The dopamine antagonist cis-flupenthixol blocks the expression of the conditioned positive but not the negative effects of cocaine in rats

Abstract

Human cocaine users report that the initial "high" produced by cocaine administration is followed by an anxiogenic "crash". Given that cocaine has such robust and opposing properties, it is likely that both positive and negative effects of cocaine contribute to an individual's motivation to administer the drug. Despite this likelihood, the neurobiology underlying cocaine's dual processes remains unclear. While much literature supports a role for dopamine (DA) in cocaine reward, it is uncertain if DA also contributes to the drug's negative effects. Our laboratory has extensively utilized a modified conditioned place test to explore cocaine's opponent processes. In this paradigm rats develop conditioned place preferences (CPPs) for an environment paired with the immediate/positive effects of cocaine, and conditioned place aversions (CPAs) for an environment paired with the delayed/negative effects present 15-min after i.v. injection. In the current study rats were conditioned to associate an environment with either the immediate or delayed effects of i.v. cocaine (1mg/kg/0.1ml) 3h after i.p. pre-treatment with either the DA D1/D2 receptor antagonist cis-flupenthixol (0.5mg/kg/ml) or saline vehicle. As expected, vehicle-treated control animals developed the normal pattern of CPPs for cocaine's immediate effects or CPAs for the delayed effects of cocaine. However, while DA receptor antagonism prevented the expression of cocaine CPPs it did not alter the expression of cocaine-induced CPAs. These data confirm a role for DA transmission in cocaine reward but suggest that different neural pathways mediate the drug's negative/anxiogenic properties.

Keywords: Aversion; Cocaine; Conditioned place preference; Dopamine; Reward; cis-Flupenthixol.

Fig. 1

Mean (+SEM) distance travelled in cm for each group during the last 5-min of a 1-h habituation session (designated as “baseline” on the far left of the graph) and during the 60-min immediately following i.p. injection of cocaine (15 mg/kg). All animals were pretreated with one of four doses of the DA antagonist cis-flupenthixol (0.0, 0.125, 0.25, or 0.5 mg/kg/ml) 2-h prior to habituation and 3-h hours prior to cocaine administration.

Fig. 2

Mean (+SEM) difference scores for animals conditioned to associate a unique environment with either the immediate/positive effects of i.v. cocaine (Immediate) or the delayed/negative effects of the drug present 15-min after injection (Delayed). Difference scores were computed as amount of time spent in the cocaine-paired environment on test day minus the time spent in that same compartment on baseline. Prior to each conditioning trial, each rat was pretreated with either 0.5 mg/kg i.p. cis-flupenthixol (right panel) or saline vehicle (left panel). Asterisks indicate that a group’s difference score was significantly different from zero. *p<.05; ** p<.02; ***p<.002.