Abuse-related effects of subtype-selective GABA receptor positive allosteric modulators in an assay of intracranial self-stimulation in rats.
Rationale: GABA positive allosteric modulators (GABA PAMs), such as diazepam and zolpidem, are used clinically for anxiety and insomnia, but abuse liability is a concern. Novel GABA PAMS may have lower abuse liability while retaining clinical utility. Objective: The present study compared abuse-rela...
| Publicado en: | Psychopharmacology Vol. 234; no. 14; pp. 2091 - 2102 |
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| Autores principales: | , , , , , |
| Formato: | Journal Article |
| Publicado: |
Springer Nature
Jul2017
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=123732634&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 123732634 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00333158 EJD jtl: Psychopharmacology issn: 00333158 maglogo: N pubinfo: dt: Jul2017 vid: 234 iid: 14 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 123732634 143970522 10.1007/s00213-017-4615-8 123732634 ppf: 2091 ppct: 11 formats: fmt: @attributes: type: P tig: atl: Abuse-related effects of subtype-selective GABA receptor positive allosteric modulators in an assay of intracranial self-stimulation in rats. aug: au: Schwienteck, Kathryn Li, Guanguan Poe, Michael Cook, James Banks, Matthew Stevens Negus, S. affil: Department of Pharmacology and Toxicology , Virginia Commonwealth University , 410 North 12th Street Richmond 23298 USA sug: ab: Rationale: GABA positive allosteric modulators (GABA PAMs), such as diazepam and zolpidem, are used clinically for anxiety and insomnia, but abuse liability is a concern. Novel GABA PAMS may have lower abuse liability while retaining clinical utility. Objective: The present study compared abuse-related effects of the non-selective GABA PAM diazepam, the α1-selective GABA PAM zolpidem, and three novel GABA 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 GABA receptors, putative in vivo selectivity at α2/α3-containing GABA 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 GABA receptors in mediating GABA PAM-induced ICSS facilitation. These results are concordant with drug self-administration studies in monkeys in suggesting that GABA PAMs with low α1 efficacy and putative α2/α3 selectivity have lower abuse liability than high-efficacy non-selective or α1-selective GABA PAMs. pubtype: Academic Journal doctype: Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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