Adolescent Risk Taking, Cocaine Self-Administration, and Striatal Dopamine Signaling

Abstract

Poor decision making and elevated risk taking, particularly during adolescence, have been strongly linked to drug use; however the causal relationships among these factors are not well understood. To address these relationships, a rat model (the Risky Decision-making Task; RDT) was used to determine whether individual differences in risk taking during adolescence predict later propensity for cocaine selfadministration and/or whether cocaine self-administration causes alterations in risk taking. In addition, the RDT was used to determine how risk taking is modulated by dopamine signaling, particularly in the striatum. Results from these experiments indicated that greater risk taking during adolescence predicted greater intake of cocaine during acquisition of self-administration in adulthood, and that adult cocaine self-administration in turn caused elevated risk taking that was present following 6 weeks of abstinence. Greater adolescent risk taking was associated with lower striatal D2 receptor mRNA expression, and pharmacological activation of D2/3 receptors in the ventral, but not dorsal, striatum induced a decrease in risk taking. These findings indicate that the relationship between elevated risk taking and cocaine self-administration is bi-directional, and that low striatal D2 receptor expression may represent a predisposing factor for both maladaptive decision making and cocaine use. Furthermore, these findings suggest that striatal D2 receptors represent a therapeutic target for attenuating maladaptive decision making when choices include risk of adverse consequences. Neuropsychopharmacology (2014) 39, 955-962;

Neural mechanisms regulating different forms of risk-related decision-making: Insights from animal models

“…After 20-25 training sessions, rats on average prefer the large reward when the risk of accompanying shock is low, but shift their choices to the small, safe reward as the risk of shock increases. expression of D2 receptor messenger RNA (mRNA) in the striatum as assessed with in situ hybridization (which likely reflects post-synaptic receptors) is inversely related to risk-taking, such that greater preference for the large, risky reward is associated with lower D2 receptor mRNA expression (Simon et al, 2011;Mitchell et al, 2014). These mRNA data are consistent with the systemic behavioral pharmacological data (D2-like receptor activation reducing choice of the large reward associated with a potential footshock), and their functional significance is supported by the findings that direct administration of a D2-like agonist (quinpirole) into NAc reduces choice of the large, risky reward (Mitchell et al, 2014).…”

“…It should be noted, however, that the type of aversive outcome (reward omission vs. punishment) is likely not the sole determinant of the effects of dopaminergic manipulations on risky decision-making. For example, whereas D2-like agonist administration into NAc decreases choice of large, risky rewards in the RDT (Mitchell et al, 2014), this same manipulation has no effect in the probabilistic discounting task (Stopper et al, 2013). Moreover, research from several laboratories employing rodent versions of the Iowa Gambling Task, in which the risky, aversive outcome is a timeout period during which rewards cannot be earned, shows that systemic amphetamine administration reduces preference for risky in favor of safer options, which is similar to its effects in the RDT (Zeeb et al, 2009;van Enkhuizen et al, 2013).…”

Age and sex differences in behavioral flexibility, sensitivity to reward value, and risky decision-making

“…Notably, adult rats that self-administer psychostimulants have been shown to have deficits in reward processing (Green, Dykstra, & Carelli, 2015), impaired behavioral flexibility (Cox et al, 2016), and increased risk taking (Mitchell et al, 2013). An alternative approach that avoids these potentially confounding drug effects on behavior is to substitute non-drug reinforcers in the analysis of potential age effects.…”

Insular neural system controls decision-making in healthy and methamphetamine-treated rats

“…By contrast, the ventral striatal signal changes dynamically over time, dependent on the phase of the reward process and on learning status, and thereby acts as a motivational engine for the continuation of behavior (25,26). Recent studies have suggested that ventral striatal dopamine D2 receptor expression is associated with risky decision-making (13,27). Accordingly, further studies are warranted to clarify the contribution of dopaminergic neurons, as well as the striatal direct and indirect efferent pathways (28), to the altered arm choice strategy in METH-treated rats.…”

“…For example, Mitchell et al (27) used a rat model of a risky decisionmaking task and cocaine self-administration to demonstrate that the relationship between elevated risk-taking and cocaine selfadministration is bidirectional and that low striatal dopamine D2 receptor expression may predispose subjects to both maladaptive decision-making and cocaine use. We believe that our findings provide some insights into alterations of decision-making following overexposure to METH that have some relevance to the related condition in humans who misuse METH.…”