Kwayoyin Neurobiology da Genetics of Disorders Control Disorders: Saduwa da Drug Addictions (2008)

Ka tafi zuwa ga:

Abstract

Gabatarwa

ICDs da Addiction

ICDs sun sha mamaki don kwance tare da bakan-na-tilasta wata rawa [4], wakilcin rikice-rikicen bakan (OC)5, 6]. Kodayake mutane da ke da ICDs suna aiki da halayen maimaitawa, sau da yawa tare da buƙatun haɗin gwiwa masu ƙarfi, halayen suna da alaƙa sau da yawa kamar farantawa ko sonsyntonic, yayin da halayyar maimaitawa ko ayyukan ibada a cikin rikici na OC (OCD) galibi misaliododystonic [7, 8]. Mutane daya-daya da ICDs yawanci suna yin maki mai zurfi akan matakan rashin hankali da kuma abubuwan da suka shafi gini kamar neman jin daɗi yayin da mutane masu OCD yawanci ke da ƙima akan matakan cutarwa [8-12]. Sharuɗɗan ganewar asali na ICDs kamar PG suna haɗuwa da waɗanda don dogaro da abubuwa, tare da takamaiman sharuɗɗan da suka shafi haƙuri, cirewa, maimaita ƙoƙarin da ba a yanke ba don yanke ko dakatar, da kuma tsangwama a cikin manyan fannonin rayuwa [1]. Kamar yadda aka bayyana a kasa, akwai yawancin cututtukan ƙwayoyin cuta da kuma kamanceceniyar jini tsakanin ICDs da kuma abubuwan maye. Don haka, ana iya ɗaukar ICDs “jarabawar halayyar"[13-16].

Addiction: Takaitaccen Tarihi

An gudanar da bincike mai zurfi a cikin tunanin kwakwalwa da ke tattare da ci gaban ayyukan ci gaba da kuma shaye-shaye (wanda aka bita a [17-19]). Ra'ayoyi masu tasowa game da jaraba sun ƙunshi ƙwayoyi ko hali don samun daidaituwa ta hanyar ƙarfafawa, tare da miƙewa ta gaba ta hanyar tsarin ilmantarwa na sakamako zuwa cikin ɗabi'a / tilastawa na [19].

Yanayin shaye-shaye shine mahimmanci mahimmanci a farkon matakan tsarin jaraba. Yanayin shaye-ciye, wanda aka ayyana a matsayin “hanyar da ake koyan sabon lada da samun saurin motsa su,” ya hada da yanayin yanayin yanayin da ke da alaƙa da lokaci tare da ayyukan jaraba [20]. Tsarin neuroanatomical da yawa waɗanda ke da mahimmanci a cikin wannan yanayin yanayin sun hada da amygdala, wanda yake da mahimmanci a cikin aikin mahimmancin motsin rai da ƙungiyoyi da aka koya a tsakanin abubuwan da suka dace da kuma in ba haka ba tsaka-tsakin motsawa [17, 21], the orbitofrontal cortex (OFC), wanda a cikin nazarin dabbobi an gabatar da shawara don sanya yiwuwar sakamako kuma ta hanyar haɗin jikinta mai ƙarfi tare da amygdala (BLA) na iya sauƙaƙe ilmantarwa cikin amygdala, da kuma ɓoye na ciki na ciki (ACC) wanda yana da tasiri a cikin nuna wariyar nuna bambanci da ikon fahimta [22]. Structuresarin fasali waɗanda ke da mahimmanci a cikin wannan tsari sun haɗa da hippocampus, wanda ke ba da ƙwaƙwalwar mahallin da ta dace da ƙwarin gwiwa, da hypothalamic da septal nuclei, waɗanda ke ba da bayanin da ya dace da halayen motsa jiki na yau da kullun kamar sufanci na jima'i da shigar abinci mai gina jiki [23, 24]. Tare, waɗannan abubuwa masu dangantaka da haɗin gwiwa sun haɗa da neurocircuitry wanda ya shagaltar da haɗin gwiwar halayen da aka motsa. Yayinda halayyar motsa jiki ke ƙara zama ƙarƙashin waɗanda ke da alaƙa da jaraba yayin ci gaban ayyukan jaraba, mai yiwuwa canje-canje a cikin tsari da aikin waɗannan yankuna suna ba da gudummawa ga wuce haddi a cikin halayen da ke tsakiyar ICDs.

Hakanan mahimmanci a cikin kwalliya da jaraba shine ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwa (NAC), wanda ya ƙunshi harsashi da ainihin. A kwasfa, ta hanyar na ciki ciki tare da ventral tegmental yanki, yana da muhimmanci a cikin modulating motsa salience, alhãli kuwa da zuciyar ya fi shiga tare da bayyana halaye koya a mayar da martani ga mai cewa da annabta dalili na dacewa al'amuran / karfafa karfafa yanayin [17, 19]. Yankin ventral tegmental (VTA), tare da tsinkayen dopaminergic ga amygdala, NAcc da prefrontal cortex (PFC, wanda ya haɗa da OFC da ACC), yana sauƙaƙe ƙungiyoyi da suka koya tare da abubuwan da ke motsa hankali mai ƙarfi ta hanyar sakin dopamine (DA) saki [25, 26]. Dopaminergic neurons an hana su, wataƙila ta hanyar ƙwayar thalamus tsakiya (habenula), lokacin da lada da ake tsammani ba su faruwa ba [27, 28]. An ba da shawarar cewa a cikin matakan karshe na jaraba, rinjaye mafi rinjaye kan juyawa na motsawa na dabi'un motsa jiki daga cikin da'irorin corticostriatal waɗanda ke tattare da ventral striatum zuwa da'irori waɗanda suka haɗa da tashin hankali, wanda aka dade yana tasiri a cikin al'ada al'ada (duba ƙasa) [29, 30].

