IZIMVO: Phonononga ngokucacileyo ukuchaza i-OCD kwiziyobisi zokuziphatha.
Ipapashwe kwi-intanethi ye-2007 kaJulayi 3. ikhonkco: 10.1016/j.bcp.2007.06.043
PMCID: PMC2222549 NIHMSID: NIHMS37091
Bona amanye amanqaku ku-PMC
Wisdom nqaku epapashwe.
Yiya e:
Abstract
Iukuphazamiseka kokulawula impulse (ICDs), kubandakanya ukungcakaza kwe-pathological, i-trichotillomania, i-kleptomania kunye nezinye, ziye zacingelwa ukuba zilale ecaleni kwe-spectrum yokunyanzeliswa. Idatha yamva nje iphakamise ukuba ezi ngxaki zinokuthathwa njengeziyobisi. Apha sivavanya iziseko zofuzo kunye ne-neuropathological of the impulse control disorder kwaye sithathela ingqalelo iziphazamiso ezingaphakathi kwezi zikhokelo zingabandakanyiyo.
intshayelelo
Iziphazamiso zokuLawula iiMpusi
Ukuphazamiseka okusesikweni kokulawulwa kwempembelelo (ICDs) apho kukho iindlela zokuxilonga kwi-Diagnostic and Statistical Manual (DSM-IV-TR) ibandakanya ukungcakaza kwe-pathological (PG), i-kleptomania, i-pyromania, ukuphazamiseka kwe-intermittent explosive disorder, i-trichotillomania kunye ne-ICD engachazwanga ngenye indlela [1]. Iikhrayitheriya zezinye ii-ICDs (ukuthenga okunyanzelekileyo, ukusetyenziswa kwe-intanethi okunengxaki, ukuziphatha okunyanzelekileyo ngokwesondo, kunye nokuchola ulusu olunyanzelekileyo) zicetyisiwe kwaye ngoku zithathelwa ingqalelo [2, 3]. Iimpawu ezisisiseko zee-ICDs ziquka ukuphinda-phinda okanye ukunyanzeliswa ukubandakanyeka kwindlela ethile yokuziphatha (umzekelo, ukungcakaza, ukutsala iinwele) ngaphandle kwemiphumo emibi, ukunciphisa ukulawulwa kokuziphatha okuyingxaki, kunye noxinzelelo okanye umnqweno wokutya ngaphambi kokuzibandakanya kwindlela yokuziphatha [2].
Ii-ICDs kunye noKulutha
Ii-ICD ziye zacingelwa ukuba zilale ecaleni kwe-spectrum enyanzelekileyo [4], emele i-obsessive-compulsive (OC) ukuphazamiseka kwe-spectrum [5, 6]. Nangona abantu abane-ICDs bezibandakanya kukuziphatha okuphindaphindayo, rhoqo beneminqweno enamandla ehambelanayo, izimilo zihlala zinxibelelene njengokuyonwabiseka okanye i-egosyntonic, ngelixa ukuphindaphinda okanye amasiko kwi-OC disorder (OCD) ngokuqhelekileyo i-egodystonic. [7, 8]. Abantu abane-ICDs bahlala befumana amanqaku aphezulu kwimilinganiselo yokungabinamdla kunye nolwakhiwo olunxulumeneyo njengokufuna imvakalelo ngelixa abantu abane-OCD bahlala befumana amanqaku aphezulu kwimilinganiselo yokuphepha ingozi [8-12]. Iikhrayitheriya zokuxilonga ii-ICDs ezifana ne-PG ziyahambelana nezo zokuxhomekeka kweziyobisi, kunye neendlela ezithile ezinxulumene nokunyamezelana, ukurhoxa, iinzame eziphindaphindiweyo ezingaphumeleliyo zokucutha okanye ukuyeka, kunye nokuphazamiseka kwiindawo eziphambili zobomi [1]. Njengoko kuchazwe ngezantsi, kukho ukufana kwe-neurobiological kunye nemfuzo phakathi kwe-ICDs kunye neziyobisi. Ke, ii-ICDs zinokugqalwa “njengeziyobisi zokuziphatha"[13-16].
Ubukhoboka: Isishwankathelo
Uphando olubanzi lwenziwe kwi-neurobiological underpinnings yophuhliso kunye nokugcinwa kweziyobisi (kuhlaziywe kwi- [17-19]). Iimbono ezivelayo zokukhotyokiswa zibandakanya ichiza okanye indlela yokuziphatha efumana amandla ngokuqiniswa, kunye notshintsho olulandelayo ngokweenkqubo zokufunda ezisekelwe kumvuzo ukuya kumanqanaba okuziqhelanisa / okunyanzelekileyo19].
Imeko yokukhanga kukuqwalaselwa okubalulekileyo kumanqanaba okuqala enkqubo yokulutha. Imeko enomdla, echazwa "njengenkqubo apho imivuzo emitsha ifundwa kwaye ifumane amandla akhuthazayo," kubandakanya ukuvuselela imeko yendawo ehambelana ngokusondeleyo neenkqubo zokulutha [20]. Izakhiwo ezininzi ze-neuroanatomical ezibalulekileyo kule nkqubo yokumisela i-conditioning ziquka i-amygdala, ebalulekileyo kwisabelo sokubaluleka kweemvakalelo kunye nobudlelwane obufundiweyo phakathi kwe-motivation efanelekileyo kunye nenye into engathathi hlangothi [17, 21], i-orbitofrontal cortex (OFC), ekufundweni kwezilwanyana kuye kwacetyiswa ukuba ifake iziphumo ezilindelekileyo kwaye ngokusebenzisa uxhulumaniso oluqinileyo lwe-anatomical kunye ne-basolateral amygdala (BLA) inokuququzelela ukufunda okuhlangeneyo kwi-amygdala, kunye ne-anterior cingulate cortex (ACC) uye wabandakanyeka ekufundeni ngocalucalulo nakulawulo lwengqondo [22]. Izakhiwo ezongezelelweyo ezibalulekileyo kule nkqubo ziquka i-hippocampus, enika imemori yomxholo ehambelana ne-motivation stimuli, kunye ne-hypothalamic kunye ne-nuclei ye-septal, enika ulwazi olufanelekileyo kwiindlela zokuziphatha ezikhuthazayo ezifana nokuziphatha ngokwesondo kunye nokungenisa izondlo [23, 24]. Ngokudibeneyo, ezi kunye nezakhiwo ezinxulumeneyo ziquka i-neurocircuitry ephantsi kokuzibandakanya kwiindlela zokuziphatha ezikhuthazayo. Njengoko izimilo ezikhuthazayo zisiya zithotyelwa ngakumbi kwizinto ezinxulumene nokulutha ngexesha lokuqhubekeka kwenkqubo yokulutha, kusenokwenzeka ukuba utshintsho kulwakhiwo kunye nomsebenzi wale mimandla lunegalelo ekuzibandakanyeni ngokugqithisileyo ekuziphatheni okusembindini we-ICDs.
