Abuse-related effects of subtype-selective GABAA receptor positive allosteric modulators in an assay of intracranial self-stimulation in rats. Psychopharmacology (Berl) 2017 Jul;234(14):2091-2101
Date
04/04/2017Pubmed ID
28365836Pubmed Central ID
PMC5875719DOI
10.1007/s00213-017-4615-8Scopus ID
2-s2.0-85016514074 (requires institutional sign-in at Scopus site) 13 CitationsAbstract
RATIONALE: GABAA positive allosteric modulators (GABAA PAMs), such as diazepam and zolpidem, are used clinically for anxiety and insomnia, but abuse liability is a concern. Novel GABAA PAMS may have lower abuse liability while retaining clinical utility.
OBJECTIVE: The present study compared abuse-related effects of the non-selective GABAA PAM diazepam, the α1-selective GABAA PAM zolpidem, and three novel GABAA PAMs (JY-XHe-053, XHe-II-053, and HZ-166) using intracranial self-stimulation (ICSS) in rats. These novel compounds have relatively low efficacy at α1-, α2-, and α3-containing GABAA receptors, putative in vivo selectivity at α2/α3-containing GABAA receptors, and produce anxiolytic-like effects with limited sedation in non-human primates.
METHODS: Adult, male Sprague-Dawley rats (n = 17) were each implanted with a bipolar electrode in the medial forebrain bundle and trained to respond under a fixed-ratio 1 schedule of reinforcement for electrical brain stimulation. The potency and time course of effects were compared for diazepam (0.1-10 mg/kg), zolpidem (0.032-3.2 mg/kg), and the three novel compounds (JY-XHe-053, XHe-II-053, and HZ-166; all 3.2-32 mg/kg).
RESULTS: Zolpidem and diazepam produced transient facilitation of ICSS at small doses and more sustained rate-decreasing effects at larger doses. JY-XHe-053 and HZ-166 produced weak and inconsistent ICSS facilitation, whereas XHe-II-053 had no effect on ICSS.
CONCLUSIONS: These results support a key role for α1-containing GABAA receptors in mediating GABAA PAM-induced ICSS facilitation. These results are concordant with drug self-administration studies in monkeys in suggesting that GABAA PAMs with low α1 efficacy and putative α2/α3 selectivity have lower abuse liability than high-efficacy non-selective or α1-selective GABAA PAMs.
Author List
Schwienteck KL, Li G, Poe MM, Cook JM, Banks ML, Stevens Negus SAuthor
James M. Cook PhD University Distinguished Professor in the Chemistry and Biochemistry department at University of Wisconsin - MilwaukeeMESH terms used to index this publication - Major topics in bold
AnimalsAnti-Anxiety Agents
Benzodiazepines
Diazepam
Imidazoles
Male
Medial Forebrain Bundle
Pyridines
Rats
Rats, Sprague-Dawley
Receptors, GABA-A
Self Administration
Self Stimulation
