Acute administration of neuroleptics decreases neurotensin metabolism on intact, regional rat brain slices

Treatment with antipsychotic agents has been shown to affect both neurotensin (NT) levels and the activities of enzymes implicated in the metabolism of NT. In the present study the effects of i.p. administered antipsychotics and dopaminergic agents on NT metabolism were examined in the microslice preparation from discrete regions of rat brain. Significant degradation of NT 1-13 with the concomitant production of NT fragments, including NT 1-8, 1-10, 1-11 and 9-13, occurred after incubating for 2 hr regionally dissected microslices with 100 μM NT 1-13. Acute administration (i.p.) of haloperidol (3 mg/kg) 1 hr before slice preparation had no effect on NT metabolism in any of the regions studied. Acute administration of either haloperidol (3 mg/kg) or chlorpromazine (20 mg/kg) 24 hr before slice preparation decreased NT metabolism significantly, as indicated by decreases in both NT degradation and formation of NT 1-8 in both the nucleus accumbens and caudate-putamen. Furthermore, a decrease in the formation of biologically active NT 9-13 was detected in the nucleus accumbens after neuroleptic administration 24 hr before slice preparation. Assay of crude membrane homogenates revealed a significant reduction in the NT-degrading enzyme metalloendopeptidase 24.15 (E.C. 3.4.24.15) activity in the caudate-putamen of haloperidol-treated rats. The level of NT metabolism remained significantly reduced at 48 hr after haloperidol administration, but returned to that of the control level by 96 hr. Acute administration of apomorphine (2 i.p. injections of 20 mg/kg) increased NT degradation on slices from the nucleus accumbens, but not on slices from the caudate-putamen. These data suggest that drugs which affect dopaminergic transmission influence the metabolism of neurotensin in specific brain regions.