PRETREATMENT WITH NEUROKININ SUBSTANCE-P BUT NOT WITH CHOLECYSTOKININ-8S CAN ALLEVIATE FUNCTIONAL DEFICITS OF PARTIAL NIGROSTRIATAL 6-HYDROXYDOPAMINE LESION

The neuropeptide substance P (SP) has been implicated in the control o f various neuro-behavioral functions including reinforcement and learn ing processes. It also exerts neurotrophic and regenerating effects in vitro and in vivo. A previous study indicated a potential therapeutic effect of SP in rats with partial 6-hydroxydopamine lesions of the ni grostriatal dopamine system when SP was administered after the lesion. The purpose of the present study was to determine whether prelesion t reatment with SP would also interact with the effects of unilateral 6- hydroxydopamine lesion of the substantia nigra. Thus, SP (50 mu g/kg) was administered i.p. on 8 consecutive days prior to unilateral lesion of the substantia nigra. Furthermore, we investigated the effects of prelesion treatment with cholecystokinin-8S (CCK; 1 mu g/kg), another neuropeptide, which is closely related to dopaminergic neurons, and wh ich also can have neurotrophic and neuroprotective functions. Our resu lts show that animals with partial neostriatal dopamine depletions (re sidual dopamine levels of more than 10%) did nor show turning asymmetr ies when pretreated with SP, whereas animals pretreated with vehicle e xhibited an initial ipsiversive asymmetry from which they recovered. I n contrast, behavioral asymmetries were most pronounced in animals whi ch had been pretreated with CCK. These peptide treatments did not affe ct the degree of neostriatal dopamine depletion: however, dihydroxyphe nylacetic acid/dopamine ratios were enhanced in the neurostriatum of a nimals with partial dopamine damage after SP-and CCK-pretreatment, and in the ventral striatum of SP-pretreated animals. These data provide evidence that prelesion treatment with SP, but not with CCK, can allev iate functional deficits induced by a partial nigro-striatal dopamine lesion. This effect may be related to enhanced ventral striatal dopami ne activity and/or to the peptide's known effects on learning, motivat ion, and emotion. (C) 1997 Elsevier Science Inc.