Yin amfani da tsararren ra'ayi a matsayin mai da hankali, ana iya samar da wani samfuri wanda a cikin yanayin kwalliya yake farawa a cikin kwarjin NAcc ta hanyar abubuwan da aka samo daga hippocampus, VTA (wanda kuma yana karɓar labari daga tsakiya na amygdala), da PFC, "canjin yanayi" don yin sharadi inarfafawa a cikin cibiyar NAcc ta hanyar abubuwan daga BLA da PFC, kuma a ƙarshe ya samo asali ga tsarin halitta a cikin ƙaddarar tashin hankali ta hanyar shigar da abubuwa daga cikin abubuwan sensorimotor da sauran yankuna kamar septal hypothalamus [19, 23]. Wadannan sauye-sauyen sun shafi iyaka, kamanceceniya da kuma yankuna yanki na mambobi, bi da bi (duba siffar 1A). Dowaƙwalwar ƙwayar cuta da ƙwalƙwalwar ƙwayar cuta (globus pallidus (ta shigar da kaya daga ƙungiyar NAcc)) suna aiki akan thalamus wanda zai ciyar da baya zuwa tsarin haɗin gwiwa. A cikin wannan tsarin, ana nazarin halittar jini da ƙwaƙwalwar ƙwayar cuta ta ICD. Bugu da ƙari, duk da cewa akwai rarrabuwar ƙwayar cutar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwa da ƙwaƙwalwar ƙwaƙwalwa a cikin matakai daban-daban na jaraba, ana gabatar da waɗannan tsarin ta hanyar daidai da daidaita yanayin canjin da aka ambata a sama.

  

Figure 1

a: Brain Cirry wanda yake haifar da jaraba. PFC = cortex na prefrontal, VTA = yankin ventral tegmental yanki, SN = substantia nigra, NAcc = tarin kwayoyin mahaifa, OFC = orbitofrontal cortex

Yawan Jama'a na Addiction da ICDs

Kwayoyin halitta suna ba da gudummawa ta farko ga tsarin jaraba, saboda sun ƙaddara abubuwan da ke haifar da rauni ga hanyoyin halayen al'ada don yin nasara. Nazarin ilimin kwayoyin halitta na ICDs suna ba da shawarar kamanceceniya da sauran jaraba [31]. Nazarin dangi da tagwaye masu cutar cuta sun kiyasta cewa gudummawar gudummawar lissafi har zuwa 60% na bambancin haɗarin don abubuwan maye [32, 33]. Hakanan an samo gudummawar abubuwan gado don PG. Amfani da bayanai daga rajista na Vietnam Era Twin (VET), an kiyasta abubuwan kayyadewa zuwa asusu tsakanin 35% da 54% na abin alhaki don alamun cutar DSM-III-R a cikin PG [34]. Matsayin heritability ya yi kama da na wasu cututtukan ƙwaƙwalwar ƙwaƙwalwa tare da rikice-rikice masu amfani da kayan maye: a cikin samfurin guda ɗaya, 34% na bambance-bambance a cikin hadarin don dogara da miyagun ƙwayoyi ya danganta ne ga abubuwan halittar jini [35]. Wani nazarin nazarin rajista na VET ya ƙididdige tarihin rayuwa na PG da dogaro na giya ta hanyar yin tambayoyin da aka tsara da kuma taƙaita gwargwadon haɗarin muhalli da kwayoyin halitta ga PG tare da dogara da barasa. Marubutan sun gano cewa babban kasada na hadarin don PG na subclinical (12-20% na kwayoyin halitta da 3-8% na muhalli) an lissafta su ta hanyar haɗarin dogara da barasa [36]. A cikin binciken da ya biyo baya na yawan jama'a guda, Slutske da abokan aiki sun kuma sami babban haɗin gwiwa tsakanin PG da halin ɗabi'ar wariyar launin fata, tare da yawancin ƙungiyar an bayyana shi ta hanyar abubuwan gado.37]. Wadannan karatun suna ba da shawarar cewa ICDs kamar PG suna da alaƙa da dogaro da barasa da halayen wariyar launin fata, kuma ana iya haɗa su ta hanyar hanyoyi na yau da kullun kamar rashin ƙarfi (duba ƙasa). Kodayake na farko, waɗannan bayanan suna ba da shawara cewa kamar yadda suke da maganin maye, abubuwan abubuwan gado suna ba da gudummawa sosai ga cututtukan cututtukan ƙwayoyin cuta na ICDs. An ba da gudummawar takamaiman abubuwan da suka shafi ƙwayoyin jini waɗanda ke cikin ICDs a ƙasa.

Impulsivity

Tasirin rayuwa yana da mahimmanci ga rikice-rikice na kwakwalwa masu yawa, ciki har da ICDs da abubuwan maye [38]. A cikin tsarin jaraba, sha'awar sha'awa tana taimakawa zuwa farkon matakai kamar gwajin ƙwayoyi. Halin halin ɗan adam yana da abubuwa da yawa; Misali, bincike daya gano abubuwa hudu (gaggawa, gaggawa, rashin jinkiri, rashin juriya, da kuma neman jin daɗi)39]) yayin da sauran matakan tsinkaye na abubuwanda zasu haifarda abubuwa guda uku (Barratt impulsivity Scale fracaates zuwa cognition, motor da tsare-tsaren kayan gini da sikelin impressi na Eysenck zuwa venturesomeness, impulsiveness domains domains [40, 41]). Moeller da abokan aiki sun ayyana halin rayuwa a matsayin “tsinkaye ga hanzari, halayen da ba a tsarawa ba game da lamuran ciki ko na waje [tare da raguwa] la’akari da mummunan sakamakon wadannan halayen ga wanda ya jawo hankalin mutane ko ga wasu [42]. ”Tare, wadannan sakamakon binciken suna nuna sha'awar samar da hadadden tsari, hadadden tsari mai dumbin yawa. A hankali, bayanai daga nazarin mutum da dabba sun nuna cewa yankuna kwakwalwa da yawa da tsarin kula da jijiyoyin jiki suna ba da gudummawa ga halayen motsa jiki a duk faɗin jaraba [32, 43].

