CHARACTERIZATION OF COCAINE-CONDITIONED LOCOMOTOR RESPONSES BY MODULATION OF ENVIRONMENTAL CONTEXT AND NEURAL PLASTICITY-SIGNALING PATHWAYS

Rodent models are commonly used for the study of substance abuse and addiction. The objective of this study was to characterize the cocaine-conditioned locomotor response, a behavioral phenomenon observed in mice, following an acute injection of cocaine, and to determine its mechanism of action for potential therapeutic targeting. Compounds known to modulate neural plasticity were evaluated for their ability to affect the acquisition and expression of the conditioned behavior. Purpose (a): In rodents, increase in locomotion is a hallmark effect of psychostimulant exposure and conditioning that is associated with activation of mesocorticolimbic dopamine signals mediating reinforcing/rewarding actions. The objective of this study was to characterize the cocaine-conditioned locomotor response following an acute injection of cocaine, specifically the modulating roles of environmental context and plasticity-associated signals. Methods (b): Cocaine (40mg/kg) was administered to different groups of Swiss-Webster, C57Bl/6, or DBA2 mice via intraperitoneal injection (i.p.), in either a locomotor activity testing apparatus or the home cage, 2 hours following an activity test under saline. Mice placed in the testing chambers were given 30 minutes to explore freely and locomotion was monitored using a Digiscan photocell apparatus. A conditioned effect of cocaine was inferred by an increase in horizontal activity counts relative to home cage cocaine controls during a test in the same apparatus on the following day. Compounds known to modulate neural plasticity-associated signaling cascades were evaluated for their ability to affect the acquisition and expression of cocaine-conditioned locomotor response, using a two-day protocol. Mice were administered haloperidol (0.05-1 mg/kg), dizocilpine (0.01-0.25mg/kg), nifedipine (0.1-10 mg/kg), cycloheximide (2.5-10mg/kg), or vehicle, prior to placement into the activity chambers on the test day for expression or prior to acquisition day. Results (c): Haloperidol (0.25-1 mg/kg) inhibited expression of the cocaine-conditioned locomotion, though failed to alter acquisition of the behavioral response. Dizocilpine (0.05-0.25 mg/kg) attenuated acquisition and exacerbated expression. Nifedipine had no effect on the conditioned locomotor response. Cycloheximide (2.5-10 mg/kg) attenuated acquisition of the conditioned response. Conclusions (d): These findings suggest that plasticity-dependent signaling pathways mediate associations of context following acute cocaine exposure and are necessary for the acquisition and expression of the cocaine-conditioned locomotor response.