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Using drug combinations to assess potential contributions of non-GABAA receptors in the discriminative stimulus effects of the neuroactive steroid pregnanolone in rats.
Physiol Behav. 2014 Oct; 137:33-41.PB

Abstract

Neuroactive steroids are increasingly implicated in the development of depression and anxiety and have been suggested as possible treatments for these disorders. While neuroactive steroids, such as pregnanolone, act primarily at γ-aminobutyric acidA (GABAA) receptors, other mechanisms might contribute to their behavioral effects and could increase their clinical effectiveness, as compared with drugs acting exclusively at GABAA receptors (e.g., benzodiazepines). The current study examined the role of non-GABAA receptors, including N-methyl-d-aspartate (NMDA) and serotonin3 (5-HT3) receptors, in the discriminative stimulus effects of pregnanolone. Separate groups of rats discriminated either 3.2mg/kg pregnanolone from vehicle or 0.32mg/kg of the benzodiazepine midazolam from vehicle while responding under a fixed-ratio 10 schedule for food pellets. When administered alone in both groups, pregnanolone and midazolam produced ≥80% drug-lever responding, the NMDA receptor antagonists dizocilpine and phencyclidine produced ≥60 and ≥30% drug-lever responding, respectively, and the 5-HT3 receptor agonist 1-(m-chlorophenyl)-biguanide (CPBG) and morphine produced <20% drug-lever responding up to doses that markedly decreased response rates. When studied together, neither dizocilpine, phencyclidine, CPBG nor morphine significantly altered the midazolam dose-effect curve in either group. Given that CPBG is without effect, it is unlikely that 5-HT3 receptors contribute substantially to the discriminative stimulus effects of pregnanolone. Similarities across groups in effects of dizocilpine and phencyclidine suggest that NMDA receptors do not differentially contribute to the effects of pregnanolone. Thus, NMDA and 5-HT3 receptors are not involved in the discriminative stimulus effects of pregnanolone.

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.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. Electronic address: gerak@uthscsa.edu.

Pub Type(s)

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

Language

eng

PubMed ID

25072672

Citation

Eppolito, Amy K., et al. "Using Drug Combinations to Assess Potential Contributions of non-GABAA Receptors in the Discriminative Stimulus Effects of the Neuroactive Steroid Pregnanolone in Rats." Physiology & Behavior, vol. 137, 2014, pp. 33-41.
Eppolito AK, Kodeih HR, Gerak LR. Using drug combinations to assess potential contributions of non-GABAA receptors in the discriminative stimulus effects of the neuroactive steroid pregnanolone in rats. Physiol Behav. 2014;137:33-41.
Eppolito, A. K., Kodeih, H. R., & Gerak, L. R. (2014). Using drug combinations to assess potential contributions of non-GABAA receptors in the discriminative stimulus effects of the neuroactive steroid pregnanolone in rats. Physiology & Behavior, 137, 33-41. https://doi.org/10.1016/j.physbeh.2014.07.003
Eppolito AK, Kodeih HR, Gerak LR. Using Drug Combinations to Assess Potential Contributions of non-GABAA Receptors in the Discriminative Stimulus Effects of the Neuroactive Steroid Pregnanolone in Rats. Physiol Behav. 2014;137:33-41. PubMed PMID: 25072672.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Using drug combinations to assess potential contributions of non-GABAA receptors in the discriminative stimulus effects of the neuroactive steroid pregnanolone in rats. AU - Eppolito,Amy K, AU - Kodeih,Hanna R, AU - Gerak,Lisa R, Y1 - 2014/07/26/ PY - 2013/12/17/received PY - 2014/06/24/revised PY - 2014/07/18/accepted PY - 2014/7/30/entrez PY - 2014/7/30/pubmed PY - 2015/6/17/medline KW - Drug discrimination KW - Midazolam KW - Neuroactive steroids KW - Pregnanolone KW - Rats SP - 33 EP - 41 JF - Physiology & behavior JO - Physiol Behav VL - 137 N2 - Neuroactive steroids are increasingly implicated in the development of depression and anxiety and have been suggested as possible treatments for these disorders. While neuroactive steroids, such as pregnanolone, act primarily at γ-aminobutyric acidA (GABAA) receptors, other mechanisms might contribute to their behavioral effects and could increase their clinical effectiveness, as compared with drugs acting exclusively at GABAA receptors (e.g., benzodiazepines). The current study examined the role of non-GABAA receptors, including N-methyl-d-aspartate (NMDA) and serotonin3 (5-HT3) receptors, in the discriminative stimulus effects of pregnanolone. Separate groups of rats discriminated either 3.2mg/kg pregnanolone from vehicle or 0.32mg/kg of the benzodiazepine midazolam from vehicle while responding under a fixed-ratio 10 schedule for food pellets. When administered alone in both groups, pregnanolone and midazolam produced ≥80% drug-lever responding, the NMDA receptor antagonists dizocilpine and phencyclidine produced ≥60 and ≥30% drug-lever responding, respectively, and the 5-HT3 receptor agonist 1-(m-chlorophenyl)-biguanide (CPBG) and morphine produced <20% drug-lever responding up to doses that markedly decreased response rates. When studied together, neither dizocilpine, phencyclidine, CPBG nor morphine significantly altered the midazolam dose-effect curve in either group. Given that CPBG is without effect, it is unlikely that 5-HT3 receptors contribute substantially to the discriminative stimulus effects of pregnanolone. Similarities across groups in effects of dizocilpine and phencyclidine suggest that NMDA receptors do not differentially contribute to the effects of pregnanolone. Thus, NMDA and 5-HT3 receptors are not involved in the discriminative stimulus effects of pregnanolone. SN - 1873-507X UR - https://www.unboundmedicine.com/medline/citation/25072672/Using_drug_combinations_to_assess_potential_contributions_of_non_GABAA_receptors_in_the_discriminative_stimulus_effects_of_the_neuroactive_steroid_pregnanolone_in_rats_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0031-9384(14)00443-0 DB - PRIME DP - Unbound Medicine ER -