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Daily treatment with diazepam differentially modifies sensitivity to the effects of gamma-aminobutyric acid(A) modulators on schedule-controlled responding in rhesus monkeys.
J Pharmacol Exp Ther. 2002 Mar; 300(3):1017-25.JP

Abstract

The present study examined how daily treatment with the benzodiazepine (BZ) diazepam modifies the effects of positive modulators acting at different sites on the gamma-aminobutyric acid(A) (GABA(A)) receptor complex and negative modulators acting at BZ sites on the receptor complex. GABA(A) modulators were administered alone or in combination with acute or chronic diazepam to rhesus monkeys (n = 4) responding under a multiple fixed ratio (FR/FR) schedule of food presentation and stimulus-shock termination (SST). There was mutual antagonism between the rate-decreasing effects of diazepam (5.6 mg/kg, p.o.) and high efficacy BZ site negative modulators [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)]. Antagonism of beta-CCE, beta-CCM, and DMCM by diazepam was markedly reduced in monkeys receiving diazepam daily. In contrast, daily diazepam treatment enhanced the rate-decreasing effects of Ro 15-4513 (ethyl 8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-alpha]-[1,4]benzodiazepine-3-carboxylate) and flumazenil. Chronic diazepam elicited cross-tolerance to the BZ triazolam and not to the barbiturate pentobarbital or the neuroactive steroid pregnanolone. These results suggest that tolerance to the rate-decreasing effects of BZs is not accompanied by cross-tolerance to positive GABA(A) modulators acting at other sites on the receptor complex. Moreover, changes in sensitivity to negative GABA(A) modulators during chronic diazepam treatment appeared to be related to negative efficacy and not clearly related to the precipitation of withdrawal for all drugs. These results indicate that changes in sensitivity to the behavioral effects of drugs that act at different sites on the GABA(A) receptor complex might be especially useful for identifying and characterizing the functional consequences of GABA(A) receptor heterogeneity.

Authors+Show Affiliations

Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, USA.No affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

11861811

Citation

McMahon, Lance R., and Charles P. France. "Daily Treatment With Diazepam Differentially Modifies Sensitivity to the Effects of Gamma-aminobutyric acid(A) Modulators On Schedule-controlled Responding in Rhesus Monkeys." The Journal of Pharmacology and Experimental Therapeutics, vol. 300, no. 3, 2002, pp. 1017-25.
McMahon LR, France CP. Daily treatment with diazepam differentially modifies sensitivity to the effects of gamma-aminobutyric acid(A) modulators on schedule-controlled responding in rhesus monkeys. J Pharmacol Exp Ther. 2002;300(3):1017-25.
McMahon, L. R., & France, C. P. (2002). Daily treatment with diazepam differentially modifies sensitivity to the effects of gamma-aminobutyric acid(A) modulators on schedule-controlled responding in rhesus monkeys. The Journal of Pharmacology and Experimental Therapeutics, 300(3), 1017-25.
McMahon LR, France CP. Daily Treatment With Diazepam Differentially Modifies Sensitivity to the Effects of Gamma-aminobutyric acid(A) Modulators On Schedule-controlled Responding in Rhesus Monkeys. J Pharmacol Exp Ther. 2002;300(3):1017-25. PubMed PMID: 11861811.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Daily treatment with diazepam differentially modifies sensitivity to the effects of gamma-aminobutyric acid(A) modulators on schedule-controlled responding in rhesus monkeys. AU - McMahon,Lance R, AU - France,Charles P, PY - 2002/2/28/pubmed PY - 2002/3/29/medline PY - 2002/2/28/entrez SP - 1017 EP - 25 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 300 IS - 3 N2 - The present study examined how daily treatment with the benzodiazepine (BZ) diazepam modifies the effects of positive modulators acting at different sites on the gamma-aminobutyric acid(A) (GABA(A)) receptor complex and negative modulators acting at BZ sites on the receptor complex. GABA(A) modulators were administered alone or in combination with acute or chronic diazepam to rhesus monkeys (n = 4) responding under a multiple fixed ratio (FR/FR) schedule of food presentation and stimulus-shock termination (SST). There was mutual antagonism between the rate-decreasing effects of diazepam (5.6 mg/kg, p.o.) and high efficacy BZ site negative modulators [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)]. Antagonism of beta-CCE, beta-CCM, and DMCM by diazepam was markedly reduced in monkeys receiving diazepam daily. In contrast, daily diazepam treatment enhanced the rate-decreasing effects of Ro 15-4513 (ethyl 8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-alpha]-[1,4]benzodiazepine-3-carboxylate) and flumazenil. Chronic diazepam elicited cross-tolerance to the BZ triazolam and not to the barbiturate pentobarbital or the neuroactive steroid pregnanolone. These results suggest that tolerance to the rate-decreasing effects of BZs is not accompanied by cross-tolerance to positive GABA(A) modulators acting at other sites on the receptor complex. Moreover, changes in sensitivity to negative GABA(A) modulators during chronic diazepam treatment appeared to be related to negative efficacy and not clearly related to the precipitation of withdrawal for all drugs. These results indicate that changes in sensitivity to the behavioral effects of drugs that act at different sites on the GABA(A) receptor complex might be especially useful for identifying and characterizing the functional consequences of GABA(A) receptor heterogeneity. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/11861811/Daily_treatment_with_diazepam_differentially_modifies_sensitivity_to_the_effects_of_gamma_aminobutyric_acid_A__modulators_on_schedule_controlled_responding_in_rhesus_monkeys_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11861811 DB - PRIME DP - Unbound Medicine ER -