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Negative GABA(A) modulators attenuate the discriminative stimulus effects of benzodiazepines and the neuroactive steroid pregnanolone in rhesus monkeys.
Psychopharmacology (Berl). 2005 Oct; 181(4):697-705.P

Abstract

RATIONALE

Negative GABA(A) modulators (i.e., inverse agonists) might be useful for identifying mechanisms at the GABA(A) receptor complex that mediate the effects of positive GABA(A) modulators, especially those for which there are no available competitive antagonists.

OBJECTIVE

Drug discrimination was used to examine antagonism of a 5-beta neuroactive steroid (pregnanolone) and a benzodiazepine (midazolam) by several negative GABA(A) modulators in rhesus monkeys.

METHODS

One group of monkeys (n=5) received 5.6 mg kg(-1) day(-1) of diazepam (p.o.) and discriminated the benzodiazepine antagonist flumazenil (0.1 or 0.32 mg/kg s.c.); another group of monkeys (n=5) discriminated the benzodiazepine midazolam (0.32 mg/kg s.c.).

RESULTS

In diazepam-treated monkeys, negative GABA(A) modulators with increasing efficacy, including Ro 15-4513, ethyl beta-carboline-3-carboxylate (beta-CCE), methyl beta-carboline-3-carboxylate (beta-CCM) and methyl-6,7-dimethoxyl-4-ethyl-beta-carboline-3-carboxylate (DMCM), substituted for flumazenil. In monkeys discriminating midazolam, pregnanolone occasioned high levels of midazolam-lever responding, and these effects were attenuated by beta-CCE and beta-CCM, but not by flumazenil, Ro 15-4513, or DMCM. The midazolam discriminative stimulus also was attenuated by beta-CCM and DMCM; Schild analysis was consistent with a simple competitive interaction between midazolam and beta-CCM but not between midazolam and DMCM.

CONCLUSIONS

Negative modulators are qualitatively similar to neutral modulators in diazepam-treated animals; however, interactions between negative modulators and midazolam suggest that different receptors mediate the effects of some (DMCM) and not other (beta-CCM) negative modulators. Negative modulators at benzodiazepine sites exert efficacy-dependent antagonism of positive modulators at neuroactive steroid sites. Without competitive antagonists at neuroactive steroid or barbiturate sites, negative modulators could prove useful for examining the mechanism of action of different classes of positive GABA(A) modulator.

Authors+Show Affiliations

Department of Pharmacology, The University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15983789

Citation

McMahon, Lance R., and Charles P. France. "Negative GABA(A) Modulators Attenuate the Discriminative Stimulus Effects of Benzodiazepines and the Neuroactive Steroid Pregnanolone in Rhesus Monkeys." Psychopharmacology, vol. 181, no. 4, 2005, pp. 697-705.
McMahon LR, France CP. Negative GABA(A) modulators attenuate the discriminative stimulus effects of benzodiazepines and the neuroactive steroid pregnanolone in rhesus monkeys. Psychopharmacology (Berl). 2005;181(4):697-705.
McMahon, L. R., & France, C. P. (2005). Negative GABA(A) modulators attenuate the discriminative stimulus effects of benzodiazepines and the neuroactive steroid pregnanolone in rhesus monkeys. Psychopharmacology, 181(4), 697-705.
McMahon LR, France CP. Negative GABA(A) Modulators Attenuate the Discriminative Stimulus Effects of Benzodiazepines and the Neuroactive Steroid Pregnanolone in Rhesus Monkeys. Psychopharmacology (Berl). 2005;181(4):697-705. PubMed PMID: 15983789.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Negative GABA(A) modulators attenuate the discriminative stimulus effects of benzodiazepines and the neuroactive steroid pregnanolone in rhesus monkeys. AU - McMahon,Lance R, AU - France,Charles P, Y1 - 2005/09/29/ PY - 2004/11/08/received PY - 2005/04/13/accepted PY - 2005/6/29/pubmed PY - 2006/3/3/medline PY - 2005/6/29/entrez SP - 697 EP - 705 JF - Psychopharmacology JO - Psychopharmacology (Berl) VL - 181 IS - 4 N2 - RATIONALE: Negative GABA(A) modulators (i.e., inverse agonists) might be useful for identifying mechanisms at the GABA(A) receptor complex that mediate the effects of positive GABA(A) modulators, especially those for which there are no available competitive antagonists. OBJECTIVE: Drug discrimination was used to examine antagonism of a 5-beta neuroactive steroid (pregnanolone) and a benzodiazepine (midazolam) by several negative GABA(A) modulators in rhesus monkeys. METHODS: One group of monkeys (n=5) received 5.6 mg kg(-1) day(-1) of diazepam (p.o.) and discriminated the benzodiazepine antagonist flumazenil (0.1 or 0.32 mg/kg s.c.); another group of monkeys (n=5) discriminated the benzodiazepine midazolam (0.32 mg/kg s.c.). RESULTS: In diazepam-treated monkeys, negative GABA(A) modulators with increasing efficacy, including Ro 15-4513, ethyl beta-carboline-3-carboxylate (beta-CCE), methyl beta-carboline-3-carboxylate (beta-CCM) and methyl-6,7-dimethoxyl-4-ethyl-beta-carboline-3-carboxylate (DMCM), substituted for flumazenil. In monkeys discriminating midazolam, pregnanolone occasioned high levels of midazolam-lever responding, and these effects were attenuated by beta-CCE and beta-CCM, but not by flumazenil, Ro 15-4513, or DMCM. The midazolam discriminative stimulus also was attenuated by beta-CCM and DMCM; Schild analysis was consistent with a simple competitive interaction between midazolam and beta-CCM but not between midazolam and DMCM. CONCLUSIONS: Negative modulators are qualitatively similar to neutral modulators in diazepam-treated animals; however, interactions between negative modulators and midazolam suggest that different receptors mediate the effects of some (DMCM) and not other (beta-CCM) negative modulators. Negative modulators at benzodiazepine sites exert efficacy-dependent antagonism of positive modulators at neuroactive steroid sites. Without competitive antagonists at neuroactive steroid or barbiturate sites, negative modulators could prove useful for examining the mechanism of action of different classes of positive GABA(A) modulator. SN - 0033-3158 UR - https://www.unboundmedicine.com/medline/citation/15983789/Negative_GABA_A__modulators_attenuate_the_discriminative_stimulus_effects_of_benzodiazepines_and_the_neuroactive_steroid_pregnanolone_in_rhesus_monkeys_ L2 - https://dx.doi.org/10.1007/s00213-005-0028-1 DB - PRIME DP - Unbound Medicine ER -