal, medial prefrontal, prelimbic/cingulate) ndi basolateral amygdala ndizofunikira kwambiri pa chilakolako cha mankhwala ndi cue mwa anthu ( Franklin et al , 2007 ). M'madera a prefrontal (monga cingulate gyrus ndi obitofrontal cortex), kusintha kumeneku kwagwirizanitsidwa ndi kuchepa kwa kupezeka kwa striatal dopamine D2 receptor komwe kumawonedwa mwa anthu omwe ali ndi vutoli ( Heinz et al , 2004 ; Volkow et al , 1993 , 2001a , 2007 ). Mabungwe awa akhoza kuwonetsa kusokonezeka kwa madera a frontal brain chifukwa cha kusintha kwa ntchito ya striatal dopamine, kapena mwina angasonyeze kusokonezeka kwakukulu kwa madera a frontal omwe amalamulira ntchito ya maselo a dopamine. Zoonadi, kafukufuku waposachedwa wa PET wapereka umboni wakuti madera a prefrontal brain amalamulira phindu la mphotho posintha kuchuluka kwa dopamine mu ventral striatum, njira yowongolera yomwe imakhala yosagwira ntchito mwa anthu omwe ali ndi vutoli ( Volkow et al , 2007 ).
Motero, dopamine ndi glutamate neurotransmission zomwe zimachitika nthawi imodzi mu dorsal striatum, dera lomwe limakhudzidwa ndi kuphunzira chizolowezi ndi kuyambitsa zochita, limakhudzidwa ndi chilakolako chodalira cue/context. Motero, dorsal striatum ikhoza kukhala gawo lofunikira la chizolowezi ( Volkow et al , 2006 ). Kafukufuku pa njira zatsopano zoletsera dopamine ndi glutamate zomwe zimayambitsidwa ndi cue ndiye cholinga chachikulu cha ntchito zamakono zopangira mankhwala.
Thalamus sinaphunziridwe mozama pankhani ya chizolowezi. Komabe, chifukwa cha ntchito yake yophatikizana pakulamulira kusinthasintha kwa chidwi ndi chidwi, derali lakhala likukhudzidwa kwambiri ndi njira yoledzera. Mwachitsanzo, kupereka mankhwala olimbikitsa kudzera m'mitsempha mwa ogwiritsa ntchito cocaine, koma osati m'ma control, kunawonjezera dopamine neurotransmission mu thalamus, zomwe zimakhudzana ndi chilakolako ( Volkow et al , 1997a ). Mosiyana ndi zowongolera, ogwiritsa ntchito cocaine molakwika amasonyeza hypoactivation ya thalamus, mwina kuwonetsa noradrenergic ndi/kapena dopaminergic deficits, akamachita ntchito yozindikira ( Tomasi et al , 2007b ). Mofananamo, thalamus inanenedwa kuti ikuwonetsa kuchepa kwa mphamvu yogwira ntchito pamene ikuchita ntchito yozindikira mwa osuta omwe ali ndi nikotini ( Sharma ndi Brody, 2009 ). Zotsatirazi zikusonyeza kuti zolakwika za thalamic mwa ogwiritsa ntchito cocaine molakwika zingathandize osati kungochepetsa mphamvu yogwiritsira ntchito komanso chidwi komanso chilakolako. Chochititsa chidwi n'chakuti, kusintha kwa dopamine mu thalamus ndi striatum kumawoneka kuti kumakhudza kuwonongeka kwa magwiridwe antchito a ubongo (monga kuyang'ana maso ndi kukumbukira ntchito) komwe kumachitika nthawi yonse yogona tulo tochepa ( Volkow et al , 2008b ). Chifukwa chake, kafukufuku wowonjezereka womwe umachokera pa deta yoyambirira yomwe ilipo ndi wofunikira.
Dorsolateral Frontal Cortex, Inferior Frontal Cortex, Hippocampus: Kuzindikira Maganizo, Kutaya Nthawi, Ndiponso Kukumbukira
Kuledzera kumaphatikizaponso kusokonezeka kwa njira zoganizira komanso zamaganizo zomwe zimayendetsedwa bwino, zomwe zimayambitsa kukwera mtengo kwa mankhwala owonjezera mphamvu potengera kuchepa kwa mankhwala owonjezera mphamvu, komanso kuchepa kwa mphamvu zoletsa mayankho a mankhwala ( Goldstein ndi Volkow, 2002 ). Zotsatira zake, njira yocheperako yoyambira imakhulupirira kuti ndi yofunika kwambiri pa njira yoledzera.
