Methamphetamine-induced dopamine terminal deficits in the nucleus accumbens are exacerbated by reward-associated cues and attenuated by CB1 receptor antagonism

Abstract

Methamphetamine (METH) exposure is primarily associated with deleterious effects to dopaminergic neurons. While several studies have implicated the endocannabinoid system in METH's locomotor, rewarding and neurochemical effects, a role for this signaling system in METH's effects on dopamine terminal dynamics has not been elucidated. Given that CB1 receptor blockade reduces the acute potentiation of phasic extracellular dopamine release from other psychomotor stimulant drugs and that the degree of acute METH-induced increases in extracellular dopamine levels is related to the severity of dopamine depletion, we predicted that pretreatment with the CB1 receptor antagonist rimonabant would reduce METH-induced alterations at dopamine terminals. Furthermore, we hypothesized that administration of METH in environments where reward associated-cues were present would potentiate METH's acute effects on dopamine release in the nucleus accumbens and exacerbate changes in dopamine terminal activity. Fast-scan cyclic voltammetry was used to measure electrically-evoked dopamine release in the nucleus accumbens and revealed markers of compromised dopamine terminal integrity nine days after a single dose of METH. These were exacerbated in animals that received METH in the presence of reward-associated cues, and attenuated in rimonabant-pretreated animals. While these deficits in dopamine dynamics were associated with reduced operant responding on days following METH administration in animals treated with only METH, rimonabant-pretreated animals exhibited levels of operant responding comparable to control. Moreover, dopamine release correlated significantly with changes in lever pressing behavior that occurred on days following METH administration. Together these data suggest that the endocannabinoid system is involved in the subsecond dopaminergic response to METH.

Figure. 1

Visual depiction of experimental design. A between subjects design (n = 31) was used to assess how the presence of reward-associated cues and rimonabant pretreatment impacts the dopaminergic deficits that follow METH administration. Animals in the different groups, FOOD+METH, FOOD+RIMO+METH, Food+Saline were shaped for 4 days, then maintained on hourly food-maintained responding sessions for seven days. On the following day animals were administered drugs, given one day of rest and returned to hourly sessions for seven days. Voltammetric experiments were then performed. T h e NoFOOD+METH group was not conditioned to lever press for food, was given food only in home cages and received vehicle pretreatment and METH administration; FOOD+Saline group was conditioned to lever press for food and received vehicle pretreatment and saline administration. FOOD+METH group was conditioned to lever press for food and received vehicle pretreatment and METH administration (25 mg/kg IP); FOOD+RIMO+METH group was conditioned to lever press for food and received rimonabant (3 mg/kg) pretreatment followed by METH. NoFOOD+METH group received equal exposure to the same environment with cues associated with reward, but lever press did not dispense food.

Figure. 2. METH is associated with nonsignificant reductions in lever pressing that is reversed by rimonabant pretreatment

Ratio of total bar presses two days before and after drug administration (Mean ±SEM, *p<0.05, One-Way ANOVA, Bonferroni post hoc test.).

Figure. 3

Animals administered METH in environments of food-maintained responding (FOOD+METH) exhibit increased rate of decay of electrically-evoked NAc dopamine release. Rimonabant pretreated animals show rates of decay comparable to control. A, Representative false color plots of electrically evoked dopamine in the NAc, where green is hot; plots are normalized to maximal release to emphasize change in uptake. Insets are Current vs. Time traces of color along +0.6V. FOOD+METH exhibits a longer tail of electrically-evoked dopamine release, demonstrating compromised reuptake. B, Mean values of rate of decay in the NAc (Mean ±SEM, One-Way ANOVA, Bonferroni post hoc test). C, Rate of decay in an input-output experiment (Mean ±SEM, One-Way ANOVA, Bonferroni post hoc test). Points are shifted in reference to NoFOOD+METH to display error bars: FOOD+Saline 6 points shifted right, FOOD+RIMO+METH 3 points shifted right, FOOD+METH is 3 points shifted left, NoFOOD+METH no shift. [*p<0.05; **p<0.01; ***p<0.001]

Figure. 4

Rimonabant pretreatment is associated with attenuated METH-induced reductions in the peak amplitude of electrically-evoked dopamine release throughout the NAc. A, Electrically evoked NAc dopamine release (Mean ±SEM, One-Way ANOVA, Bonferroni post hoc). B, Representative concentration traces of dopamine concentration vs. time vs. depth. Color plots demonstrate the effect of treatment throughout the NAc. Transparent boxes represent the electrical stimulation at 5 seconds. C, Correlation of mean dopamine release in the NAc and total bar presses ratio. Shaded region indicates 95% confidence interval (*p<0.05, 2-tailed Pearson’s correlation). [*p<.05, **p<.01, ***p<.001]

Figure. 5

Input-output experiment: effects of METH and rimonabant. A, VTA stimulation current (100–900µA) vs. peak dopamine concentration in the NAc. (Mean ±SEM, Repeated Measures, One-Way ANOVA, Bonferroni’s post hoc test). B, Representative within- subject input output experiment plotted in current vs. time traces. Colors from A indicate group. Points are shifted in reference to NoFOOD+METH to display error bars: FOOD+Saline 6 points shifted right, FOOD+RIMO+METH 3 points shifted right, FOOD+METH is 3 points shifted left, NoFOOD+METH no shift. Differences in averaging are responsible for discrepancy between figure 5 and 3: FOOD+METH displays non significant but greater average peak amplitudes in the depth analysis, where values were averaged between subject within a group at each depth and analyzed by one-way ANOVA; NoFOOD+METH displays higher peak amplitudes in Figure 3 as it was analyzed by a two-way ANOVA as data was obtained from only one depth for each subject. [*p<.05, **p<.01,***p<.001]