BEHAVIORAL FUNCTIONS OF NEUROPEPTIDES

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The past decade has witnessed the discovery of forty or more peptides localized in neurons of mammalian brain. Many cases of peptides coexisting in the same neuron with classical transmitters have been described. Our laboratory is investigating the functional significance of coexisting peptides and transmitters in the central nervous system, using behavioral tools. A) We previously showed that cholecystokinin (CCK) potentiates dopamine-induced hyperlocomotion in the nucleus accumbens, the terminal region of the mesolimbic pathway where CCK and DA coexist. This year, we began to characterize the role of CCK on DA autoreceptors in the ventral tegmentum (VTA), the cell body region of the mesolimbic pathway where CK an DA coexist. Preliminary data show that CCK potentiates the hypolocomotion induced by DA in the VTA, while having no effect alone, i.e. the potentiating effect of CCK in the VTA was not blocked by doses of proglumide which blocked the potentiating effect of CCK in the nucleus accumbens. In addition, the unsulfated form of CCK- 8 was also active in potentiating DA-induced hypolocomotion in the VTA. These preliminary behavioral data suggest that the pharmacology of CCK effects in the VTA match the "central- type" CCK-receptor, as found by Skirboll and Hommer using electrophysiological techniques. Conversely, the pharmacology of CCK effects in the nucleus accumbens match the "peripheral- type" CCK receptor in our previous behavioral data. B) The nucleus basalis of Meynert lesion rat model of Alzeheimer's disease is now ongoing in our laboratory. We have completed one experiment showing that acetylcholine (ACH) can reverse the memory deficit in a T-maze task when given directly into the lateral ventricles, the first demonstration of a central site of action for ACH. The second experiment found that atropine, but not mecamylamine, blocked the ACH effect, suggesting the involvement of a muscarinic, rather than a nicotinic cholinergic receptor. Tests of somatostatin and galanin, alone and in combination with a submaximal dose of ACH, are in progress.