Kwakhona okubalulekileyo kwimeko kunye nokulutha yi-nucleus accumbens (NAcc), equlethwe liqokobhe kunye nombindi. Iqokobhe, ngokubuyisela umva kwindawo ye-ventral tegmental, ibalulekile ekumodareyitheni inkuthazo ekhuthazayo, ngelixa undoqo ubandakanyeka ngakumbi ekubonakalisweni kokuziphatha okufundiweyo ekuphenduleni isivuseleli esixela kwangaphambili iziganeko ezikhuthazayo / ukomelezwa kwemeko [17, 19]. Indawo ye-ventral tegmental (VTA), kunye noqikelelo lwayo lwe-dopaminergic kwi-amygdala, i-NAcc kunye ne-prefrontal cortex (PFC, ebandakanya i-OFC kunye ne-ACC), iququzelela imibutho efundiweyo kunye neziganeko ezikhuthazayo ngokukhutshwa kwe-phasic dopamine (DA) [25, 26]. I-Dopaminergic neurons iyathintelwa, mhlawumbi nge-dorsal medial thalamus (habenula), xa imivuzo elindelekileyo ingenzeki [27, 28]. Kuye kwacetywa ukuba kumanqanaba okugqibela omlutha, impembelelo ephambili kutshintsho lokuziphatha olusuka kwiisekethe ze-corticostriatal ezibandakanya i-ventral striatum ukuya kwiisekethe ezibandakanya i-dorsal striatum, ekudala ibandakanyeka kulwakhiwo lomkhwa (jonga ngezantsi) [29, 30].
Ukusebenzisa i-striatum njengento ekugxilwe kuyo, imodeli inokuveliswa apho i-appetitive conditioning iqala kwiqokobhe le-NAcc ngamagalelo avela kwi-hippocampus, i-VTA (ekwafumana igalelo kwi-nucleus ephakathi ye-amygdala), kunye ne-PFC, "utshintsho" ukuya kwimeko. Ukuqiniswa kwisiseko se-NAcc ngamagalelo avela kwi-BLA kunye ne-PFC, kwaye ekugqibeleni iguqukela ekubeni ngumkhwa kwi-dorsal striatum ngegalelo elivela kwi-sensorimotor cortices kunye neminye imimandla efana ne-septal hypothalamus [19, 23]. Olu tshintsho lubandakanya i-limbic, i-associative kunye nemimandla ye-sensorimotor ye-striatum, ngokulandelelana (bona ). I-dorsal striatum kunye neglobus pallidus (ngegalelo elisuka kumbindi we-NAcc) zisebenza kwithalamus ethi iphinde ibuyele kulwakhiwo lwecortical. Ngaphakathi kwesi sikhokelo se-anatomical, i-genetics kunye ne-neurobiology ye-ICDs ihlaziywa. Ukongeza, nangona kukho ukudibana okuninzi kwi-neurocircuitry kunye nokubandakanyeka kwe-neurotransmitter kwizigaba ezahlukeneyo zokulutha, ezi nkqubo zinikezelwe ngolandelelwano ngokuhambelana nolwakhiwo lwenguqu olukhankanywe ngasentla.
a: Ukujikeleza kwengqondo kubandakanyeka kubukhoboka. PFC = i-cortex yangaphambili, i-VTA = indawo ye-ventral tegmental, i-SN = i-substantia nigra, i-NAcc = i-nucleus accumbens, i-OFC = i-cortex ye-orbitofrontal
Population Genetics of Addiction and ICDs
Iimfuza ngokubaluleka zibonelela ngegalelo lokuqala kwinkqubo yokulutha, njengoko zimisela ubuthathaka obusisiseko kwiinkqubo eziqhelekileyo zokuziphatha ukuba zihambe kakubi. Izifundo zeGenetic ze-ICDs zibonisa ukufana kwezinye iziyobisi [31]. Izifundo zosapho kunye nezamawele ze-epidemiologic ziye zaqikelela ukuba igalelo lemfuza lifikelela kwi-60% yomahluko kumngcipheko weziyobisi [32, 33]. Ngokufanayo igalelo elinamandla lemfuzo lifunyenwe kwi-PG. Ukusebenzisa idatha evela kwi-Vietnam Era Twin (VET) registry, izinto zofuzo ziqikelelwa ukuba ziphendule phakathi kwe-35% kunye ne-54% ye-liability ye-DSM-III-R ye-symptomatology kwi-PG [34]. Iqondo lokufuza liyafana nezo zezinye iziphazamiso zengqondo eziquka ukuphazamiseka kokusetyenziswa kweziyobisi: kwisampulu efanayo, i-34% yokwahluka kumngcipheko wokuxhomekeka kumachiza kwakubangelwa yimiba yemfuza [35]. Olunye uphononongo lobhaliso lwe-VET luvavanye iimbali zobomi be-PG kunye nokuxhomekeka kotywala ngodliwano-ndlebe olucwangcisiweyo kwaye lwabonisa ubungakanani bomngcipheko wokusingqongileyo kunye nofuzo we-PG okwabelwana ngawo nokuxhomekeka etywaleni. Ababhali bafumanise ukuba umngcipheko omkhulu we-PG subclinical (12-20% yemfuza kunye ne-3-8% yendalo esingqongileyo) yabalwa ngumngcipheko wokuxhomekeka kotywala [36]. Kuphononongo olwalandelayo lwabemi abafanayo, uSlutske kunye noogxa nabo bafumene unxulumano olubalulekileyo phakathi kwePG kunye nokuziphatha okuchasene noluntu, kunye nalo mbutho ucaciswa kakhulu yimiba yemfuza [37]. Ezi zifundo zicebisa ukuba ii-ICD ezinje nge-PG zinxulumene nokuxhomekeka etywaleni kunye nokuziphatha okungafunekiyo ekuhlaleni, kwaye zinokunxulunyaniswa ngeendlela eziqhelekileyo ezisisiseko ezifana nokungafuneki (jonga ngezantsi). Nangona i-preliminary, ezi datha zibonisa ukuba njengakumakhoboka eziyobisi, izinto zofuzo zinegalelo elikhulu kwi-pathophysiology ye-ICDs. Imirhumo ethile yemfuza enxulumene ne-neurotransmitters echaphazelekayo kwi-ICDs ichazwe ngezantsi.
Impulsivity
Impulsivity inento yokwenza nokuphazamiseka kwengqondo okuninzi, kubandakanya ii-ICDs kunye neziyobisi [38]. Kwinkqubo yokukhotyokiswa, ukungxama kunegalelo kumanqanaba okuqala afana nokulinga iziyobisi. I-Trait impulsivity inamacandelo amaninzi; umz., olunye uphononongo lwachonga amacandelo amane (ukungxamiseka, ukunqongophala kokucinga kwangaphambili, ukungabikho kozingise, kunye nokufuna imvakalelo [39[]40, 41]). UMoeller noogxa bakhe baye bachaza ukungxama “njengotyekelo lokusabela ngokukhawuleza, okungacwangciswanga kuvuselelo lwangaphakathi okanye lwangaphandle [ngokuncipha] ngokuphathelele imiphumo emibi yokusabela kumntu otyhutyhayo okanye kwabanye [42].” Xa zizonke, ezi ziphumo zibonisa ukuba ukungxamiseka yinto entsonkothileyo, eneenkalo ezininzi. Ngokungaguqukiyo, idatha evela kwizifundo zabantu kunye nezilwanyana zibonisa ukuba iindawo ezininzi zobuchopho kunye neenkqubo ze-neurotransmitter zinegalelo ekuziphatheni okunganyanzelekanga kuyo yonke inkqubo yokulutha [32, 43].