Dopamine, Tasiri da ICDs

Kamar yadda aka bayyana a sama, dopamine ya dace da farko a cikin ayyukan jaraba da kuma a wasu fannoni na gaba. Dopaminergic tsarin yana da tasiri cikin ruɗuwa da ICDs. Psychostimulants kamar amphetamine tasiri dopamine da sauran tsarin biogenic kuma sune magunguna masu inganci don raunin haɓakar haɓakawar jini (ADHD), rikicewar cuta wacce ke da tasirin yanayin tsakiya. Rashin daidaituwa na tsarin NAcc DA ke cikin ADHD [44]. Dopaminergic tsarin kuma suna ba da gudummawa ga ayyukan cizon jaraba. Hakanan an ba da rahoton wadatar mai karɓa na D2 a cikin masu cin zarafin cocaine watanni da yawa bayan dakatarwar, kuma wannan haɗin yana da alaƙa da raguwar metabolism a cikin OFC a tsakanin sauran yankuna kwakwalwa kamar su cingulate gyrus [18, 45]. Measuresarancin matakan tushe na disator DA D2 mai karɓar ra'ayoyi a cikin batutuwa marasa amfani da aka ƙaddara suna son likitan ƙwayoyi na methylphenidate, suna tallafawa hasashen cewa ƙarancin mai karɓar D2 yana daidaita yanayin rashin ƙarfi ga jaraba [46]. A cikin tallafi, rage yawan isowar masu karɓar D2 (wataƙila saboda raguwar lambobin masu karɓar karɓar DA ƙaddamarwa) an lura da shi a cikin tashin hankali na berayen da ke motsawa sosai, kuma wannan wadatar ya faɗi ƙima mai girma na sarrafa kansa na koko47]. Availabilityarancin mai karɓar D2 a cikin matattara kuma ya annabta mai zuwa na ƙara yawan sarrafa kansa na cocaine ta birai [48]. Matsayin da waɗannan binciken suke da alaƙa da rashin ƙarfi da ICDs na buƙatar jarrabawa kai tsaye.

DA na iya shiga tsakani ko sakamako na sha'anin caca, kuma DA ya kasance a cikin PG [49]. An samu raguwar matakan DA da matakan karuwai na metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) da kuma homovanillic acid (HVA) a cikin CSF na caca na cuta [50], kodayake ba a lura da waɗannan binciken lokacin da ake daidaita sikelin kwararar CSF ba [51]. Amphetamine, magani ne wanda ke haɓaka catecholamine na extracellular da 5-HT ta hanyar vesicular depletion, reuptake inhibition, haɓaka DA kira, da hanawar monoamine oxidase (MAO) [52], tsallake-tsallake don halayyar caca cikin matsala masu caca, amma ba don amfani da barasa ba cikin masu shaye-shaye [53]. Wadannan binciken sun ba da shawarar rawar da za a taka ga DA (da / ko sauran hanyoyin aminergic) a cikin kwayar cutar ta PG kamar yadda kwayoyi tare da nau'ikan hanyoyin aiwatar da aiki na iya ƙaddamar da Firayim don sake dawo da wasu kwayoyi a cikin wannan aji (watau amphetamine don hodar).54, 55].

Rahotanni da yawa sun danganta amfani da maganin agonist a cikin Cutar Parkinson (PD) tare da PG da sauran halayen ICD kamar a cikin wuraren jima'i da cin abinci [56-60]. Wani binciken da aka yi kwanan nan game da marasa lafiya na 272 PD waɗanda aka bincika su kuma aka tantance su don ICDs sun sami kusan ƙungiyoyi masu kama da juna a duk faɗin DA agonists tare da PG da sauran ICDs [61]. Tarihin ICD kafin farawa PD yana da alaƙa da ICD na yanzu. Yawan allurai na yau da kullun na levo-dopa sun kasance mafi girma a cikin marasa lafiya tare da ICD fiye da waɗanda ba tare da. Nazarin da ake jira game da marasa lafiya na 297 tare da PD wanda aka bincika don ci gaba da rayuwa na PG kuma sun sami haɗin gwiwa tsakanin amfani da aikin agonist DA da PG [62]. Kodayake ba a lura da wata ƙungiya ba da ke nuna bambancin ra'ayoyin agonist, ƙungiyar tare da kulawa na lokaci guda levodopa an lura, yana ba da sakamako na ƙarshe ko tasiri na levodopa [62]. Don haka, bayanan da ke gudana sun ba da shawarar cewa DA agonists, musamman a cikin mutane masu haɗari ga ICDs, suna da alaƙa da PG da sauran ICDs, suna daɗaɗa tsarin DA da ICDs.

Nazarin kwayoyin halitta sun danganta kwayoyin halittu da yawa zuwa rashin daidaituwa da jaraba, gami da tsararrun kwayoyin halittar da ke tattare da mai karɓar DA D4 (DRD4da DASLC6A3) [32, 63, 64] ADHD yana da ladabi sosai, tare da bayar da gudummuwar ƙwayoyin cuta game da kusan 80% na hadarin cuta, kuma daga cikin bambance-bambancen kwayoyin da ke da alaƙa da ADHD sune DRD4 da SLC6A3 bambance-bambancen karatu [65]. Sauran kwayoyin halittar DA kamar DRD5 an alakanta su da ADHD suma [65]. Nazarin biyu sun samo ƙungiyar polymorphisms na DRD4 tare da PG [66, 67]. Ari, da D2A1 allele na mai karɓar D2 an sanya shi cikin zagi, shan cin abinci da shan sigari [63, 68], kuma an samo shi a cikin ninki mai girma sau biyu a cikin batutuwa tare da PG idan aka kwatanta da sarrafawa [69]. Bayanan da ke sama suna ba da shawara, duka ta hanyar abubuwan gado da fitarwa na aiki, abubuwan gudummawar dopaminergic ga abubuwanda suka haifar da abubuwan ICD da sauran jaraba. Koyaya, ana buƙatar ƙarin nazarin don kwafin da tsawaita waɗannan binciken, musamman kamar yadda binciken binciken DA ya bayar da gudummawa ga halayen mutum na rayuwa ko ƙirar dangantaka mai zurfi kamar neman sabon abu sun nuna sakamako daban-daban a dangantakar su da nau'in halittar DA [70].