Chimodzi mwa zigawo zomwe zili mu dongosolo lotere ndi kulamulira kwa impulse, komwe ndi chimodzi mwa zinthu zomwe zimayambitsa matenda amisala. Cocaine ikuwoneka kuti imakhudza mwachindunji ubongo womwe umayang'anira kulamulira kwa impulse. Pambuyo pobayidwa cocaine kudzera m'mitsempha, ogwiritsa ntchito cocaine adawonetsa kusintha kwa ntchito yoletsa kuyankha kwa kayendedwe ka thupi komanso kuwonjezeka kwa kuyambika kwa ntchito m'mitsempha yawo yakumanja ya dorsolateral ndi inferior frontal cortices ( Garavan et al , 2008 ). Popeza madera awa amaonedwa kuti ndi ofunikira pakulamulira kwa impulse, izi zikusonyeza kuti zotsatira zina zoyipa za cocaine zitha kubweretsa kusintha kwakanthawi kwa hypofunction yosatha mu circuitry ya kulamulira kwa impulse.
Ntchito ina yofunika yomwe imakhala m'madera a frontocortical ndi kuthekera kosankha pakati pa mphotho zazing'ono ndi zachangu poyerekeza ndi mphotho zazikulu koma zochedwetsedwa, zomwe zitha kuyezedwa pogwiritsa ntchito ntchito yochepetsera kuchepetsedwa. Kafukufuku waposachedwa adapeza kuti dorsolateral ndi inferolateral frontal cortex imvi matter zonse zimagwirizana kwambiri ndi zomwe munthu amakonda kukhutitsidwa nthawi yomweyo popanga zisankho ( Bjork et al , 2009 ). Kupeza kumeneku kukusonyeza kuti zovuta m'madera a frontocortical zitha kukhala chifukwa cha kulephera kuchedwetsa kukhutitsidwa, khalidwe lomwe limadziwika ndi chizolowezi ndi matenda ena amisala.
Ma substrates a neural a memory ndi conditioned learning ndi ena mwa ma circuits akuluakulu omwe akukumana ndi kusintha kwa neuroadaptations chifukwa cha kugwiritsidwa ntchito kwa mankhwala osokoneza bongo kwa nthawi yayitali ( Volkow et al , 2004a ). Machitidwe osiyanasiyana okumbukira aperekedwa kuti azikhudzidwa ndi kugwiritsa ntchito mankhwala osokoneza bongo, kuphatikizapo conditioned-incentive learning (kudzera mu nucleus accumbens ndi amygdala), chizolowezi learning (kudzera mu caudate ndi putamen), ndi declarative memory (kudzera mu hippocampus; White, 1996 ), yomwe ndi gawo lofunika kwambiri la gawoli.
M'zaka khumi zapitazi, maphunziro ambiri okhudzana ndi nyama asonyeza kuti mankhwala osokoneza bongo amatha kusokoneza ma neurogeneis mu hippocampus ya akuluakulu ( Canales, 2007 ). Kuwonongeka kwa subiculum ya ventral ya hippocampus kwawonetsedwa kuti kumakhudza kudzilamulira kwa cocaine m'makoswe ( Caine et al , 2001 ). Kuwona koteroko kwapereka chidziwitso pa kuthekera kwa hippocampus yosakhazikika mu chizolowezi cha anthu. Lingaliro ili ndi kukulitsa chidziwitso chamakono chifukwa hippocampus imawonedwa kwambiri ngati yofunika kwambiri pakukhazikika kwa zinthu, makamaka pakukonza zizindikiro zomwe zikumbukiro zimatha kupezeka ndikubwezeredwa. Ndipotu, kukumbukira kofotokozera kwadziwika kwa nthawi yayitali kuti kumakhudza kuphunzira ndikugwirizanitsa zochitika kapena zochitika ndi zomwe munthu amamwa mankhwala osokoneza bongo. Kafukufuku wa PET ndi functional magnetic resonance imaging wasonyeza kuti chilakolako chochokera ku cue, komanso kuledzera kwambiri, chimayambitsa hippocampus ndi amygdala ( Volkow et al , 2004a ). Mwachitsanzo, chilakolako chomwe ogwiritsa ntchito cocaine amakumana nacho akamakumana ndi zinthu zokhudzana ndi mankhwala osokoneza bongo chimayenderana ndi kuwonjezeka kwa magazi m'dera lomwe limafalikira lomwe limakhudzidwa ndi mitundu ingapo ya kukumbukira, kuphatikizapo amygdala ( Childress et al , 1999 ; Grant et al , 1996 ; Kilts et al , 2001 ) ndi hippocampus ( Kilts et al , 2001 ).
