Comparing the discriminative stimulus effects of modulators of GABA^sub A^ receptors containing [alpha]^sub 4^-[delta] subunits with those of gaboxadol in rats

• Published in: Psychopharmacology Vol. 233; no. 10; p. 2005
• Main Authors: Zanettini, Claudio, Pressly, Jeffrey D, Ibarra, Miguel H, Smith, Kelsey R, Gerak, Lisa R
• Format: Journal Article
• Language: English
• Published: Heidelberg Springer Nature B.V 01.05.2016
• Subjects: Neurobiology; Psychopharmacology; Psychotropic drugs; Rodents
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-016-4243-8

Issue Title: Addiction Research and the Legacy of Steven R. Goldberg Rationale Gaboxadol is a selective agonist at γ-aminobutyric acid^sub A^ (GABA^sub A^) receptors that contain [alpha]^sub 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^sub 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^sub A^ receptors containing [alpha]^sub 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^sub A^ receptors containing [alpha]^sub 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 [greater than or equal to]80 % gaboxadol-lever responding and did not alter rates. No other drug produced, on average, [greater than or equal to]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^sub A^ receptors containing [alpha]^sub 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^sub A^ receptor subtype.