Dopaminergic Regulation da ICDs: Matsayi na ino-aminobutyric acid (GABA) da Glutamate

γ-aminobutyric acid (GABA) shine babban inhibitory neurotransmitter a cikin kwakwalwa. An haɗa shi a cikin tashoshin jijiya daga glutamate ta enzyme glutamate decarboxylase. Akwai shaidar yanayin aiki da haɗin gwiwa tsakanin GABA da tsarin dopaminergic har ma da ƙara tallafawa tasirin tasirin tsarin GABAergic akan rikicewar amfani da kayan [71]. Misali, tiagabine, GABA reuptake inhibitor wanda aka yi amfani dashi da farko don magance cututtukan fata, ya nuna ingancin farko a cikin jarabar hodar Iblis [72], kuma yana cikin rahoton harka, wanda aka nuna don taimakawa tare da sarrafa tsokanar zalunci [73]. Glutamate, mai nuna damuwa mai mahimmanci da mai ba da izini na GABA shima yana cikin abubuwan maye a cikin abubuwan maye da kuma ICDs.

A cikin karatuttukan daidaitacce, matakan glutamate a cikin halayen neman sakamako na sakamako na NAcc [74]. Ba a nuna fitowar glutamate nonvesicular daga cysteine ​​/ glutamate antiporters shine babban tushen karuwar glutamate extracellular a cikin NAcc; yana daidaita sakin vesicular glutamate da dopamine ta hanyar ƙarfafa glutamate kungiyar 2 / 3 metabotropic glutamate receptors [75, 76]. N-acetylcysteine ​​(NAC), maganin-cysteine ​​pro-magani, yana ƙaruwa matakan extracellular na glutamate, watakila ta hanyar ƙarfafa masu karɓar glutamate inhibitory metabotropic glutamate, don haka rage synaptic saki na glutamate. Ya nuna ingantaccen tasiri a cikin jarabar maganin cocaine [77] da PG [78]. Idan aka yi amfani da su tare, waɗannan bayanan suna ba da damar da za a iya amfani da su don glutamatergic da tsarin GABA a cikin kayan maye da halayyar halayya.

Serotonin, Bugawa da ICDs

Kamar DA, GABA da glutamate, ana ba da gudummawa ga serotonin (5-HT) a cikin halin sha'awa, ICDs da kuma abubuwan maye. Tsarin aikin neroronergic neurons shine ya samar da dorsal raphe nucleus a cikin kwakwalwa gaba daya har zuwa yankuna ciki har da hippocampus, cortex frontal da amygdala. A cikin samfurin dabbobi, an nuna raguwar 5-HT na gaba don haifar da zaɓi mai mahimmanci, yayin da kai tsaye agonist na 5-HT agonist fenfluramine yana rage irin wannan halayen [79, 80]. Bugu da ƙari, rauni na bera yana haifar da fifiko na ɗan lokaci don lada nan da nan [81]. Daidai da waɗanda ba sa zaɓar 5-HT antagonists an nuna su inganta zaɓin sarrafa kansa82]. Matsayi don takamaiman tsarin abubuwan serotonin yana da goyan baya ta hanyar binciken abubuwan da suka fi ƙarfin motsa jiki a cikin 5-HT_1B buga -ice mice [83]. Gushewar Tryptophan, wacce ta rage matakan 5-HT (tare da rage raguwa a cikin matakan 5-HT metabolites a cikin ruwa na cerebrospinal fluid (CSF)), yana kara haɓakar motsa jiki (nau'i-nau'i na gwajin-aiki iri ɗaya), amma ba zaɓi mai mahimmanci ba (ragi mai jinkiri) a cikin mutane [84, 85]. A cikin batutuwa tare da tarihin dangi na giya, jarabawar tryptophan yana rage hana halayyar dabi'a (Tsaida Tashan) amma bai yi tasiri kan jinkirin ragewa ba [84]. An samo ƙananan matakan na 5-HT metabolite 5-hydroxyindolacetic acid (5-HIAA) a cikin mutane da ke da halayen motsa jiki [86, 87], da farko-farko shan giya [64]. Levelsarancin matakan CSF 5-HIAA suma suna da alaƙa da halayen haɗari a cikin magabata; misali, birai suna daukar tsalle-tsalle a cikin dajin [88]. An ɗauka tare, layin shaida da yawa suna tallafawa rawar da 5-HT a cikin tsaka-tsakin talla, kodayake ana buƙatar ƙarin bincike don gano takamaiman abubuwan haɗin gwiwar tsarin 5-HT waɗanda ke ba da gudummawa ga takamaiman fannoni na rashin hankali.

Tsarin 5-HT yana tasiri a cikin ICDs. Kodayake maza masu PG a kan waɗanda ba tare da nuna wani bambance-bambance masu mahimmanci ba a cikin 5-HT ko 5-HIAA a cikin samfuran CSF [50, 89, 90], an gano matakan 5-HIAA sun kasance ƙasa a cikin waɗanda suke tare da PG lokacin da suke sarrafa lokacin buguwa (wanda aka haɓaka a cikin rukunin PG) [51]. Metachlorophenylpiperazine (m-CPP), metabolite na trazodone yana aiki a matsayin agonist na yanki kuma yana da kusanci sosai don masu karɓa na 5-HT (musamman 5-HT2c, wanda aka ambata a cikin sasancin yanayin yanayin yanayi, halin damuwa da aikin neuroendocrine [91]). An ba da rahoton Gudanar da m-CPP don haifar da halayyar "babba" da haɓaka matakan prolactin (wani tsari da ake tunanin zaiyi sulhu da shi ta hanyar postsynaptic 5-HT_{1A / 2A / 2C} masu karɓa) a cikin batutuwa tare da PG kamar yadda aka kwatanta da batutuwa masu iko ba tare da PG [92]. Wannan martani na magana yana kama da wanda aka ruwaito a cikin wasu rikice-rikice wanda halaye masu motsawa ko tilastawa sun shahara, gami da rikicewar halayen mutum [93], Rashin daidaiton hali94], dokanin dokin [95], da shan giya ko dogaro [96].