Chifukwa chake, njira zatsopano zosokoneza kuyanjananso kwa kukumbukira zingathandize kuwononga mgwirizano wamphamvu pakati pa nkhani ndi mankhwala ( Lee, 2008 ; Lee et al , 2005 ). Chochititsa chidwi n'chakuti, β -blockers awonetsa kale mphamvu yodalirika yoletsa mayankho okhazikika ku zolimbikitsa zachilengedwe komanso zoyambitsa zotsutsa ( Miranda et al , 2003 ). Komanso, zotsatira za kafukufuku waposachedwa zikusonyeza kuti mayankho okhazikika omwe amayambitsidwa ndi mankhwala angayambitsenso kukhudzidwa ndi chithandizo cha β -blockade ( Milton et al , 2008 ). Mofananamo, kafukufuku wowonjezereka pa mankhwala owonjezera GABA akuwonekanso kuti ndi woyenera. Kulimbikitsa kwa GABAergic, komwe kungachepetse kukhazikika kwa Pavlovian, kumawoneka kuti kumasokoneza mayankho a mankhwala ogwiritsidwa ntchito molakwika mwa nyama ( Volkow et al , 2004a ) ndipo kungakhale njira yothandiza yochizira chizolowezi mwa anthu ( Dewey et al , 1998 ).
Amygdala Wowonjezera: Kusayenerera Kosavuta Kwambiri
Kugwiritsa ntchito mankhwala osokoneza bongo mokakamiza komwe kumafotokozedwa ndi kuchuluka kwa kumwa mankhwala osokoneza bongo ndi mwayi wowonjezera kumayenderana ndi kusokonezeka kosatha mu homeostasis ya mphotho ya ubongo pogwiritsa ntchito miyeso ya miyeso ya mphotho yolimbikitsa ubongo. Kusiyanasiyana kwa kudzipatsa mankhwala osokoneza bongo kumakhudza kwambiri miyeso ya mphotho yomwe imawonjezeka pang'onopang'ono (mwachitsanzo, kuchepa kwa mphotho) mu mwayi wowonjezera, koma osati mu mwayi wochepa, makoswe nthawi zonse amadzipatsa okha ( Ahmed et al , 2002 ; Kenny et al , 2006 ; Wee et al , zotsatira zosasindikizidwa). Nyama zomwe zili ndi mwayi wowonjezera wa cocaine zimakhala zovuta kwambiri kuletsa kudzipatsa mankhwala osokoneza bongo ndi otsutsa dopamine ndi agonists ochepa ( Ahmed ndi Koob, 2004 ; Wee et al , 2007 ), ndipo mlingo wa opioid partial agonist buprenorphine umachepa kudzipatsa mankhwala osokoneza bongo m'makoswe omwe ali ndi mwayi wowonjezera, odalira opioid ( Chen et al , 2006b ), zomwe zikusonyeza kuti kusintha kwa kusowa kwa mphotho kumatha kuchepetsa mphamvu zolimbikitsira kugwiritsa ntchito mankhwala osokoneza bongo. Njira imeneyi ingathandize kwambiri pa chithandizo cha methadone ndi buprenorphine mwa anthu omwe ali ndi vuto la kugwiritsa ntchito mankhwala osokoneza bongo a heroin.