Dopamine, Impulsivity kunye ne-ICDs
Njengoko kuchaziwe ngasentla, i-dopamine ifanelekile kwangethuba kwinkqubo yokulutha kunye nakwimiba yamva. Iinkqubo ze-Dopaminergic ziye zabandakanyeka kwi-impulsivity kunye ne-ICDs. Ii-Psychostimulants ezinje nge-amphetamine zinefuthe kwi-dopamine kunye nezinye iinkqubo ze-biogenic kwaye zilunyango olusebenzayo lwe-ingqwalasela yokusilela kwe-hyperactivity disorder (ADHD), ukuphazamiseka okunokuthiwa njengento engundoqo. Ukungalawulwa kwenkqubo ye-NAcc ye-DA kubandakanyeke kwi-ADHD [44]. Iinkqubo zeDopaminergic nazo zinegalelo kwiinkqubo zokulutha. Ukufumaneka okuhlala kuphantsi kwe-D2 receptor kuye kwaxelwa kubaxhaphazi be-cocaine kwiinyanga ezininzi emva kokukhutshwa, kwaye oku kufumaneka kuye kwayanyaniswa nokwehla kwemetabolism kwi-OFC phakathi kweminye imimandla yobuchopho efana ne-cingulate gyrus [18, 45]. Imilinganiselo esisiseko esezantsi yokufumaneka kwe-DA D2 yokufumana i-receptor kwizifundo ezingakhobokiyo ziqikelela ukuthanda kwe-methylphenidate, exhasa i-hypothesis yokuba ukufumaneka kwe-D2 ye-receptor ephantsi kulamla ukuba sesichengeni sokulutha [46]. Ngenkxaso, ukunciphisa ukufumaneka kwe-D2 ye-receptor (mhlawumbi ngenxa yokuhla kwamanani e-receptor kunokuba kwandiswe ukukhutshwa kwe-DA) kwabonwa kwi-ventral striatum yeempuku ezingxamisekileyo, kwaye oku kufumaneka kwabikezelwa ngamazinga aphezulu okuzilawula kwe-cocaine ye-intravenous [47]. Ukufumaneka kwe-D2 ye-receptor ephantsi kwi-striatum kwakhona kuqikelelwe ngokulandelayo ukonyuka kokuzilawula kwe-cocaine ziinkawu [48]. Ubungakanani bokuba ezi ziphumo zinxulumene nokungxamiseka kunye nee-ICD kufuna uviwo oluthe ngqo.
I-DA inokulamla okuvuzayo okanye ukomeleza imiba yokungcakaza, kwaye iDA iye yabandakanyeka kwi-PG [49]. Ukunciphisa amanqanaba e-DA kunye nokwanda kwamanqanaba e-metabolites ye-3,4-dihydroxyphenylacetic acid (DOPAC) kunye ne-homovanillic acid (HVA) ifunyenwe kwi-CSF ye-pathological gamblers [50], nangona ezi ziphumo zazingasajongwa xa kulungiswa izinga lokuhamba kweCSF [51]. I-Amphetamine, ichiza elonyusa i-catecholamine ye-extracellular kunye ne-5-HT ekugxininiseni nge-vesicular depletion, i-reuptake inhibition, ukuphuculwa kwe-DA synthesis, kunye ne-monoamine oxidase (MAO) inhibition [52], ukhuphiswano lokungcakaza kubantu abanengxaki yokungcakaza, kodwa hayi ukusetyenziswa kotywala kwabo banengxaki yokusela [53]. Ezi ziphumo zibonisa indima ye-DA (kunye/okanye ezinye iindlela ze-aminergic) kwi-pathophysiology ye-PG njengoko iziyobisi ezineendlela ezifanayo zesenzo zinokuwela-inkulumbuso yokubuyiselwa kwezinye iziyobisi kulo didi (okt i-amphetamine ye-cocaine) [54, 55].
Iingxelo ezininzi zidibanise ukusetyenziswa kwe-agonist ye-DA kwi-Parkinson's Disease (PD) kunye ne-PG kunye nezinye iindlela zokuziphatha ze-ICD ezifana nakwiindawo zesini kunye nokutya [56-60]. Uphononongo lwakutsha nje lwezigulane ze-272 zePD eziye zavavanywa kwaye zavavanyelwa ii-ICD zafumana imibutho eyomeleleyo efanayo kuzo zonke ii-agonists ze-DA kunye ne-PG kunye nezinye ii-ICDs.61]. Imbali ye-ICD ngaphambi kokuqala kwePD idibene ne-ICD yangoku. Iidosi zemihla ngemihla zokulingana kwe-levo-dopa zaziphezulu kwizigulane ezine-ICD kunezo zingenayo. Uphononongo olulindelekileyo lwezigulana ezingama-297 ezine-PD ezivavanyelwe ukuxhaphaka kobomi be-PG zikwafumene unxibelelwano phakathi kokusetyenziswa kwe-agonist ye-DA kunye ne-PG [62]. Nangona kungekho mbutho wabonwa kunye ne-agonist subtype, unxibelelwano kunye nolawulo lwe-levodopa oluhambelanayo lwabonwa, lubonisa isiphumo sedosi epheleleyo okanye isiphumo sokuqala se-levodopa [62]. Ngaloo ndlela, idatha ekhoyo ibonisa ukuba i-agonists ye-DA, ngakumbi kubantu abasengozini ye-ICDs, inxulunyaniswa ne-PG kunye nezinye ii-ICD, ezidibanisa ngakumbi inkqubo ye-DA kunye ne-ICDs.
Izifundo zemfuzo zinxibelelanise iintlobo ezininzi zofuzo nokungxama kunye nokulutha, kubandakanywa nofuzo olufaka ikhowudi ye-DA D4 receptor (I-DRD4) kunye nomthuthi weDA (I-SLC6A3) [32, 63, 64] I-ADHD inofuzo oluphezulu, igalelo lemfuzo libalelwa phantse i-80% yomngcipheko wokuphazamiseka, kwaye phakathi kwezona ntlobo zemfuzo zichaphazeleka kakhulu ezinxulumene ne-ADHD yi-DRD4 kunye I-SLC6A3 ezahlukeneyo [65]. Olunye uhlobo lwe-DA olufana ne-DRD5 ludityaniswe ne-ADHD ngokunjalo [65]. Izifundo ezibini zifumene umbutho weepolymorphisms ze I-DRD4 nge PG [66, 67] . Ukongeza, i D2A1 i-allele ye-D2 receptor iye yabandakanyeka ekusebenziseni kakubi iziyobisi, ukutya okunyanzelekileyo kunye nokutshaya [63, 68], kwaye ifunyenwe kwi-frequency ephindwe kabini ephezulu kwizifundo ezine-PG xa kuthelekiswa nolawulo [69]. Le datha ingentla icebisa, zombini ngemfuzo kunye nesiphumo esisebenzayo, igalelo le-dopaminergic kumalungu anganyanzelekanga e-ICDs kunye nezinye iziyobisi. Nangona kunjalo, izifundo ezongezelelweyo ziyafuneka ukuphindaphinda kunye nokwandisa ezi ziphumo, ngakumbi njengoko uphando oluphanda igalelo le-DA kumanyathelo obuntu bokungabi namdla okanye ulwakhiwo olunxulumene nethiyori olufana nokufuna izinto ezintsha lubonise iziphumo ezahlukeneyo kubudlelwane babo kunye nokwahluka kofuzo lwe-DA [70].