Bugu da ƙari ga ƙalubalen magungunan, nazarin ƙwayoyin halitta sun ba da tasiri ga tsarin 5-HT a cikin duka sha'awar da ICDs. A TPH1 (tryptophan hydroxylase 1, wanda ke rufe enzyme don matakin-iyakance matakin a cikin samarwa na 5-HT) an samo bambance-bambancen hanyar gene yana da alaƙa da rage 5-HIAA a CSF da halayen kisan kai a cikin masu laifi masu tayar da hankali [97]. Sauran kwayoyin halittar serotonergic suna da alaƙa da bijirewa abubuwa da kuma jarabar abubuwa kuma sun haɗa SERT (SLC6A4) da kuma MAOA [32]. Polymorphism a cikin masu gabatarwa na yanki na jigilar kwayar halittar mutum ta mutumSLC6A4) wanda ke cike da gajeru kuma tsaran nau'ikan furotin (tare da gajeriyar hanyar samar da furotin da ake aiki da ita wanda ba shi da cikakken aiki) an danganta shi da wasu bangarori na psychopathology, gami da neuroticism, damuwa da bacin rai [98-102], kodayake ƙarin karatun da suka gabata sun ɗora tambayoyi game da ƙarfi ko amincin waɗannan ƙungiyoyi [103-105]. SLC6A4 bambancin na iya ba da gudummawa ga ICDs kamar yadda aka ruwaito ƙungiya tsakanin SLC6A4 gajere allele da PG a cikin maza amma banda mata [106]. A ƙarshe, binciken da ya shafi ƙananan samfurori na batutuwa sun ba da rahoton haɗin kai tsakanin baƙi tsakanin kwayoyin serotonin da kwayoyin monoidine oxidase da ICDs kamar PG, tilasta siye da trichotillomania [107-109]. Studiesarin karatu ta amfani da manyan samfurori da kuma hankali (alal misali, bincike) zai taimaka wajen bincika kwayoyin halittar babban iyali na ICDs.

Nazarin aikin jiyya na wakilai na serotonergic sun ba da sakamakon gauraye game da inganci a cikin maganin ICDs [110-113]. Posbo-sarrafawa, bazuwar asibiti gwaji (RCTs) na zaɓin serotonin reuptake inhibitors (SSRIs) sun ba da sakamakon gauraye, tare da wasu RCTs waɗanda ke nuna ingantaccen inganci akan placebo [114, 115] da sauransu ba [116, 117]. Yawancin karatun sun nuna ci gaban asibiti da wuri a cikin magani a duka rukuni-da magani-da placebo. Wadannan nasarorin suna ba da shawarar magani ko amsawar mutum maimakon wadataccen takamaiman ga ƙwayar mai aiki, kodayake bambancin gaba tsakanin ƙungiyoyi a wasu nazarin suna nuna tasirin aikin magani. A cikin binciken da yawa na trichotillomania, babu wani bambanci mai mahimmanci da aka lura tsakanin maganin fluoxetine da placebo [111]. A cikin binciken bazuwar citalopram vs. placebo a cikin maza na mata na 28 tare da halayen jima'i, ba a ganin bambance-bambance a cikin matakan halayen jima'i na tilastawa tsakanin ƙungiyoyi bayan makonni na 12 na far, kodayake an sami raguwa sosai a cikin hanyar jima'i da ke da alaƙa da miyagun ƙwayoyi [118]. Hanyoyi guda biyu a layi daya, nazarin da ake sarrafawa na fluvoxamine a cikin lura da tilasta siyan kayan kwalliya bai nuna bambanci tsakanin kwayoyi masu aiki da placebo [119, 120], amma binciken makonni bakwai na bayyanar citalopram wanda ya biyo bayan makonni tara na rarrabuwa ya nuna ci gaba a cikin ƙwayoyi masu aiki idan aka kwatanta da placebo [121]. Rahoton wani lamari ya ba da shawarar ingancin escitalopram, da SSRI a cikin maganin amfani da intanet na matsala, amma ana buƙatar ci gaba da nazari game da inganci a cikin magani (da kuma ganewar asali) na wannan cuta [113]. Idan aka haɗu tare, binciken ya nuna cewa SSRIs suna aiki ne ga wasu mutane da ke da ICDs amma ba wasu ba. Wadannan binciken sun bayar da shawarar cewa takamaiman kayan aikin mutum (misali, fasalin kwayar halitta ko rikicewar cuta mai kama da damuwa ko damuwa) na iya taimakawa jagorar zaɓin hanyoyin da suka dace [122].

Kamar yadda aka bayyana a sama, son rai yana ba da gudummawa ga duka abubuwan biyu na jiki da abubuwan sha. Wataƙila cewa yanayin rayuwa yana da gudummawa ta musamman ga ɗakunan ICDs da jarabawar abubuwa kamar yadda yakamata ga ɓangarorin fahimtar aiki [123]. Bugu da ƙari, kamar tare da sha'awar abubuwa, kamance tsakanin ICDs da abubuwan maye suna wanzu a cikin wasu wuraren, kamar yin yanke shawara da kuma ba da amsa gajiya, kuma waɗannan lamuran an yi la’akari da su a ƙasa.

Kimantawa na Hadarin-Hadarin, Yin Yankan Shawara, da Kayayyakin Tsarin Gida na Pentral (PFC)

Da zarar dabi'a ta wuce matakin farko na kawance na tarayya, sarrafa zartarwa akan aiwatar da hukuncin sa na zama mai mahimmanci. Yankunan PFC suna ba da gudummawa ga yanke shawara a cikin rikice-rikice na rashin sha'awar buguwa da jaraba. OFC lambobin su na dan darajar lada ne [124, 125], tsari a sashi wanda ke sulhu ta hanyar tsarin 5-HT. OFC yana sauƙaƙe sassauci ta hankali ta hanyar haɓaka sabunta bayanan haɗin haɗin gwiwa a cikin sassan kwakwalwa kamar su amygdala [126]. Bugu da ƙari, ƙarancin gabanci na gyrus / dorsolateral PFC yana da mahimmanci wajen sauya hankalin, wanda ke ba da gudummawa ga ikon yin tsayayya da bayanan kutse kamar tunani game da kwayoyi / halayen [127]. OfCC, gami da hadewar ventromedial PFC (vmPFC), yana ba da gudummawa ga aikin lada da tsinkayar [128, 129]. Abubuwan da ke cikin rauni tare da raunuka na vmPFC suna nuna ƙarancin halayyar tsari, sau da yawa yin yanke shawara da ke haifar da mummunan sakamako [130]. Bugu da kari, wadannan fannoni suna yin mummunan aiki sama da lamuran kwatankwacin iko akan ayyukan caca na Iowa (IGT), wani gwargwado wanda aka inganta don bincika ƙananan sakamako nan da nan da azaba mai banƙyama da ke da alaƙa da cin nasara na dogon lokaci da babban sakamako na wucin gadi da azaba mai banƙyama da ke da alaƙa da dogon lokaci. lokaci asara [131].

