Endocannabinoids promote cocaine-induced impulsivity and its rapid dopaminergic correlates

Abstract

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.

Keywords: CB1 receptors; cocaine; decision-making; dopamine; fast-scan cyclic voltammetry; self-control.

Figure 1

Locomotor activity for the different groups in the reversal experiment. When the activity between the first cocaine injection and the last cocaine injection are contrasted; repeated cocaine administration produces an increase in locomotor activity (p<0.05) in the groups that received AM251 (A) or vehicle (B) before the delay discounting task. In contrast, the locomotor activity of rats injected with saline (C) remained unaltered (p>0.05).

Figure 2

AM251 (1.5 mg/kg/i.p.) reverses effects of cocaine pre-exposure on choice of the delayed reward. (A) Shows how cocaine pre-exposure (red circles) consistently reduces the selection of the delayed large reward. Vehicle administration (green triangles) prior to the delay discounting task does not have any effect on the cocaine induced decrease. Both performances are statistically similar (p >0.05). The reductions in the selection of the large delayed reward observed after cocaine and vehicle are statistically significant when contrasted against the baseline performance (p<0.05 denoted by #) during the first three delays (0, 4, 10-s.). (B) As before, cocaine pre-exposure (red circles) consistently reduces the selection of the delayed large reward. However, such reduction is reversed by AM251 administration (light blue triangles) prior to the delay discounting task. When performance is contrasted against baseline, only cocaine’s effects are statistically different; this difference is particularly salient during the first three delays (0, 4, 10-s) (p<0.05 denoted by *). (C) Pre-exposure to saline instead of cocaine has no effect on the selection of the delayed large reward (p >0.05).

Figure 3

Locomotor activity for the different groups in the blockade experiment. There is an increase in the average locomotor counts between the first and the last cocaine injection in the CB1 blockade + cocaine group (A) as well as in the vehicle + cocaine group (B). However, the increase in locomotor activity between the first cocaine injection and the last cocaine injection is only statistically reliable (p<0.05) for the latter. Locomotor activity of the CB1 blockade + saline group (C) is similar for the first and last saline injection (p>0.05).

Figure 4

Rimonabant (1.5 mg/kg/i.p.) prevents the effects of cocaine pre-exposure on choice of the delayed reward. (A) When contrasted against baseline (blue triangles) vehicle administration 30-min before cocaine injections (light red circles) consistently reduces the selection of the delayed large reward. The reductions in the selection of the large delayed reward observed after vehicle and cocaine are statistically significant (p<0.05 denoted by *). These differences are particularly pronounced for the first three delays (0, 4, 10-s). These observations contrast to the results obtained when rimonabant (red circles) is administered 30-min before the cocaine injections (B). Performance during baseline and following treatment with rimonabant and cocaine are not statistically different (p>0.05). Similar results are obtained when rimonabant is administered 30-min before saline (magenta circles) (C).

Figure 5

Phasic DA release for both reward magnitudes at different delays. Release for the 4 reward pellets (dark blue) is higher for the 2 initial delays (0 and 4-s) when compared to the 1 pellet immediate option (dark red). However, it was only statistically higher (p<0.05 denoted by *) at 0-s delay. There is a peak of phasic DA release for the immediate 1 pellet option when the delay for the 4 pellets reaches 10-s, this difference in release between the options is statistically significant (p<0.05).

Figure 6

Representative example of DA release to reward delivery at different delays for vehicle pretreatment. DA release for the 1-pellet (A) and 4-pellet (B) options at 0-s and following pre-exposure to vehicle and cocaine (A′ & B′). Current at the peak oxidation potential of DA is plotted as function of time; the insets showing the cyclic voltammogram identifying the detected peak current, denoted by the arrow head, as DA. Below are two-dimensional pseudocolor plots of cyclic voltammograms over time. Dashed lines denote reward delivery. During baseline, release for the 4-pellet option is higher at 0-s (B) when contrasted against the 1-pellet option (A). However, following cocaine and vehicle this pattern reverses (A′& B′). At 10-s, during baseline, the release for the immediate 1-pellet option (C) is higher than that of the 4-pellet delay option (D). This pattern remains following vehicle and cocaine pre-exposure (C′ & D′).

Figure 7

Bar graphs of pooled DA release to reward delivery at different delays for vehicle-treated rats. (A) Shows the DA profile obtained during baseline. Release observed for the immediate 1-pellet option (blue bar) is paired with release obtained for the 4-pellet option (red bar) across different delays. Release for the 4-pellet option is statistically higher (p<0.05 denoted by *) at 0-s delay compared to its immediate counterpart. When the delay for the 4-pellet option reaches 10-s, there is a significant peak (p<0.05) of phasic DA release associated with the immediate 1-pellet alternative. (B) Injections of vehicle and cocaine produced a change in the DA release profile; following treatment, release for the immediate option (cyan bar) is significantly higher than that observed for the 4-pellet option (light red bar) at zero-delay, whereas release for the 4-pellet option remains stable across delays. Directly contrasting the effect of pre-exposure to vehicle and cocaine on DA release against baseline for the immediate (C) and delay option (D) shows that highest differences are observed when the delay is 0-s. At this delay there is a significant increase in release for the 1-pellet option following pre-exposure to vehicle and cocaine; whereas there is a significant decrease for the 4-pellet option (p<0.05).

Figure 8

Example of DA release to reward delivery at different delays in rimonabant-treated rats. Release for the 1-pellet (A) and 4-pellet (B) options at 0-s and following rimonabant pretreatment and cocaine (A′ & B′). Current at the peak oxidation potential of DA is plotted as function of time; the insets showing the cyclic voltammogram identifying the detected peak current, denoted by the arrow head, as DA. Below are two-dimensional pseudocolor plots of cyclic voltammograms over time. Dashed lines denote reward delivery. During baseline recording, DA for the 4-pellet option is higher at 0-s (B) when compared to the 1-pellet option (A). Following rimonabant and cocaine this pattern persists (A′& B′). At 10-s, release for the immediate 1-pellet option at baseline (C) is higher than that of the 4-pellet delay option (D). Following rimonabant and cocaine pre-exposure this pattern remains (C′ & D′).

Figure 9

Bar graphs of pooled DA release to reward delivery at different delays for rimonabant-treated animals. (A) Shows the DA profile obtained during baseline. Release observed for the immediate 1-pellet option (blue bar) is paired with release obtained for the 4-pellet option (red bar) across different delays. Release for the 4-pellet option is statistically higher (p<0.05 denoted by *) at 0-s delay compared to its immediate counterpart. When the delay for the 4-pellet option reaches 10-s, there is a significant peak (p<0.05) in release associated for the immediate 1-pellet alternative. (B) Injections of rimonabant prior to cocaine treatment maintained the release pattern observed during baseline; at 0-delay release is higher for the 4-pellet option (wine bars) than for the immediate option (light blue bars). Similar to baseline, when the delay for the 4-pellet option reaches 10-s, there is a significant peak (p<0.05) of phasic release associated for the immediate 1-pellet alternative. Directly contrasting the effect of pre-exposure to vehicle and cocaine on release to baseline for the immediate (C) and across delay options (D) shows that rimonabant preserves the baseline release pattern since no significant difference (p>0.05) in release at any of the delays for any of the options are observed.