Despite its pharmacological relevance, the mechanism of the development of tolerance to the action of benzodiazepines is essentially unknown. The acute sedative action of diazepam is mediated via ␣ 1 -GABA A receptors. Therefore, we tested whether chronic activation of these receptors by diazepam is sufficient to induce tolerance to its sedative action. Knock-in mice, in which the ␣ 1 -, ␣ 2 -, ␣ 3 -, or ␣ 5 -GABA A receptors had been rendered insensitive to diazepam by histidine-arginine point mutation, were chronically treated with diazepam (8 d;) and tested for motor activity. Wild-type, ␣ 2 (H101R), and ␣ 3 (H126R) mice showed a robust diminution of the motor-depressant drug action. In contrast, ␣ 5 (H105R) mice failed to display any sedative tolerance. ␣ 1 (H101R) mice showed no alteration of motor activity with chronic diazepam treatment. Autoradiography with [ 3 H]flumazenil revealed no change in benzodiazepine binding sites. However, a decrease in ␣ 5 -subunit radioligand binding was detected selectively in the dentate gyrus with specific ligands. This alteration was observed only in diazepam-tolerant animals, indicating that the manifestation of tolerance to the sedative action of diazepam is associated with a downregulation of ␣ 5 -GABA A receptors in the dentate gyrus. Thus, the chronic activation of ␣ 5 -GABA A receptors is crucial for the normal development of sedative tolerance to diazepam, which manifests itself in conjunction with ␣ 1 -GABA A receptors.

Resume Nous avons entrepris dans le cadre de cet article une approche de psychologie experimentale sur les processus d'apprentissage chez la drosophile. Cette etude vise a confirmer l'importance de l'occurrence d'une stimulation aversive (chlorhydrate de quinine) sur la probability d'extrusion proboscidienne consecutive a la presentation d'une solution sucree. En reprenant les procedures classiques d'habituation comportementale et de conditionnement associatif de Medioni et Vaysse (1975), nous avons etabli que le role de la quinine n'etait pas simplement et universellement aversif comme postule jusqu'alors, mais que seule sa presentation en consecutivite immediate avec la presentation sucree etait de nature a hater la disparition du reflexe proboscidien. En revanche, sa presentation avant ou en association, voire a intervalle d'une ou de deux minutes apres la stimulation sucree est plut6t de nature a retarder la disparition du reflexe proboscidien. Parmi les diverses hypotheses emises, seule une interpretation en termes de «punition conditionnee» est susceptible d'expliquer l'ensemble des resultats.

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