Modulation of striatal dopamine dynamics by cocaine self-administration and amphetamine treatment in female rats

Abstract

Despite decades of research into the neurobiological basis of cocaine abuse, pharmacotherapeutic treatments for cocaine addiction have been largely ineffective. Converging evidence from preclinical research and from outpatient clinical trials suggest that treatment with amphetamine is efficacious in reducing cocaine intake. Although it has been suggested that amphetamine treatment reduces cocaine intake as an agonist replacement therapy, we have shown recently that multiple aspects of dopamine signaling are altered by cocaine self-administration and returned to pre-cocaine function by amphetamine treatment in the nucleus accumbens of male rats. Here, we sought to determine if these effects were also evident in female subjects, and across regions of the striatum. Female rats performed 5 days of cocaine self-administration (1.5 mg kg^-1 inj^-1 , 40 inj/day) and were treated with a single amphetamine (0.56 mg/kg) or saline infusion 1 hr prior to killing. We then used ex vivo fast-scan cyclic voltammetry in the nucleus accumbens core or dorsolateral caudate-putamen to examine dopamine signaling and cocaine potency. We found that in the nucleus accumbens core, cocaine self-administration decreased dopamine uptake rate and cocaine potency, and both alterations were restored by amphetamine treatment. In the dorsolateral caudate-putamen, neither cocaine self-administration nor amphetamine treatment altered dopamine uptake; however, cocaine potency was decreased by self-administration and returned to control levels by amphetamine. Together, these findings support a role for amphetamine treatment for cocaine addiction outside of agonist replacement therapy, and suggest that the development of cocaine tolerance is similar across sexes.

Keywords: cocaine potency; dopamine transporter; dopamine uptake; releasers; voltammetry.

Figure 1.. Timeline of cocaine self-administration and voltammetric recordings.

(A) Experimental design depicting 5 days of cocaine self-administration, following by a single AMPH or saline infusion ~18 hours after the final self-administration session. Animals were sacrificed for ex vivo voltammetry experiments 1 hour following infusion. (B) Rate of cocaine intake over the 5 days of cocaine self-administration. (C) Rate of cocaine intake during the first hour of each session. **, p < 0.01; ***, p < 0.001 vs Day 1.

Figure 2.. Cocaine self-administration-induced reductions in dopamine uptake in the NAc core are rescued by a single AMPH infusion.

(A) Representative traces and cyclic voltammograms. (B) Dopamine release in the NAc core is unchanged by cocaine self-administration or AMPH treatment. (C) Maximal rate of dopamine uptake (V_max) is decreased by cocaine self-administration and rescued by AMPH treatment. *, p < 0.05. Control, n = 11; Cocaine+Saline, n = 9; Cocaine+AMPH, n = 8.

Figure 3.. Cocaine self-administration-induced reductions in cocaine potency in the NAc core are rescued by a single AMPH infusion.

(A) Representative traces (left) and pseudo-color plots (right) after 30 μM cocaine. (B) Concentration response curves for cocaine reveal a downward shift in cocaine effect on dopamine uptake in cocaine self-administration animals, which is returned to control levels by an AMPH infusion. (C) K_i values (inhibitory constant) for cocaine at the dopamine transporter is increased by self-administration, indicative of decreased cocaine potency, and returned to control levels by an AMPH infusion. *, p < 0.05; ***, p < 0.001 vs control; #, p < 0.05, ###, p < 0.001 vs cocaine SA+Saline. Control, n = 11; Cocaine+Saline, n = 9; Cocaine+AMPH, n = 8.

Figure 4.. Cocaine self-administration and AMPH treatment do not change dopamine release or uptake in the DLC.

(A) Representative traces and cyclic voltammograms. Both dopamine release (B) and uptake (C) in the DLC are unchanged in either treatment group as compared to control animals. Control, n = 9; Cocaine+Saline, n = 8; Cocaine+AMPH, n = 7.

Figure 5.. Cocaine self-administration produces AMPH-reversible cocaine tolerance in the DLC.

(A) Representative traces (left) and pseudo-color plots (right) after 30 μM cocaine. (B) Similar to the NAc core, we found that cocaine self-administration decreased cocaine effects on dopamine uptake rate in the DLC. Further, cocaine potency was increased greater than control levels in cocaine self-administration animals that received a single infusion of AMPH. (C) There was a main effect of group on K_i values, although post-hoc analysis did not reach significance. Δ, main effect of ANOVA; **, p < 0.01 vs control; #, p < 0.05, ###, p < 0.001 vs cocaine SA+Saline. Control, n = 9; Cocaine+Saline, n = 8; Cocaine+AMPH, n = 7.

Figure 6.. Cocaine tolerance and rescue by AMPH are similar across striatal subregion.

Cocaine-induced inhibition of dopamine uptake is similar between the DLC and NAc core in (A) control animals, (B) cocaine self-administration animals treated with saline, and (C) cocaine self-administration animals treated with AMPH.