Monga taonera pamwambapa, otsutsa a CRF adaletsa zotsatira zodetsa nkhawa komanso zosokoneza za kusiya mankhwala osokoneza bongo, komanso kusiya kugwiritsa ntchito mankhwala osokoneza bongo onse omwe adayambitsa CRF mu CeA. Izi zidapangitsa kuti pakhale lingaliro lakuti kuyambitsa CRF, makamaka CRF yakunja kwa hypothalamic mu CeA, kudathandizira kuti pakhale kukakamiza kokakamiza kuchokera ku malingaliro olimbikitsa oipa ( Koob ndi Le Moal, 2008 ). Chifukwa chake, munthu anganene kuti kutsekeka kwa machitidwe opsinjika muubongo m'zinyama zomwe zimapeza mwayi wopeza mankhwala nthawi yayitali kungalepheretse chilimbikitso chomwa mankhwala osokoneza bongo mopitirira muyeso. Otsutsa a CRF adaletsa mwachisawawa kudzipatsa mankhwala owonjezera okhudzana ndi mwayi wodzipatsa cocaine, nikotini m'mitsempha ( Koob, 2008 ), heroin ( Greenwell et al , 2009 ), ndi mowa ( Koob, 2008 ). Chitsanzo chochititsa chidwi kwambiri cha zotsatira zolimbikitsa za CRF mu amygdala yowonjezereka mu kudalira chikhoza kuwonedwa mu zitsanzo za nyama za ethanol self-administration mwa nyama zomwe zimadalira momwe CRF 1/2 peptide antagonist yomwe inalowetsedwa mu amygdala inaletsa kuwonjezeka kwa ethanol self-administration panthawi yochotsa (Funk et al , 2006; Koob, 2008 ).
Ngakhale kuti sizinapangidwe bwino, umboni umasonyeza kuti machitidwe a norepinephrine m'thupi la amygdala lomwe silinakhazikitsidwe bwino komanso kuti munthu amadzilamulira yekha chifukwa chodalira mankhwala osokoneza bongo ( Koob, 2009b ). Mogwirizana ndi udindo wa dongosolo la dynorphin- κ opioid m'matenda obwera chifukwa chosiya kugwiritsa ntchito mankhwala osokoneza bongo, munthu wotsutsana ndi κ -opioid analetsa kumwa mowa kwambiri chifukwa chosiya kugwiritsa ntchito ethanol m'makoswe odalira mankhwala ndipo analetsa mosankha kuwonjezeka kwa chiŵerengero cha anthu m'makoswe omwe ali ndi mwayi wopeza cocaine ( Koob, 2009b ; Wee et al , 2009 ).
Neuropeptide Y ili ndi mphamvu zofanana ndi za anxiolytic zomwe zimapezeka ku amygdala ndipo zaganiziridwa kuti zimakhala ndi zotsatira zosiyana ndi CRF mu mkhalidwe woipa wolimbikitsa kusiya kugwiritsa ntchito mankhwala osokoneza bongo ( Heilig et al , 1994 ; Heilig ndi Koob, 2007 ). NPY yoperekedwa mkati mwa ubongo imaletsa kuchuluka kwa mankhwala omwe amagwirizanitsidwa ndi kudalira ethanol ( Thorsell et al , 2005a , 2005b ). Kulowetsa NPY mu CeA ( Gilpin et al , 2008 ) ndi kufalikira kwa NPY mu CeA komwe kumayambitsidwa ndi ma virus mu kuletsanso kuchuluka kwa mankhwala omwe amagwirizanitsidwa ndi kudalira ethanol ( Thorsell et al , 2007 ).
Motero, kuchuluka kwa CRF mu CeA komwe kumachitika ndi kusiya mankhwala mwachangu kumakhala ndi tanthauzo lolimbikitsa osati kokha pa zotsatira za nkhawa/zonga zosokoneza za kusiya mankhwala mwachangu komanso kuwonjezeka kwa kumwa mankhwala okhudzana ndi kudalira. Kusiya mankhwala mwachangu kungawonjezere kutulutsidwa kwa norepinephrine mu BNST ndi dynorphin mu nucleus accumbens, zonse zomwe zingathandize ku mkhalidwe woipa wamaganizo wokhudzana ndi kudalira. Kuchepa kwa ntchito ya NPY mu CeA kungathandizenso ku mkhalidwe wofanana ndi nkhawa wokhudzana ndi kudalira ethanol. Kuyambitsa machitidwe opsinjika muubongo (CRF, norepinephrine, dynorphin), kuphatikiza ndi kuletsa machitidwe oletsa kupsinjika muubongo (NPY) mu amygdala yayitali kungayambitse kusokonezeka kwamphamvu kwamalingaliro komwe kumakhudza chizolowezi. Machitidwe ena ambiri a neurotransmitter aganiziridwa kuti asinthe amygdala yayitali kuchokera ku gawo loyambitsa kupsinjika (vasopressin, substance P, orexin) ndi gawo loletsa kupsinjika (nociceptin, endocannabinoids; kuti muwonenso, onani Koob, 2008 ). Kusokonezeka koteroko kungakhale kothandiza kwambiri pa njira zotsutsana pakati pa dongosolo zomwe zimathandiza kusunga kudalira komanso kuyambitsa kusintha kwa nthawi yayitali kwa malingaliro monga kudziletsa kwa nthawi yayitali.
