ENDOGENOUS NEUROTENSIN ANTAGONIZES METHAMPHETAMINE-ENHANCED DOPAMINERGIC ACTIVITY

Neurotensin (NT) has been proposed to be an endogenous neuroleptic bas ed on observations that i.c.v. administration of this peptide antagoni zes dopamine-mediated behavior. Because NT influences dopamine activit y, this peptide may contribute to the pathogenesis of psychotic disord ers such as schizophrenia; however, the precise physiological effects of NT remain speculative. In order to elucidate the function of endoge nous NT, a selective NT antiserum (NTAS) was administered i.c.v. throu gh a push-pull cannula in unanesthetized, freely moving rats in combin ation with dopamine activation caused by methamphetamine (METH). Locom otor and rearing activities induced by a low dose of METH (0.5 mg/kg) were substantially enhanced (4-5-fold) in rats receiving NTAS compared to control animals receiving METH alone. Similarly raised antiserum t o vasoactive intestinal polypeptide (VIP) did not alter METH-induced e ffects. To determine a possible mechanism for these observations, perf usate delivered into the cerebral ventricular space was collected by p ush-pull cannulae and assayed for dopamine release. METH-induced dopam ine release was enhanced 4-5-fold by co-administration of NTAS but not VIP antiserum. To verify these observations, and to identify the site of dopamine release, this experiment was repeated utilizing microdial ysis and the recently described NT antagonist, SR-48692. Results from this experiment were similar to those found using NTAS. Like NTAS, co- administration of the NT antagonist enhanced the behavioral responses to a low dose of METH. These studies with SR-48699 also revealed that blockade of NT receptors increased METH-induced release of dopamine fr om the nucleus accumbens. These findings are the first to demonstrate directly that endogenous NT antagonizes stimulated dopamine pathways a nd its inactivation substantially enhances METH-induced DA release and related behaviors.