Association of Stimulant Use With Dopaminergic Alterations in Users of Cocaine, Amphetamine, or Methamphetamine

Abstract

Importance Stimulant use disorder is common, affecting between 0.3 to 1.1% of the population, and costs over $85 billion per year globally. There are currently no licensed treatments. Several lines of evidence implicate the dopamine system in the pathophysiology of substance use disorder. Thus understanding the nature of dopamine dysfunction seen in stimulant users has the potential to aid the development of new therapeutics. Objective To comprehensively review the in-vivo imaging evidence for dopaminergic alterations in stimulant (cocaine or amphetamine/methamphetamine) drug abuse or dependence. Data sources The entire PubMed, EMBASE and PsycINFO databases were searched for studies from inception date to May 14, 2016. Study selection A total of 31 studies were identified that compared dopaminergic measures between 519 stimulant users and 512 controls using positron emission tomography or single-photon emission computed tomography to measure striatal dopamine synthesis or release, or dopamine transporter or receptor availability. Data extraction and synthesis Demographic, clinical and imaging measures were extracted from each study and meta-analyses and sensitivity analyses were conducted for stimulants combined and cocaine and amphetamines separately where there were sufficient studies. Main Outcomes and Measures We determined the difference in dopamine release (assessed using change in the D2/3 receptor availability following administration of amphetamine or methylphenidate), transporter and receptor availability in cocaine, amphetamine and methamphetamine users and healthy controls. Results In majority of the studies the duration of abstinence varied from 5 days to 3 weeks. There was a significant decrease in striatal dopamine release (stimulants combined: Hedge’s g= −0.84; cocaine: −0.87, both p<0.001), dopamine transporter availability (stimulants combined: Hedge’s g= −0.91, p<0.01; amphetamine and methamphetamine: Hedge’s g: −1.47, p<0.001) and D2/3 availability (stimulants combined: Hedge’s g= −0.76; cocaine: −0.73; amphetamine and methamphetamine: −0.81, all p<0.001). We did not find consistent alterations in vesicular monoamine transporter, dopamine synthesis or D1 receptor studies. Conclusion and relevance Our data suggest that both pre and post-synaptic aspects of the dopamine system in the striatum are down-regulated in stimulant users. We discuss the commonality and difference between these findings and the discrepancies with the preclinical literature as well as their implications for future drug development.

Striatal presynaptic dopaminergic dysfunction in gambling disorder: A 123I‐FP‐CIT SPECT study

“…To date, studies focusing on targets of dopamine functioning have led to different results in GD compared with Substance Use Disorders (SUDs). Our results are consistent with findings in psychostimulant addicts . Similarly to cocaine intoxication, reduced DAT function may induce hyperdopaminergic states after dopamine release.…”

“…Besides, reflecting the integrity of dopaminergic neurons projecting to the striatum, DAT terminates dopamine signaling at the synapse through high affinity reuptake of dopamine into presynaptic terminals, thereby controlling the spatial and temporal dynamics of dopaminergic neurotransmission . Dopamine transporter (DAT) dysregulation, resulting in aberrant dopamine clearance, has long been suggested to result in dopaminergic dysfunction, as well as having a role in the pathophysiology of substance addictions …”

Exercise as a Sex-Specific Treatment for Substance Use Disorder

“…For example, recent findings in humans show that modest levels of aerobic exercise during treatment reversed methamphetamine-induced deficits in striatal D2/D3 receptors (78). This finding is significant considering that deficits in D2/D3 receptors can persist even after months/years of abstinence, and are believed to underlie vulnerability to relapse in both men and women (79). Wheel running during abstinence also blocked the incubation of methamphetamine-craving and normalized associated increases in periaqueductal gray dopamine neurons (52), which project to the VTA (80).…”

Exercise as a Prevention for Substance Use Disorder: a Review of Sex Differences and Neurobiological Mechanisms

“…Inactivation of this pathway decreases drug self-administration (e.g., 55), with recent findings demonstrating that such manipulations similarly disrupt wheel running in males and females (56). Several markers of mesolimbic dopaminergic signaling predict sensitivity to drug reinforcement (enhanced D1/reduced D2 signaling in NAc; 57), and recent findings indicate that such markers are also predictive of wheel running activity in males and females (excitatory/inhibitory dopamine mRNA expression in the NAc; 58). Dopamine signaling in the NAc, in particular, is critical for mediating the reinforcing effects of drugs of abuse and exercise (52–53).…”