D2 Dopamine Receptor Mediation of Risky Decision-making

Abstract

Excessive risk-taking is a characteristic of several psychopathological disorders. In order to alleviate maladaptive risky behavior, a thorough understanding of the neurobiological and pharmacological substrates of risky choice must be developed. In this dissertation, the “risky decision-making task” was utilized to explore the mechanisms by which dopamine mediates risky choice. In experiment 1, we characterized rats in risky decision-making as well as a variety of other behavioral traits. This was performed to determine if the behavioral patterns obtained in the risky decision-making task represent an independent cognitive construct rather than a function of a separate behavioral trait. Risky decision-making performance was not correlated with measures of motivation, anxiety, pain tolerance, or other types of decision-making. In contrast, risky choice was correlated with impulsive action as assessed by the Differential Rates of Low Responding Task, suggesting that risky choice may be mechanistically similar to impulsive action. In experiment 2, the effects of various dopaminergic drugs on risky decision-making was investigated. Amphetamine administration attenuated risky choice, while the dopamine antagonist α-flupenthixol had no effect on risky choice. Agonists and antagonists specific to D1 dopamine receptors had no effects on risky choice; however, the D2 dopamine receptor agonist bromocriptine reduced risky choice in a manner similar to amphetamine. Furthermore, coadministration of amphetamine with a D2 antagonist abolished amphetamine’s effects on risky choice, and amphetamine’s effects were unaffected by coadministration of a D1 antagonist. These data suggest that D2 signaling at the receptor is particularly critical to risky decision-making behavior. In experiment 3, D2 dopamine receptor mRNA abundance was assessed in rats that had been previously characterized in risky decision-making using in situ hybridization. Levels of D2 cRNA hybridization in both orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC) predicted risky decision-making behavior as assessed by nonlinear curve estimation analyses. Interestingly, opposite relationships between D2 mRNA abundance and risky choice were observed in these two cortical areas, with OFC D2 mRNA abundance showing a U-shaped relationship with risky choice, and mPFC D2 mRNA resembling an inverted U-curve. Additionally, increased levels of D2 mRNA in dorsal striatum were observed in risk-averse rats in comparison to risk-taking rats. In conclusion, these data suggest that signaling via D2 dopamine receptors is an important mediator of risky decision-making behavior, and that D2 signaling in frontostriatal circuitry may be particularly relevant toward these behaviors.