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 membrane (pSPM) were isolated and time-course incubated with NT (100 microM; 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.
Davis
T P
TP
Department of Pharmacology, University of Arizona College of Medicine, Tucson 85724.
Culling-Berglund
A
A
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002746:Chlorpromazine / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D006220:Haloperidol / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009496:Neurotensin / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013574:Synaptosomes / Q000378:metabolism*; D013997:Time Factors
D009496:Neurotensin; D006220:Haloperidol; D002746:Chlorpromazine