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Comparing the discriminative stimulus effects of modulators of GABAA receptors containing α4-δ subunits with those of gaboxadol in rats.
Psychopharmacology (Berl). 2016 05; 233(10):2005-13.P

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.

Authors+Show Affiliations

Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr.-mail code 7764, San Antonio, TX, 78229-3900, USA. Medication Development Program, Molecular Targets and Medications Discovery Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr.-mail code 7764, San Antonio, TX, 78229-3900, USA.Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr.-mail code 7764, San Antonio, TX, 78229-3900, USA.Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr.-mail code 7764, San Antonio, TX, 78229-3900, USA.Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr.-mail code 7764, San Antonio, TX, 78229-3900, USA. gerak@uthscsa.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

26900079

Citation

Zanettini, Claudio, et al. "Comparing the Discriminative Stimulus Effects of Modulators of GABAA Receptors Containing Α4-δ Subunits With Those of Gaboxadol in Rats." Psychopharmacology, vol. 233, no. 10, 2016, pp. 2005-13.
Zanettini C, Pressly JD, Ibarra MH, et al. Comparing the discriminative stimulus effects of modulators of GABAA receptors containing α4-δ subunits with those of gaboxadol in rats. Psychopharmacology (Berl). 2016;233(10):2005-13.
Zanettini, C., Pressly, J. D., Ibarra, M. H., Smith, K. R., & Gerak, L. R. (2016). Comparing the discriminative stimulus effects of modulators of GABAA receptors containing α4-δ subunits with those of gaboxadol in rats. Psychopharmacology, 233(10), 2005-13. https://doi.org/10.1007/s00213-016-4243-8
Zanettini C, et al. Comparing the Discriminative Stimulus Effects of Modulators of GABAA Receptors Containing Α4-δ Subunits With Those of Gaboxadol in Rats. Psychopharmacology (Berl). 2016;233(10):2005-13. PubMed PMID: 26900079.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comparing the discriminative stimulus effects of modulators of GABAA receptors containing α4-δ subunits with those of gaboxadol in rats. AU - Zanettini,Claudio, AU - Pressly,Jeffrey D, AU - Ibarra,Miguel H, AU - Smith,Kelsey R, AU - Gerak,Lisa R, Y1 - 2016/02/22/ PY - 2015/09/24/received PY - 2016/02/06/accepted PY - 2016/2/23/entrez PY - 2016/2/24/pubmed PY - 2017/2/12/medline KW - Drug discrimination KW - Ethanol KW - Flumazenil KW - GABAA receptors KW - Gaboxadol KW - Neuroactive steroids KW - Rats SP - 2005 EP - 13 JF - Psychopharmacology JO - Psychopharmacology (Berl) VL - 233 IS - 10 N2 - 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. SN - 1432-2072 UR - https://www.unboundmedicine.com/medline/citation/26900079/Comparing_the_discriminative_stimulus_effects_of_modulators_of_GABAA_receptors_containing_α4_δ_subunits_with_those_of_gaboxadol_in_rats_ L2 - https://dx.doi.org/10.1007/s00213-016-4243-8 DB - PRIME DP - Unbound Medicine ER -