Amphetamine Reverses Escalated Cocaine Intake via Restoration of Dopamine Transporter Conformation

Abstract

Cocaine abuse disrupts dopamine system function, and reduces cocaine inhibition of the dopamine transporter (DAT), which results in tolerance. Although tolerance is a hallmark of cocaine addiction and a DSM-V criterion for substance abuse disorders, the molecular adaptations producing tolerance are unknown, and testing the impact of DAT changes on drug taking behaviors has proven difficult. In regard to treatment, amphetamine has shown efficacy in reducing cocaine intake; however, the mechanisms underlying these effects have not been explored. The goals of this study were twofold; we sought to (1) identify the molecular mechanisms by which cocaine exposure produces tolerance and (2) determine whether amphetamine-induced reductions in cocaine intake are connected to these mechanisms. Using cocaine self-administration and fast-scan cyclic voltammetry in male rats, we show that low-dose, continuous amphetamine treatment, during self-administration or abstinence, completely reversed cocaine tolerance. Amphetamine treatment also reversed escalated cocaine intake and decreased motivation to obtain cocaine as measured in a behavioral economics task, thereby linking tolerance to multiple facets of cocaine use. Finally, using fluorescence resonance energy transfer imaging, we found that cocaine tolerance is associated with the formation of DAT-DAT complexes, and that amphetamine disperses these complexes. In addition to extending our basic understanding of DATs and their role in cocaine reinforcement, we serendipitously identified a novel therapeutic target: DAT oligomer complexes. We show that dispersion of oligomers is concomitant with reduced cocaine intake, and propose that pharmacotherapeutics aimed at these complexes may have potential for cocaine addiction treatment. Tolerance to cocaine's subjective effects is a cardinal symptom of cocaine addiction and a DSM-V criterion for substance abuse disorders. However, elucidating the molecular adaptions that produce tolerance and determining its behavioral impact have proven difficult. Using cocaine self-administration in rats, we link tolerance to cocaine effects at the dopamine transporter (DAT) with aberrant cocaine-taking behaviors. Further, tolerance was associated with multi-DAT complexes, which formed after cocaine exposure. Treatment with amphetamine deconstructed DAT complexes, reversed tolerance, and decreased cocaine seeking. These data describe the behavioral consequence of cocaine tolerance, provide a putative mechanism for its development, and suggest that compounds that disperse DAT complexes may be efficacious treatments for cocaine addiction.

Amphetamine maintenance differentially modulates effects of cocaine, methylenedioxypyrovalerone (MDPV), and methamphetamine on intracranial self-stimulation and nucleus accumbens dopamine in rats

“…Second, the present study also evaluated the effects of a lower amphetamine maintenance dose (0.1 mg/kg/h) on cocaineinduced ICSS facilitation, and this dose was not effective to alter ICSS facilitation by cocaine. The overall potency of amphetamine maintenance to attenuate ICSS facilitation in this study was similar to amphetamine-maintenance potency to reduce cocaine selfadministration in rats responding in various drug selfadministration procedures, including progressive-ratio, longaccess, and cocaine-vs.-food choice procedures [16,41,42]. These effects are also consistent with amphetamine-maintenance effectiveness to decrease cocaine self-administration in monkeys and humans and to decrease metrics of cocaine use in clinical trials [9,43,44].…”

Adolescent cannabinoid exposure induces irritability-like behavior and cocaine cross-sensitization without affecting the escalation of cocaine self-administration in adulthood

“…The sample size ( n = 6–9) was chosen based on a pre hoc power analysis (Power = 0.8, p < 0.05) to detect effect sizes (Cohen’s d = 1.3–1.6) that were similar to previously published effect sizes and demonstrated the effect of exposure to cannabinoid receptor agonists on cocaine sensitization (Cohen’s d = 1.6) 15 and cocaine self-administration (Cohen’s d = 1.7) 39 . The sample size in the present study was also similar to previous studies that employed the escalation model of drug self-administration 40 – 44 . The level of intake in the present study was also comparable to previous studies that employed the escalation model of cocaine self-administration with larger sample sizes 34 , 35 , 45 .…”

Dopamine “Ups and Downs” in Addiction Revisited

“…Interestingly, amphetamine maintenance therapy during IntA cocaine decreases subsequent motivation for cocaine and the expression of psychomotor sensitization, while reversing the sensitization of cocaine's action at the DAT [59]. The latter effect is opposite that seen after LgA, where amphetamine maintenance reverses the tolerance to cocaine's effects at the DAT produced by LgA cocaine [60].…”