I-Dopaminergic Regulation kunye ne-ICDs: Iindima ze-γ-aminobutyric acid (GABA) kunye ne-Glutamate
γ-aminobutyric acid (GABA) yeyona neurotransmitter inhibitory inhibitory kwingqondo. Idityaniswe kwiitheminali zemithambo-luvo ukusuka kwi-glutamate yi-enzyme glutamate decarboxylase. Kukho ubungqina bonxibelelwano lwe-anatomic kunye nokusebenza phakathi kwe-GABA kunye neenkqubo ze-dopaminergic kunye nokunyusa inkxaso yeziphumo zokumodareyitha kweenkqubo ze-GABAergic kukuphazamiseka kokusetyenziswa kweziyobisi [71]. Ngokomzekelo, i-tiagabine, i-GABA reuptake inhibitor esetyenziselwa ikakhulu ukunyanga ukuxhuzula, ibonise ukusebenza kwangaphambili kwi-cocaine.72], kwaye kwingxelo yetyala, iboniswe ukunceda ukulawula ubundlobongela obungxamisekileyo73]. I-Glutamate, i-neurotransmitter enomdla kunye ne-precursor ye-GABA iye yabandakanyeka kwiziyobisi kunye nee-ICDs.
Kwizifundo zangaphambi kweklinikhi, amanqanaba e-glutamate ngaphakathi kwe-NAcc elamla indlela yokuziphatha yokufuna umvuzo [74]. I-nonvesicular glutamate release from cysteine / glutamate antiporters ibonakaliswe njengomthombo oyintloko we-extracellular glutamate kwi-NAcc; imodareyitha ukukhutshwa kwe-glutamate ye-vesicular kunye ne-dopamine ngokuvuselela iqela le-glutamate i-2/3 ye-metabotropic glutamate receptors [75, 76]. I-N-acetylcysteine (NAC), i-cysteine pro-drug, inyusa amanqanaba e-extracellular ye-glutamate, mhlawumbi ngokuvuselela i-inhibitory metabotropic glutamate receptors, ngaloo ndlela inciphisa ukukhululwa kwe-synaptic ye-glutamate. Ibonise ukusebenza kwangaphambili kokulutha kwe-cocaine [77] kunye ne-PG [78]. Zithathiwe kunye, ezi datha zicebisa iindima ezinokwenzeka ze-glutamatergic kunye ne-GABAergic iinkqubo kwiziyobisi kunye nokuziphatha.
I-Serotonin, Impulsivity kunye ne-ICDs
Njenge-DA, i-GABA kunye ne-glutamate, indima ye-serotonin (i-5-HT) ixhaswa kwi-impulsivity, ii-ICD kunye neziyobisi. Iprojekthi ye-serotonergic neurons yenza i-dorsal raphe nucleus kuyo yonke ingqondo ukuya kwimimandla ebandakanya ihippocampus, i-frontal cortex kunye ne-amygdala. Kwimizekelo yezilwanyana, i-forebrain ye-5-HT yokunciphisa ibonakaliswe ukukhokelela ekukhetheni okungafunekiyo, ngelixa i-5-HT engathanga ngqo i-agonist fenfluramine inciphisa ukuziphatha okunjalo [79, 80]. Ukongeza, inxeba le raphe lempuku likhokelela ekukhetheni okwethutyana kwimivuzo yangoko [81]. Ngokunxulumene nabachasi be-5-HT abangakhethiyo baye baboniswa ukukhuthaza ukhetho oluzilawulayo [82]. Indima yamacandelo athile enkqubo ye-serotonin ixhaswa ngokufunyaniswa kwempembelelo enkulu yemoto kwi-5-HT1B iimpuku eziphumayo [83]. I-Tryptophan depletion, ehlisa amanqanaba e-5-HT (kunye nokunciphisa i-5-HT metabolites kwi-cerebrospinal fluid (CSF)), kwandisa i-motor impulsivity (i-continuous-performance test-device pairs), kodwa kungekhona ukhetho olukhawulezayo (ukulibazisa isaphulelo) ebantwini. [84, 85]. Kwizifundo ezinembali yosapho yokukhotyokiswa butywala, i-tryptophan depletion yehlisa isithintelo sokuziphatha (Yeka uMsebenzi) kodwa ayizange ichaphazele ukulibaziseka kwesaphulelo [84]. Amanqanaba aphantsi e-5-HT metabolite i-5-hydroxyindolacetic acid (5-HIAA) afunyenwe kubantu abaneempawu ezichukumisayo [86, 87], kunye nokusela utywala kwangethuba [64]. Amanqanaba aphantsi e-CSF 5-HIAA aphinde adibaniswa nokuziphatha okuyingozi kwi-primates; umz., iinkawu zithatha umtsi omde ehlathini [88]. Kuthatyathwe ndawonye, imigca emininzi yobungqina ixhasa indima ye-5-HT ekulamleni ukunyanzeliswa, nangona uphando oluninzi lufunekayo ukuchonga amacandelo athile enkqubo ye-5-HT enegalelo kwiinkalo ezithile zokunyanzeliswa.
Iinkqubo ze-5-HT ziye zabandakanyeka kwii-ICDs. Nangona amadoda ane-PG ngokuchasene nalawo angabonisi mahluko ubalulekileyo kwi-5-HT okanye i-5-HIAA kwiisampuli ze-CSF [50, 89, 90], amanqanaba e-5-HIAA afunyenwe esezantsi kwabo bane-PG xa belawula ixesha lokucofa (elandiswe kwiqela lePG) [51]. I-Metachlorophenylpiperazine (m-CPP), i-metabolite ye-trazodone yenza njenge-agonist inxalenye kwaye inobudlelwane obuphezulu be-5-HT receptors (ingakumbi i-5-HT2c, echaphazelekayo ekulungelelaniseni imiba yesimo sengqondo, ukuziphatha okuxhalabisayo kunye nomsebenzi we-neuroendocrine [91]). Ulawulo lwe-m-CPP luye lwabikwa ukuba luvelise ukuziphatha "okuphezulu" kunye nokunyusa amanqanaba eprolactin (inkqubo ekucingelwa ukuba ixutywe yi-postsynaptic 5-HT1A/2A/2C abamkeli) kwizifundo ezine-PG xa kuthelekiswa nezifundo zolawulo ngaphandle kwePG [92]. Le mpendulo ifana naleyo ichazwe kwezinye iziphazamiso apho ukuziphatha ngokungxama okanye okunyanzelekileyo kubalaseleyo, kubandakanywa ukuphazamiseka kobuntu obuchasene noluntu [93], ukuphazamiseka kobuntu bomda [94], ukuxhomekeka kwicocaine [95], kunye nokusebenzisa kakubi utywala okanye ukuxhomekeka [96].
