EFFECT OF CNS LESIONS ON DRUG ACTION

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Pavlovian conditioning of the rabbit's nictitating membrane response, a corneal-VIth nerve reflex, is generally agreed to provide a reliable measure of associative learning and memory. This model system will be used to identify the anatomical pathways and neurochemical systems involved in learning and memory and to examine the behavioral and neurochemical processes through which drugs act to alter learning and memory. Experiments will be carried out under three major aims that will provide converging approaches to origin additional knowledge of these basic processes. Aim 1 will examine those brain regions that have been suggested to play an essential or important role in the acquisition and/or performance of conditioned responses. This will include a thorough examination of recent proposals that the cerebellum is essential for the learning of motor acts by the use of cortical (VIth lobe) and subcortical (interpositus) lesions of the cerebellum and from reversible lesions produced by infusion of lidocaine. The reversible lesion will then be employed to establish whether interpositus is essential for the acquisition of conditioned responses. These reversible lesions will also be used to identify other pathways of the conditioned and unconditioned response. Aim 2 will examine the uptake of 3H- and 14C-2-deoxy-D-glucose in a double isotope technique employing quantitative autoradiography to identify the areas of brain that are differentially activated by the contiguous presentation of a conditioned and unconditioned stimulus and whether such heterosynaptic facilitation of neuronal activity can predict subsequent rates of learning. For example, the effect of some drugs on learning appear to be secondary to their ability to increase or decrease such heterosynaptic facilitation. Aim 3 will use intraventricular injections of drugs that activate or inhibit the cAMP system to examine the role of this second messenger in learning and in the effects of drugs on learning. Such knowledge should provide clues concerning the neural systems involved in human disorders of learning and memory (e.g., Alzheimer's disease) and identify the drugs that might be effective in their treatment.