Kafufuzidwe pa njira zopanda mphamvu zowononga anthu zakhala zochepa. Mwachitsanzo, pogwiritsa ntchito cocaine, amygdala ndi lateral orbitofrontal cortex amavomerezedwa kuti ayambidwe ndi zosayembekezereka koma osati kuyembekezeredwa ndi mankhwala a cocaine m'magulu owononga mankhwala a cocaine (Kufahl Et al, 2008), koma kukana kokaine kunagwirizanitsidwa ndi kuchepetsedwa kwakukulu mu ntchito ya dopamine ziwonetsero zigawo, kuphatikizapo amygdala (Tomasi Et al, 2007a). Mwachiwonekere chosiyana, kusuta kudziletsa kunkagwirizana ndi kuwonjezeka kwa magazi kuwonjezera pa amygdala, pakati pa zigawo zina (Wang Et al, 2007), pamene nicotine ya m'mimba imachepetsanso m'magazi amygdala komanso imasiya kusuta kwa anthu omwe amamwa fodya omwe amachitidwa ndi 12.h za kusuta fodya (Zubieta Et al, 2001).
Amygdala ikhoza kukhala yofunikira kwambiri pokonza mphotho yabwino ( Murray, 2007 ) ndi nthawi yoyembekezera mphotho ( Holland ndi Gallagher, 2004 ), mofanana ndi kukonza mphotho yoipa. Chosangalatsa kwambiri pankhani yofufuza za ubongo ndicho kumvetsetsa ntchito ya amygdala popanga nkhawa ndi malingaliro oipa omwe nthawi zambiri amawonedwa panthawi yodziletsa.
Lipoti laposachedwapa linawonetsa kufunika kwa chizolowezi cha dera lolowerera lomwe mwina limalumikizana ndi amygdala ndi ventral striatum. Kafukufukuyu adawonetsa kuti osuta omwe adawonongeka ndi insula yawo (koma osati osuta omwe ali ndi zilonda zakunja kwa insular) adatha kusiya kusuta mosavuta komanso popanda kukumana ndi chilakolako kapena kubwereranso ( Naqvi et al , 2007 ). Insula, makamaka madera ake akunja, imalumikizidwa molumikizana ndi madera angapo a limbic (monga ventromedial prefrontal cortex, amygdala, ndi ventral striatum) ndipo ikuwoneka kuti ili ndi ntchito yolowerera, kuphatikiza chidziwitso cha autonomic ndi visceral ndi malingaliro ndi chilimbikitso ndikupereka chidziwitso chozindikira za zilakolako izi ( Naqvi ndi Bechara, 2009 ). Zoonadi, kafukufuku wa zilonda za ubongo akuwonetsa kuti ventromedial prefrontal cortex ndi insula ndi zigawo zofunika kwambiri m'magawo ogawidwa omwe amathandizira kupanga zisankho zamaganizo ( Clark et al , 2008 ). Mogwirizana ndi lingaliro ili, maphunziro ambiri ojambula zithunzi akuwonetsa kusinthasintha kwa ntchito mu insula panthawi ya chilakolako ( Naqvi ndi Bechara, 2009 ). Kugwira ntchito kwa dera la ubongo limeneli kwanenedwa kuti kumagwira ntchito ngati chizindikiro chodziwira kubwereranso kwa matendawa.
