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

Abstract

Rationale

Gaboxadol is a selective agonist at γ-aminobutyric acidA (GABAA) receptors that contain α4-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 GABAA 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 GABAA receptors containing α4-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 GABAA receptors containing α4-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 GABAA receptors containing α4-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 GABAA receptor subtype.

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Acknowledgments

These studies were supported by US Public Health Service Grant DA017240. The authors wish to thank T. Bentley, A. Hernandez, A. Mensah, and C. Moreno for their excellent technical assistance. This work is dedicated to the memory of Dr Steven R. Goldberg, a mentor and a friend.

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Correspondence to Lisa R. Gerak.

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Zanettini, C., Pressly, J.D., Ibarra, M.H. et al. Comparing the discriminative stimulus effects of modulators of GABAA receptors containing α4-δ subunits with those of gaboxadol in rats. Psychopharmacology 233, 2005–2013 (2016). https://doi.org/10.1007/s00213-016-4243-8

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  • DOI: https://doi.org/10.1007/s00213-016-4243-8

Keywords

  • Gaboxadol
  • Ethanol
  • Neuroactive steroids
  • GABAA receptors
  • Drug discrimination
  • Rats
  • Flumazenil