ACUTE ADMINISTRATION OF NEUROLEPTICS DECREASES NEUROTENSIN METABOLISMON INTACT, REGIONAL RAT-BRAIN SLICES

Treatment with antipsychotic agents has been shown to affect both neur otensin (NT) levels and the activities of enzymes implicated in the me tabolism 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. Sign ificant degradation of NT 1-13 with the concomitant production of NT f ragments, including NT 1-8, 1-10, 1-11 and 9-13, occurred after incuba ting for 2 hr regionally dissected microslices with 100 mu M 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 stud ied. Acute administration of either haloperidol (3 mg/kg) or chlorprom azine (20 mg/kg) 24 hr before slice preparation decreased NT metabolis m 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 administrat ion 24 hr before slice preparation. Assay of crude membrane homogenate s revealed a significant reduction in the NT-degrading enzyme metalloe ndopeptidase 24.15 (E.C. 3.4.24.15) activity in the caudate-putamen of haloperidol-treated rats. The level of NT metabolism remained signifi cantly reduced at 48 hr after haloperidol administration, but returned to that of the control level by 96 hr. Acute administration of apomor phine (2 i.p. injections of 20 mg/kg) increased NT degradation on slic es from the nucleus accumbens, but not on slices from the caudate-puta men. These data suggest that drugs which affect dopaminergic transmiss ion influence the metabolism of neurotensin in specific brain regions.