ZINTHU ZOFUNIKA KWAMBIRI KWA NEUROPLASTICITY: BINGE / KUCHITA, KUTHANDIZA / KUSAKHALA, KUSAKHALA / KUCHITA (KUCHITA)
Cholinga cha ndemangayi chili pa neurocircuitry ya chizolowezi. Komabe, mofanana ndi neuroplasticity ya neurocircuitry pali kusintha kwa mamolekyu komwe kumachitika m'mapangidwe omwewo. Kukumana ndi ma opiates ndi cocaine nthawi zonse kumabweretsa kuyambitsa kwa cyclic adenosine monophosphate response-element binding protein (CREB) mu nucleus accumbens ndi CeA ( Shaw-Lutchman et al , 2002 ; Edwards et al , 2007 ). CREB ikhoza kupangidwa ndi phosphorylated ndi protein kinase A ndi protein kinase yolamulidwa ndi zinthu zokulira, zomwe zimaiyika pamalo olumikizana ndi njira zingapo zotumizirana mauthenga zomwe zimatha kuwongolera kufotokozera kwa majini. Kuyambitsa kwa CREB mu nucleus accumbens ndi mankhwala olimbikitsa psycho kumagwirizana ndi zizindikiro zolimbikitsa za kusiya psychostimulant, monga dysphoria, mwina kudzera mu kuyambitsa kwa opioid peptide dynorphin, yomwe imamangirira ku κ -opioid receptors ndipo yaganiziridwa kuti ikuyimira njira yolekerera ndi kudalira ( Nestler, 2005 ). Kubwerezabwereza kwa CREB kumalimbikitsa kuwonetsa kwa dynorphin mu nucleus accumbens, zomwe zimachepetsa ntchito ya dopaminergic, zonse ziwiri zomwe zingathandize kubweretsa malingaliro oipa. Extracellular signal-regulated kinase ndi chinthu china chofunikira kwambiri cha intracellular signaling chomwe chimaonedwa kuti ndi gawo lofunika kwambiri mu plasticity yogwirizana ndi kuperekedwa mobwerezabwereza kwa cocaine, makamaka khalidwe lolimbikitsa, cocaine reward, ndi kuwonjezeka kwa nthawi yofunafuna cocaine pambuyo posiya (mwachitsanzo, incubation effect; Lu et al , 2006 ; Li et al , 2008 ).
Cholinga china cha mamolekyulu chowongolera kusinthasintha kwa pulasitiki komwe kumabweretsa chizolowezi ndi kusokonekera kwa kusinthana kwa cystine-glutamate, komwe kumaganiziridwa kuti kumalimbikitsa zizindikiro za glutamate zokhudzana ndi zigawo zingapo za chizolowezi. Pano, kupereka mobwerezabwereza kwa cocaine blunts kusinthana kwa cystine-glutamate, zomwe zimapangitsa kuti glutamate yoyambitsidwa ndi cocaine ichepe komanso kuchuluka kwa cocaine mu nucleus accumbens komwe kumapitilira kwa milungu itatu pambuyo pa chithandizo chomaliza cha cocaine ( Baker et al , 2003 ). Chochititsa chidwi kwambiri ndikuwona kuti chithandizo ndi N -acetylcysteine, poyambitsa kusinthana kwa cystine-glutamate, chinaletsa kukwera kwa cocaine komanso kukhudzidwa kwa khalidwe, chinabwezeretsa mphamvu yoyambitsa LTP ndi kupsinjika kwa nthawi yayitali mu nucleus accumbens, ndikuchepetsa kubwezeretsedwa kwa nyama ndikukhazikika kwa reactivity ku zizindikiro za mankhwala mwa anthu ( Moussawi et al , 2009 ; LaRowe et al , 2007 ; Madayag et al , 2007 ).
CREB ndi ma messenger ena amkati mwa maselo amatha kuyambitsa zinthu zolembera, zomwe zingasinthe mawonekedwe a majini ndikupanga kusintha kwa nthawi yayitali mu mawonekedwe a mapuloteni, ndipo, chifukwa chake, ntchito ya neuronal. Ngakhale kupereka mwachangu mankhwala osokoneza bongo kungayambitse kuyambika mwachangu (mkati mwa maola) kwa mamembala a banja la mapuloteni a Fos, monga c- fos , FosB, Fra-1, ndi Fra-2 mu nucleus accumbens, zinthu zina zolembera, isoforms za ΔFosB, mtundu wokhazikika kwambiri wa FosB, zawonetsedwa kuti zimasonkhana kwa nthawi yayitali (masiku) ndi kuperekedwa mobwerezabwereza kwa mankhwala ( Nestler, 2005 ). Nyama zomwe zili ndi ΔFosB yogwira ntchito zimakhala ndi chidwi chochulukirapo ndi zotsatira zabwino za mankhwala osokoneza bongo, ndipo ΔFosB ikhoza kukhala 'switch' yokhazikika yomwe imathandiza kuyambitsa ndikusunga mkhalidwe woledzera ( McClung et al , 2004 ). Kaya (ndi momwe) zinthu zolembera zotere zimakhudzira ntchito ya machitidwe opsinjika ubongo, monga CRF ndi zomwe zafotokozedwa pamwambapa, zikadali zodziwikiratu.
