GABAB receptor positive allosteric modulators with different efficacies affect neuroadaptation to and self ‐administration of alcohol and cocaine

Conditioned rewarding effects of morphine were blunted, while those of the stimulants methamphetamine and mephedrone normal, in δ‐GABAA receptor knockout mice with deficient extrasynaptic tonic inhibition. Would selective antagonists of the extrasynaptic GABAA receptors decrease the development of opioid addiction? AbstractDrugs of abuse induce widespread synaptic adaptations in the mesolimbic dopamine (DA) neurons. Such drug ‐induced neuroadaptations may constitute an initial cellular mechanism eventually leading to compulsive drug‐seeking behavior. To evaluate the impact of GABAB receptors on addiction ‐related persistent neuroplasticity, we tested the ability of orthosteric agonist baclofen and two positive allosteric modulators (PAMs) of GABAB receptors to suppress neuroadaptations in the ventral tegmental area (VTA) and reward ‐related behaviors induced by ethanol and cocaine. A novel compound (S)‐1‐(5‐fluoro‐2,3‐dihydro‐1H‐inden‐2‐yl)‐4‐methyl‐6,7,8,9‐tetrahydro‐[1,2,4]triazolo[4,3‐a]quinazolin‐5(4H)‐one (ORM‐27669) was found to be a GABAB PAM of low efficacy as agonist, whereas the reference compound (R,S) ‐5,7‐di‐tert‐butyl‐3‐hydroxy‐3‐trifluoromethyl‐3H‐benzofuran‐2‐one (rac‐BHFF) had a different allosteric profile being a more potent PAM in the calcium‐based assay and an agonist, coupled with potent PAM activity, in the [35S] GTP γS binding assay in rat and human recombinant receptors. Using...
Source: Addiction Biology - Category: Addiction Authors: Tags: ORIGINAL ARTICLE Source Type: research