Elsevier

Biological Psychiatry

Volume 75, Issue 6, 15 March 2014, Pages 487-498
Biological Psychiatry

Archival Report
Endocannabinoids Promote Cocaine-Induced Impulsivity and Its Rapid Dopaminergic Correlates

https://doi.org/10.1016/j.biopsych.2013.09.005Get rights and content

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.

Section snippets

Subjects and Surgery

Thirty-six male Long-Evans (Charles-River, St. Constant, Quebec, Canada, or Wilmington, Massachusetts) rats weighing 300 to 350 g at the time of arrival, served as subjects. Rats were individually housed in a temperature- and humidity-controlled room with a 12-hour light-dark cycle (lights on at 07:00 hours). Animals were divided as follows: 18 rats were used in the reversal experiment; 12 of those received cocaine and 6 received saline. The remaining 18 were used in the blockade experiment. Of

Blockade of CB1 Receptors Reverses Cocaine-Induced Changes in Preference for the Large Reward

The initial injection of cocaine produced similar increases in locomotor activity in both groups, the group that would be injected with the CB1R antagonist and the one injected with vehicle (t10 = −1.17, p = .26). Rats of both groups were sensitized to the locomotor effects of cocaine (t5 vehicle-group = 2.86, p = .035; t5 CB1 blockade-group = 3.32, p = .020) (Figure 1A,B; Figure S2 in Supplement 1). Saline-injected rats showed no statistical difference between the first and last saline

Discussion

The current study documents the role of eCBs in the development and maintenance of changes in impulsive choice that arise from cocaine exposure and adds to a growing body of evidence related to the modulatory role that eCBs play in self-control—in particular when it is altered by psychostimulants 72, 73, 74. We demonstrate that cocaine produces a decrease in self-control that is reversed and blocked by interfering with CB1R signaling. Rats exposed to cocaine show a preference for immediate

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