Abubuwan da ke tattare da rikice-rikice masu amfani da kwayoyi suna nuna yanayin aiki sosai a kan IGT [132], kuma wannan wasan kwaikwayon mara kyau yana da alaƙa da raguwar kwararar jini zuwa vmPFC da sauran yankuna na cortical [133-136]. Mutane daban-daban tare da PG kuma suna zaɓar rashin nasara kamar yadda aka kwatanta da sarrafawa akan IGT [12, 137]. Mutane daya-daya da PG da sauri za su zabi ƙananan kuɗin da aka alkawarta nan da nan sama da babbar lada na kuɗin da aka alkawarta bayan jinkirin jinkiri (“rage ragi”) idan aka kwatanta da batutuwa masu iko [138]. Rage farashin lada na wucin gadi an nuna cewa yana da sauri a cikin mutane tare da PG tare da rikice-rikicen amfani da sinadarai, daidai da hanyoyin da ke ba da gudummawa ga kowace cuta a cikin kayan haɗi ko yanayin synergistic [138]. Rashin lalacewa na vmPFC circuitry na iya ba da gudummawa ga waɗannan bambance-bambance na halayya tsakanin PG da abubuwan sarrafawa, kamar yadda ya bayyana a cikin maganin jaraba. Rage kunna kunna vmPFC an lura dashi a cikin batutuwa na PG yayin gabatar da alamun caca [9], wasan kwaikwayon Takaitaccen Tsaranin Tsarin-Furuciya mai suna [139], da siminlated caca [140]. A cikin wannan binciken na ƙarshe, kunna vmPFC yana da dangantaka da tsananin caca tsakanin batutuwan PG. Tare, waɗannan bayanan suna ba da shawarar muhimmiyar rawa ga vmPFC a cikin PG. Karatun na gaba zai taimaka haɓaka har zuwa gwargwadon yadda waɗannan binciken suke kaiwa zuwa wasu ICDs.

Abubuwan da ke dogara da abubuwan maye suna nuna rashin ƙarfi a cikin OfC. Kwatancen ga mutane tare da lalacewar OfC, batutuwa tare da dogaro mai ƙarfi suna nuna ƙaddamar da yanke shawara mafi kyau, tare da tsawaita shawara kafin zaɓin zaɓi [141]. Inarancin kunnawa na OFC da cingulate gyrus yana da alaƙa da amfani da ƙwayar cocaine na kullum [142]. Orarancin aiki a kan maganin launi mai launi Stroop ɗawainiya ya daidaita tare da hypoactivation na OFC a cikin mutanen da ke shan kwayoyi.142]. Idan aka haɗu tare da juna, waɗannan bayanan suna ba da shawarar yankuna na PFC suna da mahimmanci a cikin yanke shawara.

Yin yanke hukunci, Bugawa, da Amygdala

Amygdala aikin yana ba da gudummawa sosai wajen yanke hukunci da sha'awar aiki. Amygdala tana karɓar shigarwar serotonergic da dopaminergic daga raphe da VTA bi da bi, kuma an kunna aikinta ta hanyar daidaituwa tsakanin haɓakar glutamate da inhibition na GABA.143, 144]. Amygdala tana cikin aiki da ƙwaƙwalwar motsin rai. Dangane da hypothesis na somatic (wanda ya bayyana cewa yanke shawara ya dogara ne da abubuwan da ke canza yanayin gida wanda yake daidaita yanayin gida, ji da motsin rai), abubuwan da suka shafi tasirin abubuwan motsa jiki ana tursasa su ne ta hanyar abubuwan motsa jiki kamar su hypothalamus da sauran nau'ikan kwakwalwar kwakwalwa [127]. Amygdala yana aiki tare da vmPFC / OFC a cikin yanke shawara, tare da kowane yanki yana ba da gudummawa ta hanyar daban. A cikin ƙwayoyin cuta, raunuka na ɓacin rai na BLA suna haɓaka zaɓi na aiki cikin jinkiri-ƙarfafa aiki [145]. A cikin mutane, batutuwa masu lalata vmPFC da batutuwan da ke da amygdalar lalata duka suna nuna kasawa a cikin yanke hukunci a cikin IGT [146]. Koyaya, martani mai cin gashin kansa (wanda aka auna ta hanyar martabar fata) ga ribar kuɗi ko asarar kuɗi ƙaranci ne cikin mutane da raunikan amygdalar raunuka; da bambanci, waɗannan amsoshin suna da daidaituwa a cikin marasa lafiya tare da lalacewar vmPFC [146]. Koyaya, jira martani game da fata yayin aiwatar da IGT yana nuna yanayin daban: batutuwa tare da lalacewar vmPFC suna nuna kasawar, yayin da waɗanda ke da lalacewa na amygdalar suna nuna martani na al'ada. Tare, waɗannan binciken cewa aikin amygdala-ventral striatum na mahaukaci na iya tasiri tasiri cikin ayyukan jaraba, watakila ta hanyar tasirin ƙima na halayen [148]. A cikin mutane masu shan kwayoyi, karin maganganu masu ikon sani kai tsaye suna haifar da abubuwan da ke cikin miyagun ƙwayoyi [149]. Abygdalar mara ƙarfi na aiki ana iya rinjayar shi ta hanyar bambance-bambancen kwayoyin halitta a cikin halittar 5-HT [100]. Ba a bincika rawar amygdala a cikin ICDs kai tsaye ba.