SUMMARY AND CONCLUSIONS
Mwachidule, madera ambiri a ubongo ndi ma circuits amasokonezeka mu chizolowezi cha mankhwala osokoneza bongo ndipo mwina amathandizira mosiyana ku mawonekedwe ovuta omwe amawonedwa mwa anthu omwe ali ndi chizolowezi ( Chithunzi 5 ). Ngakhale kuti zina mwa zolakwika izi zitha kukhalapo kwambiri kapena pang'ono m'magulu onse a chizolowezi cha mankhwala osokoneza bongo, kusintha kwina kungakhale kwapadera pa mitundu ina ya mankhwala osokoneza bongo. Mwachitsanzo, kuchepa kwa nthawi yayitali mu DAT mu striatum kumawoneka mu methamphetamine koma osati mu chizolowezi cha mowa kapena cocaine. Mosiyana ndi zimenezi, kuchepa kwa dopamine D2 receptors mu striatum kumawoneka mwa anthu omwe ali ndi chizolowezi cha mankhwala osokoneza bongo omwe afufuzidwa, ndipo kuwonjezeka kwa kuyambitsa kwa machitidwe a ubongo monga CRF kwawonedwa m'zinyama panthawi yosiya mankhwala osokoneza bongo amitundu yonse. Chofunika kwambiri, zovuta za neuronal zomwe zimaonekera mwa munthu woledzera ndipo zomwe zitha kuwululidwa ndi kujambula ndi/kapena maphunziro a neuropsychopharmacological ndi chiwonetsero cha osati kokha njira yodziwira mankhwala osokoneza bongo, komanso magulu enieni a munthu omwe ali ndi majini, chitukuko, ndi chilengedwe.
ZOKHUDZA ZOTHANDIZA ZOCHITA
Kupita patsogolo komwe kunanenedwa pamwambapa kumaphatikizapo njira zowonjezereka za kufufuza mu neurocircuitry ya chizoloŵezi chogwiritsira ntchito mofanana ndondomeko yoledzeretsa / kuledzeretsa, kuchotsa / kukhumudwitsa, ndi kusamala / kuyembekezera. Zolemera za sayansi zamakono za sayansi zamakono zomwe zimagwiritsidwa ntchito ku sayansi yokhudzana ndi mankhwala ozunguza bongo zimapereka mpata wosamvetsetsa kokha magulu opanga mankhwala omwe amamwa mowa mwauchidakwa komanso kupereka zofunikira kuti amvetsetse chiopsezo ndi kupereka chithandizo cha matendawa.
Kulimbitsa thupi / kumwa mowa mwauchidakwa, momwe nthenda yotchedwa neuroplasticity yomwe imayambira ndi kusintha kwa kuwombera ku mesolimbic dopamine neurons panthawi yoyamba ya mankhwala akumasuliridwa kuti agwirizane ndi doralum striatum, kusokonezeka kwa ntchito yoyamba, ndikugwiritsanso ntchito machitidwe opsinjika ubongo ndi Zimapangitsa kuti magalimoto atsitsire mofulumira chifukwa chofunafuna mankhwala osokoneza bongo ngakhale miyezi isanafike pambuyo pake. Mwachitsanzo, kodi pali mgwirizano wotani pakati pa chiopsezo chokhudzidwa ndi kukhudzidwa ndi chidziwitso chotsatira mwazomwe zimapangidwira m'masitiramu omwe tatchulidwa pamwambapa? Maphunziro oterowo angaphatikizepo njira zobadwa za maselo omwe amatha kuswana kapena kugogoda kwa njira zamakono m'madera ena a ubongo pogwiritsa ntchito njira zamakono za RNA.
