SCH 32615 is a novel inhibitor of the
enzyme,
neutral endopeptidase (NEP, E.C. 3.4.24.11), the so called '
enkephalinase', which plays a functional role in the degradation of [Met5]- and [Leu5]
enkephalin. The present study was designed to assess whether
SCH 32615 is able to modify the activity of dopaminergic neurons as reflected by changes in the content of the major
dopamine metabolite, dihydroxyphenylacetic
acid (
DOPAC), in three different areas of the rat brain: the nucleus accumbens, the striatum, and the prefrontal cortex. When administered at analgesically active doses (1-100 mg/kg s.c., 60 min before killing),
SCH 32615 induced a dose-dependent increase in
dopamine metabolism in the nucleus accumbens but was ineffective in the striatum and in the prefrontal cortex. This effect appears to be mediated via
opioid receptors, since it was completely prevented by
naloxone (5 mg/kg s.c.). The increase in
DOPAC content in the prefrontal cortex elicited by foot-
shock was unaffected by pretreatment with
SCH 32615. In the nucleus accumbens,
dopamine metabolism was increased to the same extent by foot-
shock and
SCH 32615 administered separately, but these effects were not additive, suggesting that
SCH 32615 and foot-
shock act via a common mechanism. Taken together, these results support the hypothesis that inhibition of the in vivo degradation of
enkephalins induced by the systemic administration of
SCH 32615 increases the enkephalinergic tone in the central nervous system and thereby activates the mesolimbic dopaminergic neurons.