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Comparing the discriminative stimulus effects of modulators of GABAA receptors containing α4-δ subunits with those of gaboxadol in rats

Zanettini, Claudio ; Pressly, Jeffrey D. ; Ibarra, Miguel H. ; Smith, Kelsey R. ; Gerak, Lisa R.

Psychopharmacology, 2016-05, Vol.233 (10), p.2005-2013 [Periódico revisado por pares]

Berlin/Heidelberg: Springer Berlin Heidelberg

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  • Título:
    Comparing the discriminative stimulus effects of modulators of GABAA receptors containing α4-δ subunits with those of gaboxadol in rats
  • Autor: Zanettini, Claudio ; Pressly, Jeffrey D. ; Ibarra, Miguel H. ; Smith, Kelsey R. ; Gerak, Lisa R.
  • Assuntos: Animals ; Biomedical and Life Sciences ; Biomedicine ; Dose-Response Relationship, Drug ; Ethanol - pharmacology ; Flumazenil - pharmacology ; GABA Agonists - pharmacology ; GABA Modulators - pharmacology ; Isoxazoles - pharmacology ; Male ; Midazolam - pharmacology ; Neurosciences ; Original Investigation ; Pharmacology/Toxicology ; Pregnanolone - pharmacology ; Protein Subunits ; Psychiatry ; Rats ; Receptors, GABA-A - metabolism
  • É parte de: Psychopharmacology, 2016-05, Vol.233 (10), p.2005-2013
  • Notas: ObjectType-Article-1
    SourceType-Scholarly Journals-1
    ObjectType-Feature-2
    content type line 23
    Current affiliation: Medication Development Program, Molecular Targets and Medications Discovery Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland
  • Descrição: Rationale Gaboxadol is a selective agonist at γ-aminobutyric acid A (GABA A ) receptors that contain α 4 -δ subunits, and it produces anxiolytic and sedative effects. Although adverse effects preclude its clinical use, its mechanism of action suggests that those receptors might provide novel therapeutic targets, particularly for modulators of those GABA A receptor subtypes, by retaining therapeutic effects of gaboxadol and not adverse effects. Objectives The current study compared discriminative stimulus effects of gaboxadol with those of modulators acting at GABA A receptors containing α 4 -δ subunits. Materials Eight rats discriminated 5.6 mg/kg gaboxadol from vehicle while responding under a fixed - ratio 10 schedule for food. Modulators acting at GABA A receptors containing α 4 -δ subunits (pregnanolone, ethanol, and flumazenil) and receptors that do not contain those subunits (midazolam) were studied alone; pregnanolone and ethanol were also combined with gaboxadol. In addition, gaboxadol was studied in separate groups discriminating 0.32 mg/kg midazolam, 3.2 mg/kg pregnanolone, or 0.75 g/kg ethanol from vehicle. Results Gaboxadol produced ≥80 % gaboxadol-lever responding and did not alter rates. No other drug produced, on average, ≥80 % drug-lever responding up to doses that decreased rates, although 1.78 mg/kg midazolam produced 32 % gaboxadol-lever responding. Ethanol and pregnanolone did not enhance the effects of gaboxadol. Rats discriminating midazolam, pregnanolone, or ethanol from vehicle responded predominantly on the vehicle lever after receiving gaboxadol. Conclusions Drugs that modulate GABA A receptors containing α 4 -δ subunits neither mimicked nor enhanced the discriminative stimulus effects of gaboxadol, indicating that at least some effects of gaboxadol are not shared with modulators of that GABA A receptor subtype.
  • Editor: Berlin/Heidelberg: Springer Berlin Heidelberg
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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