title: Abuse-related effects of subtype-selective GABAAreceptor positive allosteric modulators in an assay of intracranial self-stimulation in rats.
abstract: BACKGROUND
  GABAApositive allosteric modulators (GABAAPAMs), such as diazepam and zolpidem, are used clinically for anxiety and insomnia, but abuse liability is a concern. Novel GABAAPAMS may have lower abuse liability while retaining clinical utility.
  
  
  OBJECTIVE
  The present study compared abuse-related effects of the non-selective GABAAPAM diazepam, the α1-selective GABAAPAM zolpidem, and three novel GABAAPAMs (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 GABAAreceptors, putative in vivo selectivity at α2/α3-containing GABAAreceptors, 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 GABAAreceptors in mediating GABAAPAM-induced ICSS facilitation. These results are concordant with drug self-administration studies in monkeys in suggesting that GABAAPAMs with low α1 efficacy and putative α2/α3 selectivity have lower abuse liability than high-efficacy non-selective or α1-selective GABAAPAMs.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, PO Box 980613, Richmond, VA, 23298, USA.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Schwienteck
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
authors.forename: Guanguan
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Poe
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Cook
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, PO Box 980613, Richmond, VA, 23298, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Banks
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, PO Box 980613, Richmond, VA, 23298, USA. sidney.negus@vcuhealth.org.
authors.forename: S
authors.initials: S
authors.lastname: Stevens Negus
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D008474:Medial Forebrain Bundle / Q000187:drug effects*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology*; D012054:Reinforcement, Psychology; D012646:Self Administration; D012653:Self Stimulation; D000077334:Zolpidem
chemical_list: C558116:8-ethynyl-6-(2'-pyridine)-4H-2,5,10b-triazabenzo(e)azulene-3-carboxylic acid ethyl ester; D014151:Anti-Anxiety Agents; D007093:Imidazoles; D011725:Pyridines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D000077334:Zolpidem; D003975:Diazepam
keywords: Abuse liability; Diazepam; GABAA positive allosteric modulators; ICSS; Intracranial self-stimulation; Rats; Zolpidem