Ukongeza kwimingeni ye-pharmacological, izifundo zofuzo ziye zachaphazela inkqubo ye-5-HT kuzo zombini impulsivity kunye ne-ICDs. A I-TPH1 (i-tryptophan hydroxylase 1, efaka i-enzyme kwisinyathelo sokunciphisa izinga kwimveliso ye-5-HT) ukwahluka kofuzo kufunyenwe kuhambelana nokunciphisa i-5-HIAA kwi-CSF kunye nokuziphatha kokuzibulala kubaphuli-mthetho abanobundlobongela [97]. Ezinye iijini ze-serotonergic zidityaniswe kuko zombini ukungxama kunye nokuba likhoboka leziyobisi kwaye zibandakanya I-SERT (I-SLC6A4) Kunye MAOA [32]. I-polymorphism kummandla okhuthazayo wegene yokuthutha i-serotonin yomntu (SLC6A4) Ukufakwa kweekhowudi ezimfutshane kunye neendlela ezinde zeprotheyini (kunye nokwahluka okufutshane okuvelisa iprotheyini encinci esebenzayo) inyanyaniswa nemilinganiselo emininzi ye-psychopathology, kubandakanya neuroticism, ixhala kunye nokudakumba [98-102], nangona izifundo zamva nje ziye zaphakamisa imibuzo malunga namandla okanye ukufaneleka kwale mibutho [103-105]. I-SLC6A4 ukwahluka kunokufaka isandla kwii-ICD njengoko umbutho uxeliwe phakathi kwe I-SLC6A4 i-allele emfutshane kunye ne-PG emadodeni kodwa hayi abafazi [106]. Okokugqibela, izifundo ezibandakanya iisampulu ezincinci zezifundo ziye zaxela ngokungahambelani amakhonkco phakathi kwe-serotonin kunye ne-monoamine oxidase genes kunye ne-ICDs ezinje ngePG, ukuthenga okunyanzelekileyo kunye ne-trichotillomania [107-109]. Izifundo ezongezelelweyo zisebenzisa iisampulu ezinkulu kunye nononophelo (umzekelo, ukuxilongwa) iimvavanyo ziya kunceda ukuphanda imfuzo yosapho olubanzi lwee-ICDs.
Izifundo zonyango ze-serotonergic agents ziye zavelisa iziphumo ezixubileyo malunga nokusebenza kunyango lwee-ICDs [110-113]. Ukulawulwa kwe-placebo, izilingo zekliniki ezikhethiweyo (RCTs) ze-serotonin reuptake inhibitors (SSRIs) ezikhethiweyo ziye zavelisa iziphumo ezixubileyo, kunye nezinye ii-RCT ezibonisa ukusebenza okuphezulu kwi-placebo [114, 115] nabanye abangayiyo [116, 117] . Uninzi lwamaphononongo lubonise ukuphucuka kwezonyango kwangethuba kunyango kuwo omabini amaqela anyangwe ngamachiza kunye ne-placebo. Ezi nzuzo zibonisa unyango okanye impendulo ye-placebo kunokuba uzuze okuthe ngqo kwichiza elisebenzayo, nangona umahluko kamva phakathi kwamaqela kwezinye izifundo zibonisa iziphumo zamayeza asebenzayo. Kwizifundo ezininzi ze-trichotillomania, akukho mahluko ubalulekileyo owabonwayo phakathi kwe-fluoxetine kunye nonyango lwe-placebo.111]. Kuphononongo olungacwangciswanga lwe-citalopram vs. placebo kumadoda angama-28 abathandana besini esinyanzelekileyo, akukho mahluko ubonwe kumanyathelo okuziphatha okunyanzelekileyo ngokwesondo phakathi kwamaqela emva kweeveki ze-12 zonyango, nangona kukho ukwehla okukhulu kwi-drive yesondo ehambelana neziyobisi ezisebenzayo [118]. Iingalo ezimbini ezihambelanayo, izifundo ezilawulwayo ze-fluvoxamine kunyango lokuthenga okunyanzelekileyo alubonisi mahluko phakathi kwechiza elisebenzayo kunye ne-placebo [119, 120], kodwa uphononongo lweeveki ezisixhenxe ze-citalopram ezivulekileyo ezilandelwa ziiveki ezisithoba zokungahleliwe zibonise ukuphuculwa kweziyobisi ezisebenzayo xa kuthelekiswa ne-placebo [121]. Ingxelo yetyala icebise ukusebenza kwe-escitalopram, kunye ne-SSRI kunyango lokusetyenziswa kwe-intanethi okuyingxaki, kodwa kufuneka kuqhutyelwe izifundo ezongezelelweyo malunga nokusebenza kunyango (kunye nokuxilongwa) kwesi sifo [113]. Zithathiwe kunye, iziphumo zicebisa ukuba ii-SSRIs zisebenzela abantu abathile abane-ICDs kodwa hayi abanye. Ezi ziphumo zibonisa ukuba iimpawu ezithile zomntu (umzekelo, iimpawu zemfuza okanye ukuphazamiseka okwenzeka kunye njengexhala okanye ukudakumba) kunokunceda ukukhokela ukhetho lonyango olufanelekileyo [122].
Njengoko kuchaziwe ngasentla, ukungxamiseka kunegalelo kuzo zombini ii-ICDs kunye neziyobisi. Kusenokwenzeka ukuba ukunyanzeliswa kunegalelo elikhethekileyo kwi-ICDs kunye nakwiziyobisi njengoko kunjalo kwimiba yokusebenza kwengqondo [123]. Ukongeza, njengokungxama, ukufana phakathi kwe-ICDs kunye neziyobisi zikhona kwezinye iindawo, ezinjengokwenza izigqibo kunye nokuphendula ngoxinzelelo, kwaye ezi ndawo zithathelwa ingqalelo apha ngezantsi.
Uvavanyo loMvuzo woMngcipheko, ukwenza izigqibo, kunye ne-Ventral Prefrontal Cortex (PFC)
Nje ukuba indlela yokuziphatha ihambe ngaphaya kwamanqanaba okuqala okufunda okuhlangeneyo, ulawulo lwesigqeba sokwenziwa kwayo luba lubaluleke ngakumbi. Imimandla ye-PFC inegalelo ekwenziweni kwezigqibo kuphazamiseko lolawulo lwempembelelo kunye nokuba likhoboka. I-OFC ikhowudi kwixabiso elihambelanayo lovuselelo lomvuzo [124, 125], inkqubo eyinxalenye yenkqubo ye-5-HT. I-OFC iququzelela ukuguquguquka kwengqondo ngokukhuthaza uhlaziyo lwe-encoding ye-associative kwiindawo ezisezantsi zengqondo ezifana ne-amygdala [126]. Ukongezelela, i-gyrus yangaphambili engaphantsi / i-dorsolateral PFC ibalulekile ekutshintsheni ingqalelo, enegalelo ekukwazini ukuchasana nolwazi oluphazamisayo olufana nokucinga malunga neziyobisi / ukuziphatha [127]. I-OFC, kubandakanya i-PFC ye-ventromedial (vmPFC), inegalelo ekuqhubeni umvuzo kunye noqikelelo [128, 129] . Izifundo ezinezilonda ze-vmPFC zibonisa ukusilela ekucwangciseni, zihlala ziphindaphinda ukwenza izigqibo ezikhokelela kwiziphumo ezibi [130]. Ngaphaya koko, ezi zifundo zenza kakubi ngakumbi kunokulawula uthelekiso lwezifundo kwi-Iowa Gambling Task (IGT), umlinganiselo owaphuhliswa ukuphanda umvuzo omncinci okhawulezileyo kunye nesohlwayo sethutyana esihambelana nenzuzo yexesha elide ngokuchasene nomvuzo omkhulu okhawulezileyo kunye nesohlwayo esiphakathi esinxulunyaniswa nesohlwayo esinexesha elide. ilahleko yexesha [131].
