Discriminative Stimulus Effects of Drugs Acting at GABAA Receptors: Differential Profiles and Receptor Selectivity

doi:10.1016/S0091-3057(99)00081-7

Pharmacology Biochemistry and Behavior

Volume 64, Issue 2, October 1999, Pages 269-273

https://doi.org/10.1016/S0091-3057(99)00081-7 Get rights and content

Abstract

The GABA_A receptor complex contains a number of binding sites at which a variety of psychotropic drugs, including benzodiazepines, barbiturates, and some neurosteroids, act to potentiate or inhibit the effect of the transmitter. Many studies have reported that these drugs can produce discriminative stimulus actions, but the cueing effects of compounds acting at different sites to enhance the effects of GABA are not identical. The discriminative stimulus effects of benzodiazepines have been analyzed in detail, and there is also a great deal of information available on the effects of nonbenzodiazepine compounds acting at BZ(ω) recognition sites, which form part of the GABA_A receptor complex. Of particular interest are compounds with selectivity for the BZ₁(ω₁) receptor subtype including zolpidem, zaleplon, and Cl 218,872. BZ₁(ω₁)-selective drugs substitute for the discriminative stimulus produced by chlordiazepoxide only partially and at sedative doses. This is consistent with the view that sedative effects of BZ(ω) receptor agonists are mediated by the BZ₁(ω₁) receptor subtype, whereas the discriminative stimulus produced by chlordiazepoxide may be produced by activity at the BZ₂(ω₂) subtype. Analysis of this hypothesis is complicated by the variety of levels of intrinsic activity shown by different drugs.

Section snippets

Stimulus effects of benzodiazepines and related drugs

Experimental animals including rats, pigeons, rhesus monkeys, and baboons readily learn to discriminate benzodiazepines from placebo. The stimulus effects of this group of drugs have been analyzed in great detail following early studies using chlordiazepoxide (3) and diazepam (9). In general, there is complete cross-substitution between different benzodiazepines, and the potencies of different drugs to substitute for diazepam were found to correlate highly with their in vitro affinities to bind

Chlordiazepoxide cue in rats

Rats were trained to discriminate a dose of 5 mg/kg of chlordiazepoxide from saline using a standard fixed-ratio (FR)10 food reinforcement schedule during daily 15 min sessions [see (20) for more details of the procedure]. The discrimination was rapidly learned, and the chlordiazepoxide ED₅₀ doses for drug lever choice and decreases in rates of responding were approximately 2 and 12 mg/kg, respectively (values differed only slightly for a number of experiments carried out during a period of

Conclusions

Experimental animals can be trained to discriminate compounds acting at a variety of sites on the GABA_A receptor complex. This method, therefore, has considerable potential for allowing a fine analysis of the pharmacology of drugs that potentiate or inhibit GABAergic neurotransmission. Although the discriminative stimulus effects of compounds acting at BZ(ω) binding sites have been investigated in some depth, a number of questions deserve further study. These include the significance of BZ(ω)

Acknowledgements

This article was presented at the Meeting “Drug Discrimination in Behavioural Neuroscience,” Beerse (Antwerp), August 30–September 1, 1998.

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ArticlesDiscriminative Stimulus Effects of Drugs Acting at GABAA Receptors: Differential Profiles and Receptor Selectivity

Abstract

Section snippets

Stimulus effects of benzodiazepines and related drugs

Chlordiazepoxide cue in rats

Conclusions

Acknowledgements

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Discriminative stimulus properties of the benzodiazepine partial agonist β-carbolines abecarnil and ZK 95962A comparison with chlordiazepoxide

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Discriminative Stimulus Effects of Drugs Acting at GABA_A Receptors: Differential Profiles and Receptor Selectivity