Pa kuchotsa / kusokoneza gawo, kugwiritsidwa ntchito kwa machitidwe opanikizika a ubongo, monga CRF, mu zitsanzo za zinyama ziyenera kuwonjezeredwa ku machitidwe ena opanikizika a ubongo ndi kufufuza mu maphunziro aumunthu. Machitidwe ena ambiri a mphuno omwe amagwirizana ndi ubongo wa ubongo amangofufuzidwa tsopano, monga dynorphin, NPY, mankhwala P, nociceptin, ndi orexin. Zomwe sizinawonetsedwe panthawi ino ndizofukufuku waumunthu wa chigawo ichi cha chizoloŵezi choledzeretsa ndi kuganiza kwaumunthu kwa njira za ubongo za ubongo zimakhudzidwa ndi zolimbikitsa zokhudzana ndi kuchotsa mankhwala. Kupititsa patsogolo magetsi a zowonongeka kwa maphunziro a kujambula kwaumunthu omwe amamanga kwa ovomerezeka a machitidwe a m'mwamba omwe ali pamwambawa angakhale othandizira kwambiri kumunda.
Poganizira / kuyembekezeratu, maphunziro a anthu okhudza ubongo amawonetsa kuti chigoba choyambirira (orbitofrontal, medial prefrontal, prelimbic / cingulate) ndi amygdala chotsalira ndizofunikira kwambiri pa chilakolako cha mankhwala osokoneza bongo. Kaya maubwenzi oterewa amachititsa kusokonezeka kwa malo a ubongo m'mbuyo mwasinkhu ndi kusintha kwa ntchito yopweteka ya dopamine, kapena kusonyeza kusokonezeka kwapadera kwa madera omwe akutsogolera dopamine maselo, sakanatsimikiziridwa. Njira yatsopano yophunzirira kumbukumbu reconsolidation ingathandize kuthetsa mgwirizano wamphamvu pakati pa nkhani ndi mankhwala. Kufunika kwa kuledzera kwa dera lakumidzi lomwe limagwirizanitsa ndi insula ndi madera ena omwe amatha kugwiritsidwa ntchito ndi amygdala ndi ventral striatum otsala. Kuyanjanitsa kwa ma diskiti a ubongo kungakhale ngati chithunzithunzi chothandizira kubwereza kubwereza ndikuthandizira kulongosola mphamvu ya mankhwala. Kafukufuku wophunzira anthu, maphunziro a ma laboratory, ndi maphunziro a neurocircuitry mu zofanana zinyama zikhoza kutulutsa zotsatira zowonjezera m'dera ili.
Potsirizira pake, kusintha kwa maselo ndi majini omwe amasonyeza kusintha kwa ntchito za maurotriti mu magawo onse atatu a chizolowezi choledzeretsa chomwe tafotokozedwa pamwambapa tsopano akungosinthika. Zosintha zowonetsera kayendetsedwe ka zinthu, zolemba zolembera, komanso ngakhale ma genetiki pamtundu wa epigenetic zingathe kufotokoza momwe maulendo amatha kukhalira osokonezeka, kusungidwa, ndikupereka chiopsezo choyambitsa kusokoneza poyamba kapena kukhala kutali. Potsirizira pake, zolinga za sayansi zomwe zimagwiritsidwa ntchito pogwiritsa ntchito njira zogwiritsira ntchito mankhwala osokoneza bongo zimapereka zofuna zowonetsera kuti chiwerengero cha chiopsezo cha chibadwa cha anthu chimasokonekera, ndipo chiopsezo cha majeremusi m'zochitika zaumunthu chikhoza kuzindikira zolinga zomwe ziyenera kufotokozedwa pamaphunziro a zinyama.
Kuvomereza
Ili ndilo buku la 20084 lochokera ku The Scripps Research Institute. Kukonzekera kwa ntchitoyi kunathandizidwa ndi Pearson Center for Alcoholism and Addiction Research ndi National Institutes of Health kupereka AA12602, AA08459, ndi AA06420 kuchokera ku National Institute on Alcohol Abuse and Alcohol; DA04043, DA04398, ndi DA10072 kuchokera ku National Institute on Abuse; DK26741 kuchokera ku National Institute of Diabetes ndi Digestive and Kidney Diseases; ndi 17RT-0095 kuchokera ku Fodya-Related Related Disease Research Program kuchokera ku State of California. Tikuthokoza Michael Arends ndi Ruben Baler kuti awathandize polemba mapepala.
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