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Discriminative stimulus effects of ω (BZ) receptor ligands: correlation with in vivo inhibition of [3H]-flumazenil binding in different regions of the rat central nervous system

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Abstract

Rats can be trained to discriminate benzodiazepines (BZ) from vehicle and there is considerable evidence that the stimulus effects of these drugs are mediated by activity atω (BZ) modulatory sites of the GABAA receptor complex. A number of recent studies, however, have indicated that differences may exist between the discriminative stimulus effects of benzodiazepines and those of certain non-benzodiazepine ligands for theω (BZ) receptors (e.g. zolpidem, abecarnil). As it is known that several subtypes ofω (BZ) sites are found in the central nervous system, and that drugs such as zolpidem have selectivity for certain subtypes, it is possible that differential stimulus effects may be associated with receptor selectivity. In the present study, correlations were calculated between the potencies of nine compounds with affinity forω receptors (diazepam, lorazepam, triazolam, clonazepam, alprazolam, zopiclone, suriclone, CL 218, 872 and zolpidem) to substitute for chlordiazepoxide in rats trained to discriminate a dose (5 mg/kg) of this benzodiazepine and the ability of the same compounds to inhibit the binding of [3H]-flumazenil from different structures in the rat central nervous system in vivo. The correlations obtained were: cerebellum 0.46, cortex 0.39, striatum 0.78 (P<0.05), hippocampus 0.79 (P<0.05) and spinal cord 0.95 (P<0.001). These different structures are known to contain different relative concentrations ofω 1 (BZ1) andω 2 (BZ2) sites with the spinal cord containing the greatest (80%) and cerebellum the lowest (5%) concentration ofω 2 (BZ2) sites. Good correlations were also observed between the ability of these compounds to substitute for chlordiazepoxide and their potency to inhibit (3H)-flumazenil binding in both cerebellar (r=0.88) and spinal cord (r=0.91) membranes in vitro indicating that the physiological relevance ofω receptor subtypes cannot be deduced from in vitro studies. The present results are consistent with the possibility that the discriminative stimulus produced by chlordiazepoxide is mediated by activity atω 2 (BZ2) sites. No correlations were observed between inhibition of [3H]-flumazenil binding and response rate decreases, suggesting that the mechanism underlying this behavioural effect is different from that mediating the discriminative stimulus.

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  1. Synthélabo Recherche (L.E.R.S.), 31 Avenue P.V. Couturier, P-92220, Bagneux, France

    D. J. Sanger & J. Benavides

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Sanger, D.J., Benavides, J. Discriminative stimulus effects of ω (BZ) receptor ligands: correlation with in vivo inhibition of [3H]-flumazenil binding in different regions of the rat central nervous system. Psychopharmacology 111, 315–322 (1993). https://doi.org/10.1007/BF02244947

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  • DOI: https://doi.org/10.1007/BF02244947

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