Neuroleptic drug treatment alters in vitro central neurotensin metabolism

Neurotensin (NT) has been shown to possess pharmacological properties associated with neuroleptic drugs. To determine if chronic haloperidol (HL; 3.5 mg/kg/day) or chlorpromazine (CPZ; 4.2 mg/kg/day) treatment affects central NT metabolism, HL and CPZ were perfused via Alzet® minipumps into male Sprague-Dawley rats for 8 days. Purified synaptosomal plasma membranes (pSPM) were isolated and time-course incubated with NT (100 μM; 30-120 min). All samples were analyzed by high resolution, reversed-phase high performance liquid chromatography. HL and CPZ caused an increase in NT metabolism at the pSPM. Although an increase in NT metabolism would result in a loss of biological activity, it does lead to a significant accumulation of the biologically active NT fragment NT-(9-13), which has been shown to bind to the NT receptor. Therefore, neuroleptic drug treatment alters NT metabolism at the pSPM, leading to the formation of a fragment with antinociceptive activity.