Izifundo ezinokuphazamiseka kokusetyenziswa kweziyobisi zibonisa ukusebenza kakubi kwi-IGT [132], kwaye oku kusebenza kakubi kuye kwanxulunyaniswa nokuncipha kokuhamba kwegazi kwi-vmPFC kunye neminye imimandla ye-cortical [133-136]. Abantu abanePG bakhetha ngokungalunganga xa kuthelekiswa nolawulo kwi-IGT [12, 137]. Abantu abane-PG ngokulula ngakumbi bakhetha imbuyekezo yemali ephantsi ethenjiswe ngokukhawuleza ngaphezulu kwemivuzo ephezulu yemali ethenjisiweyo emva kwexesha lokulibaziseka (“isaphulelo sokulibaziseka”) xa kuthelekiswa nezifundo zolawulo [138]. Isaphulelo sexeshana sembuyekezo sibonakaliswe ukuba sikhawuleza ngakumbi kubantu abane-PG abaneengxaki zokusetyenziswa kweziyobisi, ngokuhambelana neendlela ezinegalelo kwingxaki nganye ngendlela eyongezelelweyo okanye ehambelanayo [138]. Ukungasebenzi kakuhle kwe-vmPFC yesekethe kunokuba negalelo kolu mahluko kwindlela yokuziphatha phakathi kwePG kunye nezifundo zolawulo, njengoko kubonakala kunjalo kwimeko yeziyobisi. Ukuncipha kokusebenza kwe-vmPFC kuye kwabonwa kwizifundo ze-PG ngexesha lokuboniswa kweempawu zokungcakaza [9], ukusebenza kweStroop Color-Word Interference Task [139], kunye nokungcakaza okufanisiweyo [140]. Kolu phononongo lokugqibela, ukusebenza kwe-vmPFC kunxibelelene ngokuchaseneyo nobungqongqo bokungcakaza phakathi kwezifundo zePG. Ngokudibeneyo, ezi datha zibonisa indima ebalulekileyo ye-vmPFC kwi-PG. Amaphononongo exesha elizayo aya kunceda ekucaciseni ubungakanani bendlela ezi zinto zifunyaniswayo zandisa ngayo kwezinye ii-ICDs.
Abantu abaxhomekeke kwiziyobisi babonisa izinto ezingaqhelekanga kwi-OFC. Ngokufana nabantu abanomonakalo kwi-OFC, abantu abaxhomekeke kwi-stimulant babonisa ukuthathwa kwezigqibo ezona zilungileyo, kuxoxwe ixesha elide phambi kokhetho [141]. Ukuncipha kokusebenza kwe-OFC kunye ne-cingulate gyrus iye yanxulunyaniswa nokusetyenziswa okungapheliyo kwe-cocaine [142]. Ukusebenza kakubi kwiziyobisi ezinemibala ye-Stroop umsebenzi ohambelana ne-hypoactivation ye-OFC kubantu abalikhoboka le-cocaine [142]. Xa zidibene, ezi datha zibonisa ukuba imimandla yePFC ibalulekile ekwenzeni izigqibo.
Ukwenza Izigqibo, Ukungabinamdla, kunye ne-Amygdala
Umsebenzi we-Amygdala unegalelo elikhulu ekwenzeni izigqibo kunye nokunyanzeliswa. I-amygdala ifumana igalelo le-serotonergic kunye ne-dopaminergic ukusuka kwi-raphe kunye ne-VTA ngokulandelelana, kwaye ukusebenza kwayo kulawulwa yibhalansi phakathi kwe-glutamate-induced excitation kunye ne-GABA-mediated inhibition [143, 144]. I-amygdala ithatha inxaxheba ekuqhutyweni nasekukhunjweni kweempendulo zeemvakalelo. Ngokutsho kwe-somatic marker hypothesis (echaza ukuba ukwenza izigqibo kuxhomekeke kwi-neural substrates elawula i-homeostasis, imvakalelo kunye neemvakalelo), iimpendulo ezichaphazelayo kwi-stimuli zivuswa ngokusebenzisa i-visceral motor structures ezifana ne-hypothalamus kunye nezinye ii-nuclei ze-autonomic brainstem [127]. I-amygdala isebenza ngokubambisana ne-vmPFC/OFC ekwenzeni izigqibo, kunye nommandla ngamnye unegalelo ngendlela eyahlukileyo. Kwiimpuku, izilonda ze-excitotoxic ze-BLA zikhuthaza ukukhetha ngokungxamisekileyo kumsebenzi wokulibaziseka-ukuqinisa [145]. Ebantwini, izifundo ezinomonakalo we-vmPFC kunye nezifundo ezinomonakalo we-amygdalar zombini zibonisa iintsilelo ekwenzeni izigqibo kwi-IGT [146]. Nangona kunjalo, iimpendulo ezizimeleyo (ezilinganiswa ngempendulo ye-skin conductance) kwinzuzo enkulu yemali okanye ilahleko ayinakho kubantu abanezilonda ze-amygdalar ezimbini; ngokuchaseneyo, ezi mpendulo zifanelekile kwizigulana ezinomonakalo we-vmPFC [146]. Nangona kunjalo, ngokulindelekileyo iimpendulo ze-skin conductance ngexesha lokusebenza kwe-IGT zibonisa ipateni eyahlukileyo: izifundo ezinomonakalo we-vmPFC zibonisa iintsilelo, kanti abo banomonakalo we-amygdalar babonisa iimpendulo eziqhelekileyo. Ngokudibeneyo, ezi zinto zifunyanisiweyo zokuba umsebenzi ongaqhelekanga we-amygdala-ventral striatum unokuphembelela ukungxamiseka kwiinkqubo zokulutha, mhlawumbi ngenxa yempembelelo kwixabiso lenkuthazo ye-cues [148]. Kubantu abakhotyokiswe ziziyobisi, iimpendulo ezizilawulayo zibaxiweyo zibangelwa ziziyobisi [149]. Umsebenzi ongaqhelekanga we-amygdalar unokuphenjelelwa ngokuhlukahluka kofuzo kwi-5-HT yofuzo [100]. Indima ye-amygdala kwii-ICD ayizange iphandwe ngokuthe ngqo.
