Ukusetyenziswa okunokwenzeka kwi-GABA-Targeting Drugs entsha kwi-Disorder Use Disorder

Ukusetyenziswa kweGABA_B (I-GABA uhlobo lwe-B) i-agonist, i-ADX71441, kwiimvavanyo zangaphambili zabangela ukunciphisa okukhulu ekusetyenzisweni kotywala. Ichiza liye layinciphisa ngamandla inkuthazo ekuseleni nasekuziphatheni ngokufuna utywala.

I-Gamma-aminobutyric acid (GABA) yeyona nto iphambili ekuthinteleni i-neurotransmitter¹. GABA yenye ye-neurotransmitters eneempawu zayo eziphenjelelwa butywala² kwaye kubalulekile ukubonakaliswa kweziphumo zotywala emzimbeni. Uphononongo lwakutsha nje kwinoveli yeGABA_B (i-GABA uhlobo B) i-receptor positive allosteric modulator (i-molecule ebophelela kwindawo kwi-receptor ngaphandle kwendawo esebenzayo ukunyusa amandla eemolekyuli zokubopha kwi-receptor ngoko ukwandisa ukusebenza kwe-receptor) ibonisa inzuzo ethembisayo ekunyangeni. alcohol ukusetyenziswa ukuphazamiseka¹.

I-GABA uhlobo A (GABA_A) i-receptor nayo ibandakanyeka kwimiphumo yotywala kwinkqubo ye-nervous central (CNS) njengoko i-ethanol yandisa isenzo se-GABA kwi-GABA_A zamkeli³. Oku kuxhaswa kukufumanisa ukuba i-benzodiazepine, i-flumazenil, eyimodyuli ye-allosteric engalunganga ye-GABA._A i-receptor (i-molecule ebophelela kwindawo kwi-receptor ngaphandle kwendawo esebenzayo ukunciphisa amandla eemolekyuli zokubopha kwi-receptor ngoko ke ukunciphisa ukusebenza kwe-receptor), ibuyisela umva iziphumo ezinxilisayo ze-ethanol.³. Ngaphaya koko, i-flumazenil ikwasusa ukonyuka kobundlongondlongo kunye nokozela okufunyanwa etywaleni³ ebonisa ukuba iGABA_A I-receptor ibandakanyeka kakhulu kwiziphumo zomzimba zotywala kwaye iyinjongo esebenzayo ekuthinteleni utshintsho lokuziphatha olubangelwa yi-ethanol.

Indima yeGABA_B i-receptor ekusetyenzisweni kotywala nayo ihlolwe, kunye ne-GABA_B I-receptor agonist i-baclofen ivunyiwe njengonyango lokuphazamiseka kokusetyenziswa kotywala kwi Fransi ¹. GABA_B i-receptor agonists ibangela i-anticonvulsant kunye ne-anxiolytic effects, kwaye i-baclofen isetyenziselwa ukunyanga i-spasticity.¹. I-Baclofen inciphisa inkuthazo yeempuku ekuzilawuleni ngokwazo iziyobisi ezikhobokisayo, mhlawumbi ngenxa yesiphumo sayo esibonwayo sokunciphisa i-morphine, i-cocaine kunye nokukhutshwa kwe-nicotine-induced dopamine kwi-nucleus accumbens.¹ apho ukukhutshwa kwe-dopamine kubangela ukomelezwa kokuziphatha okukhobokisayo⁴. Nangona kunjalo, ngaphandle kweGABA_B Ikhono le-agonist i-baclofen yokunceda ukuphatha ingxaki yokusetyenziswa kotywala¹, i-baclofen ineempembelelo ezahlukahlukeneyo ezifana ne-sedation kunye nokunyamezela-uphuhliso olucebisa ukuba i-GABA_B i-receptor positive allosteric modulators (PAMs) inokufanela ulingo lokufuna ichiza elinesalathiso esingcono sonyango¹.

Inoveli ethi GABA_B I-PAM, i-ADX71441, kwizilingo ze-rodent zabangela ukunciphisa okukhulu ekuthathweni kotywala (ukuya kwi-65% kunye ne-dose ephezulu ye-200mg / kg)¹. Iyeza likwazile ukunciphisa inkuthazo ekuseleni nasekufuneni utywala¹, ecebisa ukuba kuthintelwe impendulo ye-dopamine eyenziwe ngotywala kwaye ke ngoko kuncitshiswe umlutha. I-ADX71441 iphinde yabangela ukuncipha okubonakalayo kokufuna utywala okubangelwa yimeko yotywala-utywala kunye nokuvezwa koxinzelelo, iphakamisa ukusetyenziswa konyango ekuthinteleni ukuphazamiseka kokusetyenziswa kotywala kwakhona njengoko ngaphezu kwe-50% yezigulane zibuyela emva kwiinyanga ezintathu kuphela.¹. Izifundo zangaphambi kweklinikhi zibonisa ukongama kwe-GABA_B Ii-PAM ngokubhekiselele ekusebenzeni kwimiphumo emibi. Oku kuqinisekisa uphando olongezelelweyo kunye novavanyo lokuzisa amachiza amatsha okunyanga ingxaki yokusetyenziswa kotywala¹ , ngaloo ndlela kuncitshiswa ukusetyenziswa kakubi kotywala okubangela umthwalo omkhulu kwimpilo nakwintlalontle yezoqoqosho kwihlabathi liphela.

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Iingxelo:  

1. U-Eric Augier, Inkqubela phambili yakutsha nje kwithuba le-Positive Allosteric Modulators ye-GABA_B I-Receptor yokuNyanga ingxaki yokusetyenziswa kotywala, Utywala kunye notywala, Umqulu 56, INkupho yesi-2, kaMatshi 2021, amaphepha 139–148, https://doi.org/10.1093/alcalc/agab003 

1. Banerjee N. (2014). I-Neurotransmitters kwi-alcohol: uphononongo lwezifundo ze-neurobiological kunye nemfuzo. Ijenali yaseIndiya yemfuzo yabantu, 20(1), 20-31. https://doi.org/10.4103/0971-6866.132750 

3. UDavies M. (2003). Indima ye-GABAA receptors ekulungelelaniseni imiphumo yotywala kwinkqubo ye-nervous central. Ijenali yengqondo & iNeuroscience JPN, 28(4), 263-274. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC165791/  

4. INzululwazi Ngqo 2021. Nucleus Accumbens. Iyafumaneka kwi https://www.sciencedirect.com/topics/neuroscience/nucleus-accumbens  

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