Endocannabinoids promote cocaine-induced impulsivity and its rapid dopaminergic correlates

摘要

Background Impaired decision making, a hallmark of addiction, is hypothesized to arise from maladaptive plasticity in the mesolimbic dopamine pathway. The endocannabinoid system modulates dopamine activity through activation of cannabinoid type 1 receptors (CB1Rs). Here, we investigated whether impulsive behavior observed following cocaine exposure requires CB1R activation. Methods We trained rats in a delay-discounting task. Following acquisition of stable performance, rats were exposed to cocaine (10 mg/kg, intraperitoneal) every other day for 14 days and locomotor activity was measured. Two days later, delay-discounting performance was re-evaluated. To assess reversal of impulsivity, injections of a CB1R antagonist (1.5 mg/kg, intraperitoneal) or vehicle were given 30 minutes before the task. During the second experiment, aimed at preventing impulsivity rather than reversing it, CB1Rs were antagonized before each cocaine injection. In this experiment, subsecond dopamine release was measured in the nucleus accumbens during delay-discounting sessions before and after cocaine treatment. Results Blockade of CB1Rs reversed and prevented cocaine-induced impulsivity. Electrochemical results showed that during baseline and following disruption of endocannabinoid signaling, there was a robust increase in dopamine for immediate large rewards compared with immediate small rewards, but this effect reversed when the delay for the large reward was 10 seconds. In contrast, dopamine release always increased for one-pellet options at minimal or moderate delays in vehicle-treated rats. Conclusions Endocannabinoids play a critical role in changes associated with cocaine exposure. Cannabinoid type 1 receptor blockade may thus counteract maladaptive alterations in afferents to dopamine neurons, thereby preventing changes in dopaminergic activity underlying a loss of self-control.