Ukuqulunqwa komkhwa
Njengoko indlela yokuziphatha itshintsha ukusuka ekufundeni okusebenzayo ukuya kwimpendulo yesiqhelo, utshintsho olusuka kunxibelelwano lwe-cortico-basal ganglia network ebandakanya i-PFC kunye ne-ventral striatum ukuya kwi-dorsomedial striatum/caudate kwaye emva koko iye kwinethiwekhi ye-cortico-basal ganglia engaphezulu ebandakanya i-dorsolateral striatum/putamen. bona ) [29]. Ukugqithiswa kokuziphatha kutshintsha ukusebenza ukusuka kwi-dorsolateral PFC kunye ne-caudate ukuya kwi-putamen kunye ne-motor cortices [150, 151]. Kumlutha, ukuzilawula okuphindaphindiweyo kwe-cocaine kwiinkawu kunxulumene nokuqhubekeka kokusebenza kwe-ventral striatum ukubandakanyeka kwe-dorsal striatum [152]. Njengoko isimilo siqhelekile, isivuseleli esinemeko, izinto ezibalulekileyo zenkqubo yokulutha, zikholisa ukwenza iimpendulo zemikhwa endaweni yomsebenzi ojolise kwinjongo [153]. Le mpendulo yahlukileyo inokuphenjelelwa ngokungathanga ngqo yi-NAcc ngoqikelelo lwayo kwi-VTA/substantia nigra ngegalelo elilandelayo le-dopaminergic ukusuka kokugqibela ukuya kwinethiwekhi ye-sensorimotor [154]. Ukufakwa komchasi oxubeneyo we-DA receptor alpha-flupenthixol kwi-dorsal striatum kodwa hayi kwi-NAcc core kunciphisa ukufunwa kwe-cocaine kwiimodeli zezilwanyana zokulutha [155]. Ulawulo oluphantsi lwe-D2 receptors ze-DA luye lwabonwa kuqala kwi-ventral kwaye emva koko i-dorsal striatum kwiinkawu ezithatha i-cocaine, ngokuhambelana noqwalaselo olwenziwe ngabaxhaphazi abangapheliyo be-cocaine [156, 157].
Ii-ICDs zichazwe ngokwemigaqo yokwakheka komkhwa [158]. Njengakwikhoboka leziyobisi, ukungasebenzi kakuhle kokujikeleza kwe-striatal kubandakanyeka kolu kuphazamiseka. Umzekelo, kuphononongo lokungcakaza okufanisiweyo, abantu abane-PG babonise iyantlukwano ekusebenzeni ngokubulala xa kuthelekiswa nezifundo zolawulo, kwaye ukwenziwa kusebenze kwakunxulumene nobungqongqo bokungcakaza [140]. Idatha yangaphambili ngokufanayo ibandakanya umsebenzi wokungcakaza kwi-PG kunye neminqweno ye-cocaine kuxhomekeke kwi-cocaine [159]. Ukuncipha kwevolumu ye-putamenal kuye kwabonwa kwizifundo ezine-trichotillomania xa kuthelekiswa nezifundo zolawulo, nangona ukufaneleka kokusebenza kwalo mahluko we-anatomical kufuna uphando olongezelelweyo [160]. Ukusuka kwezi datha, i-hypothesis inokwakhiwa ukuba izenzo ezijoliswe kwiinjongo zihamba ukusuka ekufundeni okusebenzayo ukuya kwimpendulo engasebenziyo, esekelwe kumkhwa kwii-ICD ngendlela efanayo naleyo ibonwa kubantu abasebenzisa iziyobisi.
Ukuphendula koxinzelelo kunye nee-ICDs
Iziganeko ezicinezelayo kunye noxinzelelo lwengqondo zihlala zinegalelo ekubuyeleni ekusebenziseni iziyobisi phakathi kwabantu abaxhomekeke kwi-opiate kunye ne-cocaine [161, 162]. Ubungqina bezonyango bubonisa ukuba uxinzelelo oluqatha lukhokelela ekwandeni kokuzilawula kwamachiza afana ne-amphetamines [163], icocaine [164, 165], notywala [166, 167]. Iinkqubo ezinxulumene noxinzelelo zibalulekile ekusekweni kweziyobisi kunye nokusasazeka kwazo njengokuphazamiseka okungapheliyo [168]. Ukubonakaliswa koxinzelelo kuvelisa imeko yokuvuselela inkanuko efana neziyobisi ngokwazo [169]. Inani leziyobisi zokuxhatshazwa, njenge-psychostimulants [170-172] kunye notywala [173] sebenzisa i-stress circuitry kunye ne-HPA axis. Kwiimpuku, i-opioids ivuselela i-axis ye-HPA, kodwa umphumo ochaseneyo ubonwa kwiiprimates, kuquka nabantu (ihlaziywe kwi- [174]). Ukongezelela, i-benzodiazepines ibonakaliswe ukuba ithintele ukusebenza kwe-HPA ebantwini.175] Njengoko kusebenze i-axis ye-HPA ngokuphindaphindiweyo kwandisa ukuhanjiswa kwe-mesolimbic dopamine, ukuvezwa kuxinzelelo kunokubonelela nge-neural substrate eqhelekileyo apho uxinzelelo lonyusa isimilo sokufuna iziyobisi [169]. Izivuseleli ezinxulumene noxinzelelo, njengokuzibamba kunye nokushukuma kweenyawo, ukonyusa ukukhutshwa kwe-NAcc DA [176, 177]. Iiparadigms ezibangelwa luxinzelelo kunyango kubantu abakhotyokisiweyo bavula i-striatum kwaye banciphise ukusebenza kwi-cingulate yangaphambili. Ezi ziphumo zibonisa indima yoxinzelelo kwi-prefrontal dysfunction kunye nokubandakanyeka ngaxeshanye komkhwa wokujikeleza kumlutha [178]. Indlela olu tshintsho lunxulumene ngayo nokungxama kunye/okanye ukuthathwa kwezigqibo okulilize kufuna uphando olongezelelweyo [179].
Uphononongo lwabantu abane-ICDs luvelise iziphumo ezahlukeneyo malunga nokubandakanyeka kweendlela zoxinzelelo kwezi ngxaki [180]. Umzekelo, amanqanaba e-CSF e-corticotrophin-releasing hormone (CRH) awahlukanga kwizifundo ezine-PG xa kuthelekiswa nolawulo [89]. Ukonyuka okwethutyana kwe-cortisol kuphawulwe kuphononongo lokungcakaza lwamavolontiya aqeshwe kwiikhasino anengxaki yokungcakaza abonisa ubukhulu obufanayo bokuphendula kulawulo [181-183]. Iziganeko zobomi obunoxinzelelo ezifana nokwenzakala kubomi bangaphambili ziye zabandakanyeka kwi-PG njengoko zinjalo kumlutha weziyobisi [177]. Ngokudibeneyo, ezi datha zibonisa ukuba kuya kubaluleka ukuphonononga ngakumbi iindlela ezichanekileyo apho uxinzelelo kunye neendlela zoxinzelelo zinegalelo kwi-pathophysiology ye-ICDs.
I-Opioids, uxinzelelo kunye nee-ICDs
I-opioids imodareyitha iindlela ze-mesolimbic ze-DA kwi-VTA ngokuvula i-μ i-opioid receptors kwii-interneuron zesibini ezibangela i-hyperpolarization kunye nokuthintela ukukhutshwa kwe-GABA kwii-neuron eziphambili (i-dopaminergic output neurons) okubangele ukwanda kokukhululwa kwe-DA [184]. Nangona kunjalo, ukusebenza kwe-κ opioid receptors kwii-neurons eziphambili kubangela ukuba zithintele ngokuthe ngqo.185]. Kutshanje kuye kwaboniswa ukuba i-opioid receptor activation (κ vs. μ) inqanda ngokwahlukileyo i-mesolimbic neurons ngokuxhomekeke kuqikelelo lwazo (Nacc vs. BLA) [186]. Inkqubo ye-opioid engapheliyo, ngokusebenzisa zombini i-μ kunye ne-opioid i-receptors, i-tonic ithintela i-axis ye-HPA, iphakamisa ukuba ukuphendula okungaqhelekanga kunegalelo kumlutha [32]. Ukuxhasa le ngcamango, iimpuku ezingenayo i-opioid receptor gene (I-OPRM1) bonisa akukho morphine analgesia okanye indawo ekhethwayo [187].
