CNS LESIONS EFFECTS ON DRUG ACTION

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DESCRIPTION: (Applicant's Abstract) Our previous research, employing classical conditioning of the rabbit's nictitating membrane response has demonstrated that both associative learning and motor performance are critically dependent on the normal activity of the inferior olivary nucleus. Learning during classical conditioning involves a precise timing mechanism as indicated by its exquisite sensitivity to the temporal parameters of stimulus interval. Our work and that of others suggest that the synchronized oscillatory activity of olivary neurons may provide this timing mechanism. Moreover, serotonin (5-HT) has been demonstrated to regulate the rhythmic activity of the inferior olivary nucleus and also to determine the rate of learning and its motor expression. Both of these actions are mediated by the 5-HT2A receptor. Thus, we have hypothesize that 5-HT agonists and antagonists can increase or decrease the rate of learning and optimum level of motor function by acting at 5-HT2A receptors located on olivary neurons so as to enhance the ability of the olive to coordinate a neural network that determines the efficiency of learning and its motor expression. Experiments will be carried out to produce general or specific 5-HT denervations in order to assess the role of presynaptic 5-HT release on the acquisition of learning and motor performance. Systemic and intracerebral injections of 5-HT2A agonists and antagonists will allow us to identify the critical sites at which normal function can be restored. Other experiments will examine the 5-Ht mechanisms through which tremorogenic agents that act directly on the inferior olive impair learning and performance. Finally, we will examine whether the ability of some 5-HT2A antagonists to retard learning and motor function is due to their actions as inverse agonists. These experiments will provide clues concerning the role of the olivocerebellar system in learning and motor performance and possibly in the treatment of dysfunctions in learning and motor function. For example, 5-HT has been implicated in essential tremor and 5-HT2A receptor blockade has been demonstrated to be sufficient for antipsychotic action.