Tsarin Hutu

Kamar yadda hali ya sauya daga karantarwa mai karfi zuwa amsawar al'ada, sarrafa motsi daga hanyar haɗin cortico-basal ganglia wanda ke tattare da PFC da ventral striatum zuwa dorsomedial striatum / caudate sannan kuma zuwa cibiyar sadarwar sensitimotor cortico-basal ganglia da ke tattare da cibiyar sadarwar rikici / putamen ( gani Hoto 1b) [29]. Kiyayewa da halayen yana motsa kunnawa daga PFC mai ban sha'awa da caudate zuwa putamen da motoci [150, 151]. A jaraba, maimaita maganin saƙar kai a cikin birai yana da alaƙa da ci gaban gwagwarmayar motsa jiki zuwa shiga cikin matakin tashin hankali [152]. Kamar yadda dabi'a ta zama al'ada, ƙarancin yanayi, mahimman abubuwa na ayyukan jaraba, sukan fi mayar da martani ga al'ada maimakon aikin da aka gabatar da nufin-[153]. Ana iya rinjayar wannan bambancin amsa kai tsaye ta hanyar NAcc ta hanyar hangen nesa zuwa VTA / substantia nigra tare da shigarwar dopaminergic mai zuwa daga ƙarshen zuwa cibiyar sadarwar sensorimotor [154]. Jiko na cakuda mai karɓar maganin antagonist na alpha-flupenthixol a cikin ɗakunan ƙwayar cuta amma ba a cikin ƙungiyar NAcc ba ta rage kafaffen cocaine da ke nema a cikin sifofin dabbobi na jaraba [155]. Beenaddamar da tsarin D2 DA masu karɓar magani an lura da farko a cikin ventral sannan sai a shanyewar rigakafi a cikin birai masu shan cocaine, daidai da abubuwan lura da aka yi tare da cin zarafin ɗan adam na cocaine [156, 157].

An bayyana ICDs dangane da yanayin al'ada [158]. Kamar yadda yake game da jaraba na miyagun ƙwayoyi, lalata dysregulation na striatal circuitry yana cikin waɗannan rikice-rikice. Misali, a cikin binciken wasan kwaikwayo na caca, mutane tare da PG sun nuna bambance-bambance a cikin tashin hankali kamar yadda aka kwatanta da abubuwan sarrafawa, kuma kunnawa yana da dangantaka da tsananin caca [140]. Bayanai na farko daidai wannan na haifar da tashin hankali a ayyukan caca da PG da sha'awar hodar Iblis a cikin dogaro159]. Kusancin ƙara ƙimar putamenal an lura da batutuwa tare da trichotillomania kamar yadda aka kwatanta da batutuwa masu iko, kodayake mahimmancin wannan bambancin ɗan adam yana buƙatar ƙarin bincike [160]. Daga waɗannan bayanan, ana iya ƙirƙirar ra'ayi cewa ayyukan da aka tsara na burin ƙaura daga koyo mai aiki zuwa mafi rashin aiki, martani na al'ada a cikin ICDs a cikin irin wannan yanayin da aka lura a cikin mutane masu maye.

Amsar Damuwa da damuwa da ICDs

Abubuwan da ke faruwa na damuwa da damuwa na hankali suna ba da gudummawa ga koma baya ga amfani da miyagun ƙwayoyi a tsakanin mutane waɗanda ke da opiate da kuma dogaro da maganin cocaine [161, 162]. Shaida ta preclinical tana nuna cewa matsanancin damuwa yana haifar da ƙaruwa a cikin gudanar da aikin kai magunguna kamar amphetamines [163], cocaine [164, 165], da barasa [166, 167]. Hanyoyin da ke da alaƙa da damuwa suna da mahimmanci a cikin kafa abubuwan maye da kuma yaduwar su kamar cuta na kullum [168]. Danniyawar damuwa yana haifar da yanayin hauhawa mai kama da kwayoyi da kansu [169]. Da dama da kwayoyi na zagi, kamar psychostimulants [170-172] da kuma barasa [173] kunna damuwa mai ɗaukar jijiya da ƙwaƙwalwar HPA. A cikin ƙwayoyin tsoka, opioids suna ta da ƙwayar HPA, amma ana ganin tasirin sabanin a cikin magabata, gami da mutane (an sake nazarin su [174]). Bugu da ƙari, an nuna benzodiazepines don ɗaukar nauyin kunnawar HPA a cikin mutane [175] Kamar yadda kunna gwagwarmayar ƙwayar cuta ta HPA ta ƙara yawan watsa kwayar mesolimbic, watsawa ga damuwa na iya samar da madaidaicin ƙwayar jijiya wanda ta hakan ke inganta halayen neman magani [169]. Rashin daidaituwa da damuwa, kamar hanawa da footshock, suna ƙaruwa da sakin NAcc DA [176, 177]. Misalai masu saurin motsa jiki a cikin mutanen da aka kamu da magani suna kunna tashin hankali da rage yawan kunna jijiyoyin gaba. Wadannan binciken sun ba da shawarar rawar da za su iya haifar da damuwa ga damuwa a cikin matsalar rashin aikin yi da kuma daidaita al'adun gargajiyar a cikin jaraba [178]. Matsayin da waɗannan canje-canje ke da alaƙa da rashin ƙarfi da / ko yanke shawara mara kyau na buƙatar ƙarin bincike [179].

Nazarin mutane tare da ICDs sun ba da sakamakon sakamako daban-daban dangane da shiga hanyoyin damuwa a cikin waɗannan rikice-rikicen [180]. Misali, matakan CSF na corticotrophin-mai saki hormone (CRH) bai banbanta da batutuwa tare da PG ba idan aka kwatanta da sarrafawa [89]. An lura da ƙarancin lokaci a cikin cortisol a cikin karatun caca da masu ba da agaji da aka karɓa daga casinos tare da masu caca matsala da ke nuna irin girman martani na sarrafawa [181-183]. Abubuwan da suka faru na rayuwa mai wahala kamar tashin hankali na rayuwa yana faruwa a cikin PG kamar yadda suke a cikin jaraba na miyagun ƙwayoyi [177]. Tare, waɗannan bayanan suna ba da shawara cewa yana da mahimmanci a bincika ƙarin ƙididdigar hanyoyin da damuwa da hanyoyin damuwa suka ba da gudummawa ga cututtukan cututtukan zuciya na ICDs.