Iipolymorphisms kwi I-OPRM1 zidibene nokubophelela okungafaniyo kwi-endorphins (umzekelo, iikhowudi ezihlukeneyo ze-A118G ze-receptor ezinezibophelelo eziphindwe kathathu kunye nokusebenza kweprotheyini ye-G-idityaniswe yangaphakathi yokulungiswa kwesiteshi se-potassium [188]). Ukwahluka kwe-A118G kuye kwanxulunyaniswa nokuxhomekeka kwi-opioid [32], kunye nezifundo ezinolu tshintsho zibonise iimpendulo ezithandekayo kwi-naltrexone yonyango lokuxhomekeka kotywala [64, 189]. IiHaplotypes zejini ye-kappa opioid receptor (OPRK1) kunye nommandla okhuthazayo we-endogenous ligand precursor, i-prodynorphin, iye yadibaniswa nokuxhomekeka kwe-opiate kunye nezinye izilingo [33].
Ukungcakaza okanye ukuziphatha okunxulumeneyo kuye kwanxulunyaniswa namanqanaba aphezulu egazi le-opioid engapheliyo β-endorphin [190]. Ngokunikwa indlela yabo yokwenza [191] kunye nokusebenza kakuhle kunyango lokuxhomekeka kotywala kunye ne-opiate [192], abachasi be-opioid receptor baye bavavanywa kunyango lwe-ICDs. INaltrexone ibonise ukongama kwi-placebo kuphononongo lwendawo enye yePG [193], kunye ne-nalmefene, umchasi we-opioid osebenza ixesha elide, ubonise ukongama kwi-placebo kwisifundo esikhulu esingaboniyo kabini, esigxile kwizinto ezininzi nge-PG [194]. I-Naltrexone ibonise inzuzo kwimeko yezifundo zokuziphatha okunyanzelekileyo ngokwesondo [195] kunye nolingo oluvulelekileyo lwabaphuli-mthetho ngokwesondo abafikisayo [196]. INaltrexone ibonise impumelelo yokuqala ekuthengeni okunyanzelekileyo [121]. Ezi datha zibonisa ukuba, iinkqubo ze-opioid zibalulekile kuzo zombini iikhemikhali kunye neziyobisi zokuziphatha. Njengoko i-opioids inefuthe kwiinethiwekhi ezininzi ze-neural kunye neendlela ezinxulumene noxinzelelo, izifundo zexesha elizayo ziya kuchaza iindlela ezichanekileyo zokwenza kwii-ICDs.
Iziphetho kunye nemiyalelo yexesha elizayo
Idatha evelayo malunga ne-neurobiology yokunyanzeliswa kunye nee-ICDs zicebisa ukuhambelana neziyobisi. Nangona uninzi lwezifundo ezimbalwa ziye zaphanda ii-ICDs kunokuba neziyobisi (kwaye uninzi lwezifundo ezikhoyo ziye zaphanda i-PG), idatha yemfuza, yokuziphatha kunye neyonyango ibandakanya iinkqubo ezininzi ze-neurotransmitter kunye neesekethe ze-neuronal ekusekweni nasekugcinweni kokulutha kokuziphatha. Ngaphandle kolu kuqhubela phambili, impikiswano ihleli malunga ne-nosology kunye ne-pathophysiology esisiseko yee-ICDs ezithile.
Ii-Endophenotypes zibonelela ngokuqonda kwi-etiology yokuphazamiseka kwaye ulwazi olunjalo lunokwazisa ngokweendidi zokuphazamiseka. Iimbono ze-Endophenotypic zeengxaki zengqondo ezifana nokudakumba kunye ne-schizophrenia ziyavela [197, 198]. I-Endophenotypes "ngamacandelo anokulinganiswa angabonakaliyo ngeliso" kwaye ingaba neuropsychological, endocrinological, cognitive, neuroanatomical okanye biochemical in nature. I-Endophenotypes yazisa ukuqondwa kwezinto zofuzo ezisisiseko seenkqubo zesifo ngokujolisa kwiimpawu ezithile zebhayoloji kuneendidi zoxilongo apho kunyango lwengqondo ziqhelekile ngokwendalo [198]. Njengoko kusaziwa ngakumbi malunga nobume kunye nokubonakaliswa kwee-ICDs, iimbono ze-endophenotypic zamacandelo azo angaphantsi zinokuvela. Umzekelo, ukungxamiseka, ukwahlula iimpendulo ze-endocrine kuxinzelelo, okanye amacandelo alo anokubonisa i-endophenotypes ebalulekileyo ye-PG, ezinye ii-ICDs kunye neziyobisi. Ukuchonga i-endophenotypes kufuneka kuncede ukwahlula i-subclasses of disorders (ngokusekwe ngokwemfuza nangenye indlela), ekugqibeleni ukuhlonipha ukubonakaliswa, ukuxilongwa kunye nonyango olululo. Utshintsho kumanyathelo e-endophenotypic afanayo anokulindeleka ukuba ahambe kunye nokuphuculwa kweempawu kuzo zombini ii-ICDs kunye neziyobisi. Ii-endophenotypes ezifanelekileyo ngokweklinikhi zinokukhokelela kuphuhliso lwemizekelo yezilwanyana zezi zifo eziya kuthi ekugqibeleni zisincede siqonde i-etiology ye-ICDs kunye neziyobisi, siphuhlise iindlela ezisebenzayo zokuthintela kunye nokwandisa unyango lokuziphatha kunye ne-pharmacological.
Imibulelo
Sithanda ukubulela uGqr Christopher Pittener ngokuphononongwa kwakhe ngokucokisekileyo kunye namagqabaza aluncedo malunga nalo mbhalo-ngqangi. Inkxaso yolu phando yanikezelwa yi-NIH isibonelelo T32-MH19961 Clinical Neuroscience Research Training in Psychiatry (JAB), i-Mind and Life Institute Research Varela Grant (JAB), i-National Institute on Drug Abuse grants R01-DA019039 (MNP) kunye ne-R01- I-DA020908 (MNP), i-Women's Health Research e-Yale (MNP), kunye ne-VA VISN1 MIRECC (MNP) kunye ne-REAP (MNP).
Imihlathi
Iphepha elichazayo ukuba awusenanto oyifunayo: Le fayili yeFayile yombhalo wesandla ongabhalwanga owamkelwe ukushicilelwa. Njengenkonzo kumakhasimende ethu sinika le ngcaciso yokuqala kwincwadi yesandla. Umbhalo wesandla uza kufumana ukukopishwa, ukufakela, nokuphonononga ubungqina obunokubakho ngaphambi kokuba kukhutshwe kwifomu yayo yokugqibela. Nceda uqaphele ukuba ngexesha lokuveliswa kweeprogram ezinokuthi zifumaneke ezinokuthi ziphazamise umxholo, kunye nazo zonke izisemthethweni ezichasayo ezisetyenziswa kwiphephancwadi.
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