Preexposure to, but Not Cotreatment with, the Neurotensin Antagonist SR 48692 Delays the Development of Cocaine Sensitization

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Abstract
This study examined the role of neurotensin (NT) in the development of cocaine sensitization using the novel nonpeptide NT antagonist SR 48692. Male Sprague-Dawley rats received five daily administrations of SR 48692 (80 μg/kg, IP or PO) or vehicle. Following a 7 day drug-free period, cocaine-induced (15 mg/kg, IP) locomotor activity was assessed. Subsequent cocaine tests occurred every other day. No differences were observed between groups during the first day of cocaine testing. Sensitization to the locomotor activating effects of cocaine occurred rapidly in the controls reaching peak effects by the third cocaine challenge injection. By contrast, subjects preexposed to SR 48692 IP were delayed in the development of cocaine sensitization maintaining significantly lower cocaine-induced activity counts relative to controls until the sixth cocaine challenge injection. Preexposure to SR 48692 PO also produced an attenuating effect on the development of cocaine sensitization. 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 following a high dose (30 mg/kg, IP) cocaine challenge injection. In an additional experiment, the effect of cotreatment with SR 48692 on the development of cocaine sensitization was assessed. Subjects were cotreated with SR 48692 (80 μg/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 development of sensitization to cocaine. These data suggest that chronic preexposure to SR 48692 produces lasting effects rendering subjects resistant 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.

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