Opioids, Damuwa da ICDs

Opioids suna daidaita hanyoyin MULKI a cikin VTA ta hanyar kunna μ opioid masu karɓa a kan interneurons na haifar da hauhawar jini da hana ƙaddamar da GABA a kan neurons na farko (fitowar fitowar neurons na dopaminergic) tare da ƙara ƙaddamar da DA [184]. Koyaya, kunna masu κ opioid masu karɓa akan ƙananan ƙwayoyin cuta suna haifar da hanawa kai tsaye [185]. Kwanan nan an nuna cewa opioid receptor kunnawa (κ vs. μ) bambanta yana hana ƙananan mesolimbic neurons dangane da tsinkayarsu ta manufa (Nacc vs. BLA) [186]. Tsarin opioid na endogenous, ta hanyar masu karɓa na μ da io io da kuma masu karɓa, yana hana ƙimar HPA, yana ba da shawara cewa rashin daidaitaccen aiki yana ba da gudummawa ga jaraba [32]. Tare da goyan bayan wannan tunanin, berayen da basu rasa kyautar mu opioid receptor gene (OPRM1) nuna babu ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar hoto ko zaɓi187].

Polymorphisms a cikin OPRM1 ana haɗuwa da bambanci dauri ga endorphins (alal misali, lambobin bambance-bambancen na A118G don mai karɓar abubuwa da yawa mai girma sau uku da kuma kunna tasirin furotin na G wanda aka haɗu da su ta hanyar daidaita tasirin potassium188]). Bambancin A118G yana da alaƙa da dogara da opioid [32], kuma batutuwa tare da wannan bambance-bambancen sun nuna mafi kyawun martani ga naltrexone don lura da dogaro na giya [64, 189]. Haplotypes na kappa opioid mai karɓar gene (OPRK1) da kuma mai inganta yankin da ke tattare da yanayin aikinta na asali, na prodynorphin, an kuma hade su da dogaron opiate da sauran jaraba [33].

Cutar caca ko halayyar da ke da alaƙa tana da alaƙa da haɓaka matakan jini na endogenous opioid β-endorphin [190]. Da aka basu tsarin aikinsu [191] da kuma inganci a maganin shaye-shaye da kuma dogara da kai [192], an duba opioid antagonists a cikin lura da ICDs. Naltrexone ya nuna fifikon placebo a cikin binciken dabarun-PG guda daya [193], da nalmefene, mai adawa da opioid mai adawa da dogon lokaci, ya nuna fifikon placebo a cikin babban binciken makafi, mai dabaibaye da yawa game da batutuwa tare da PG [194]. Naltrexone ya nuna fa'ida idan aka karanci karatun halayen tilas [195] da kuma bayyanannen gwaje-gwaje na masu laifin jima'i [196]. Naltrexone ya nuna ingantaccen inganci a cikin siyan tilas [121]. Waɗannan bayanan suna ba da shawarar cewa, tsarin opioid yana da mahimmanci a cikin abubuwan da ake amfani da su na sinadarai da halayyar mutum. Kamar yadda opioids ke tasiri akan hanyoyin sadarwa da yawa na hanyoyin damuwa da hanyoyi masu alaƙa da damuwa, binciken da za a yi nan gaba zai baiyana ainihin hanyoyin aikinsu a cikin ICDs.

Ƙarshe da kuma Gudun Nan gaba

Haɓaka bayanai game da ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwar ƙwaƙwalwa da ICDs suna ba da shawarar daidaituwa tare da jaraba na miyagun ƙwayoyi. Kodayake yawancin bincike da yawa sun bincika ICDs fiye da masu shan kwayoyi (kuma yawancin karatun da ke yanzu sun bincika PG), ƙwayoyin cuta, halayyar da bayanan kulawa suna ba da damar tsarin neurotransmitter da yawa da kuma da'irar jijiyoyi a cikin kafa da kuma kula da jaraba na halayyar. Duk da waɗannan ci gaba, har yanzu gardama ta kasance game da nosology da ƙananan ƙwayoyin cuta na takaddama na ICDs.

Endophenotypes yana ba da haske game da etiology na rikice-rikice kuma irin wannan bayanan na iya sanar da rarrabuwa na rikice-rikice. Ra'ayoyin Endophenotypic na rikicewar kwakwalwa kamar rashin jin daɗi da schizophrenia suna fitowa [197, 198]. Endophenotypes sune “abubuwanda za'a iya auna gani wanda ido bai waye ba” kuma yana iya kasancewa neuropsychological, endocrinological, fahimi, neuroanatomical ko biochemical a cikin yanayin. Endophenotypes suna sanar da fahimtar abubuwanda suka haifar da cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan halitta.198]. Yayinda aka sami sananne ga yanayin da sifofin ICDs, ra'ayoyin endophenotypic game da abubuwanda ke tattare da su. Misali, turawa, bambance bambancen endocrine game da damuwa, ko abubuwanda ke tattare dashi na iya wakiltar mahimmancin maganganu don PG, sauran ICD da abubuwan maye. Bayyanar da cututtukan endophenotypes yakamata su taimakawa bambance-bambancen tabo na rikice-rikice (asalin asali da sauransu), kyakkyawan bayyanar halayyar, ganewar asali da ingantaccen magani. Canjin canje-canje a cikin matakan guda ɗaya na endophenotypic za a iya tsammanin su bi rashi ci gaban alama ga duka ICD da abubuwan maye. Har ila yau, maganin cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan na iya kasancewa jagorar haɓaka halayen dabbobi na waɗannan cututtukan waɗanda a ƙarshe za su taimaka mana fahimtar etiology na ICDs da kuma abubuwan da ke addabar abubuwa, haɓaka dabarun rigakafin ingantattun abubuwa da haɓaka halayyar da magunguna.

Acknowledgments

Bayanan kalmomi

References