PREEXPOSURE TO, BUT NOT COTREATMENT WITH, THE NEUROTENSIN ANTAGONIST SR-48692 DELAYS THE DEVELOPMENT OF COCAINE SENSITIZATION

This study examined the role of neurotensin (NT) in the development of cocaine sensitization using the novel nonpeptide NT antagonist SR 486 92. Male Sprague-Dawley vats received five daily administrations of SR 48692 (80 mu g/kg, IP or PO) or vehicle. Following a 7 day drag-free period, cocaine-induced (15 mg/kg, IP) locomotor activity was assessed . Subsequent cocaine tests occurred every other day. No differences we re observed between groups during the first day of cocaine testing. Se nsitization to the locomotor activating effects of cocaine occurred ra pidly in the controls reaching peak effects by the third cocaine chall enge injection. By contrast, subjects preexposed to SX 48692 IP were d elayed in the development of cocaine sensitization maintaining signifi cantly lower cocaine-induced activity counts relative to controls unti l the sixth cocaine challenge injection. Preexposure to SR 48692 PO al so produced an attenuating effect on the development of cocaine sensit ization. The decreased cocaine-induced activity in SR 48692-preexposed subjects did not appear to be the result of a locomotor deficit as SR 48692-preexposed subjects exhibited increased activity rates followin g a high dose (30 mg/kg, IP) cocaine challenge injection. In an additi onal experiment, the effect of cotreatment with .SR 48692 on the devel opment of cocaine sensitization was assessed. Subjects were cotreated with SX 48692 (80 mu g/kg, IP) or vehicle 60 minutes prior to each of two cocaine (15 mg/kg, IP) or saline preexposure injections. Following a drug-free day, subjects were tested for cocaine-induced (15 mg/kg, IP) locomotor activation. SR 48692 cotreatment had no effect on the de velopment of sensitization to cocaine. These data suggest that chronic preexposure to SR 48692 produces lasting effects rendering subjects r esistant to the development of sensitization to the activating effects of cocaine. Further, these data provide direct evidence for a role of NT in the development of cocaine sensitization.