Low Dopamine D2/D3 Receptor Availability is Associated with Steep Discounting of Delayed Rewards in Methamphetamine Dependence

Abstract

Background:Individuals with substance use disorders typically exhibit a predilection toward instant gratification with apparent disregard for the future consequences of their actions. Indirect evidence suggests that low dopamine D2-type receptor availability in the striatum contributes to the propensity of these individuals to sacrifice long-term goals for short-term gain; however, this possibility has not been tested directly. We investigated whether striatal D2/D3 receptor availability is negatively correlated with the preference for smaller, more immediate rewards over larger, delayed alternatives among research participants who met DSM-IV criteria for methamphetamine (MA) dependence.Methods:Fifty-four adults (n = 27 each: MA-dependent, non-user controls) completed the Kirby Monetary Choice Questionnaire, and underwent positron emission tomography scanning with [18F]fallypride.Results:MA users displayed steeper temporal discounting (p = 0.030) and lower striatal D2/D3 receptor availability (p < 0.0005) than controls. Discount rate was negatively correlated with striatal D2/D3 receptor availability, with the relationship reaching statistical significance in the combined sample (r = -0.291, p = 0.016) and among MA users alone (r = -0.342, p = 0.041), but not among controls alone (r = -0.179, p = 0.185); the slopes did not differ significantly between MA users and controls (p = 0.5).Conclusions:These results provide the first direct evidence of a link between deficient D2/D3 receptor availability and steep temporal discounting. This finding fits with reports that low striatal D2/D3 receptor availability is associated with a higher risk of relapse among stimulant users, and may help to explain why some individuals choose to continue using drugs despite knowledge of their eventual negative consequences. Future research directions and therapeutic implications are discussed.

Modulation of impulsivity and reward sensitivity in intertemporal choice by striatal and midbrain dopamine synthesis in healthy adults

“…First, in adult men with ADHD with or without cocaine dependence, the degree to which methylphenidate increased DA signaling in the putamen predicted the drug's ability to decrease Now bias (Crunelle et al 2013). Second, in a mixed population of control subjects and people with methamphetamine dependence, which included adults up to age 51 yr (the majority of whom were smokers), DA D 2 /D 3 receptor binding in the whole striatum was inversely related to Now bias (Ballard et al 2015). In examining striatal subdivisions, among the methamphetaminedependent participants the putamen was the only subdivision that showed this relationship after accounting for effects of age.…”

“…Two more recent reports from primarily clinical samples also support a role for lower subcortical DA being associated with increased Now bias (Ballard et al 2015;Joutsa et al 2015), although neither study included substantial numbers of healthy nonsmoking young adults. Notably, the degree to which COMT inhibition decreases synchrony between the putamen and the pregenual anterior cingulate cortex (pgACC) during Now/Later choices predicts how much COMT inhibition decreases Now bias (Kayser et al 2012).…”

Effect of Exercise Training on Striatal Dopamine D2/D3 Receptors in Methamphetamine Users during Behavioral Treatment

“…A deficit in striatal D2/D3 dopamine receptor binding is a common feature across substance use disorders (Bonci et al, 2013;Broft and Martinez, 2012). In stimulant dependence, this deficit is linked to treatment success rates (Martinez et al, 2011;Wang et al, 2012) and measures of impulsivity (Lee et al, 2009) and decision making (Ballard et al, 2015). Although these observations suggest that augmenting signaling at D2/D3 receptors may be an effective therapeutic target in substance use disorders, dopamine agonist therapy has shown limited success in improving treatment outcomes for stimulant dependence (Ling et al, 2006).…”

“…In recently abstinent methamphetamine-dependent individuals (4-7 days), D2/D3 receptor availability is negatively associated with self-reported impulsivity (Lee et al, 2009), discounting of delayed rewards (Ballard et al, 2015), and caloric intake, suggesting that food is used as a substitute reinforcer in a reward deficiency syndrome (Zorick et al, 2012). Moreover, D2/D3 receptor availability and even more so function of the striatal element, as inferred from dopamine release, was positively associated with treatment outcomes for methamphetamine use disorder (Wang et al, 2012).…”

Cannabis use by women during pregnancy does not influence infant DNA methylation of the dopamine receptor DRD4

“…Prenatal cannabis exposure has been associated with decreased dopamine receptor D2 expression in human fetal brain specimens (30). Dopamine receptor deficiency has been linked to increased choice and immediacy to use drugs, and is observed in people with substance use disorders (31). DRD4 , a D2-like dopamine receptor, was chosen as a strong candidate gene in this study due to its key role in dopamine signaling, and its links to drug use in genetic association studies.…”