Efficacy and the discriminative stimulus effects of negative GABAA modulators, or inverse agonists, in diazepam-treated rhesus monkeys.

Full Abstract

In benzodiazepine (BZ)-dependent animals, the effects of negative GABA(A) modulators at BZ sites are not clearly related to differences in negative efficacy (i.e., inverse agonist activity). A flumazenil discriminative stimulus in diazepam (5.6 mg/kg/day)-treated rhesus monkeys was used to test the hypothesis that the effects of negative GABA(A) modulators at BZ sites do not vary as a function of efficacy in BZ-dependent animals. Negative GABA(A) modulators varying in efficacy were studied in combination with positive modulators acting at different modulatory sites (BZ, barbiturate, and neuroactive steroid sites). The negative modulators Ro 15-4513 (ethyl 8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-alpha]-[1,4]benzodiazepine-3-carboxylate) and ethyl beta-carboline-3-carboxylate (beta-CCE) substituted for the flumazenil discriminative stimulus. Acute pretreatment with diazepam (3.2 and 10 mg/kg s.c., in addition to 5.6 mg/kg/day p.o.), pentobarbital (3.2 and 10 mg/kg), or pregnanolone (1 and 3.2 mg/kg) attenuated the flumazenil discriminative stimulus and also attenuated the flumazenil-like discriminative stimulus effects of Ro 15-4513 and beta-CCE. Attenuation of the discriminative stimulus effects of flumazenil, Ro 15-4513, and beta-CCE did not systematically vary as a function of negative efficacy. Compared with their discriminative stimulus effects in untreated monkeys discriminating midazolam, both pregnanolone and pentobarbital were relatively more potent than diazepam in attenuating the discriminative stimulus effects of flumazenil, Ro 15-4513, and beta-CCE in diazepam-treated monkeys. These results show that the discriminative stimulus effects of BZ-site neutral and negative modulators are not different in BZ-dependent animals trained to discriminate flumazenil, and extend the results of a previous study showing that positive modulators acting at non-BZ sites are especially potent in attenuating the effects of flumazenil in diazepam-treated monkeys (i.e., diazepam withdrawal).

Learn Faster Today Improve your study skills

Author information

Author/s: McMahon, Lance R (LR); Gerak, Lisa R (LR); France, Charles P (CP);

Affiliation: Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900, USA.

Grants: DA09157 (Agency:NIDA NIH HHS) ; K05 DA17918 (Agency:NIDA NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural

Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther), published in United States. (Language: eng)

Reference: 2006-Aug; vol 318 (issue 2) : pp 907-13

Dates: Created 2006/07/14; Completed 2006/08/31; Revised 2008/11/21;

PMID: 16705082, status: MEDLINE (last retrieval date: 12/26/2008)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

External Links for this article (including full text providers, if available):

Click Electronic Full-text Provider Links to see options for finding the electronic full text links to this article. Note there may be a subscription or fee required for access to the full text. See our FAQ for information on finding FREE full text articles.

This article may also be located in paper journal collections available in many libraries. Use the Journal and Publication Information above to find the full article.

MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals
Azides - pharmacology
Benzodiazepines - pharmacology
Conditioning, Operant - drug effects
Cues
Diazepam - pharmacology
Discrimination (Psychology) - drug effects
Dose-Response Relationship, Drug
Female

Flumazenil - pharmacology
GABA Agonists - pharmacology
GABA Modulators - pharmacology
Hypnotics and Sedatives - pharmacology
Macaca mulatta
Male
Pentobarbital - pharmacology
Pregnanolone - pharmacology
Receptors, GABA-A - drug effects

Associated Chemicals: Azides (0) ; GABA Agonists (0) ; GABA Modulators (0) ; Hypnotics and Sedatives (0) ; Receptors, GABA-A (0) ; Benzodiazepines (12794-10-4) ; Pregnanolone (128-20-1) ; Diazepam (439-14-5) ; Pentobarbital (76-74-4) ; Flumazenil (78755-81-4) ; Ro 15-4513 (91917-65-6)

These are the highest related articles currently in the database:

See 100+ related articles.