Prefrontal cortical–striatal dopamine receptor mRNA expression predicts distinct forms of impulsivity

Abstract

Variation in dopamine receptor levels has been associated with different facets of impulsivity. To further delineate the neural substrates underlying impulsive action (inability to withhold a prepotent motor response) and impulsive choice (delay aversion), we characterised rats in the Differential Reinforcement of Low Rates of Responding task and a delay discounting task. We also measured performance on an effort-based discounting task. We then assessed D1 and D2 dopamine receptor mRNA expression in subregions of the prefrontal cortex and nucleus accumbens using in situ hybridisation, and compared these data with behavioral performance. Expression of D1 and D2 receptor mRNA in distinct brain regions was predictive of impulsive action. A dissociation within the nucleus accumbens was observed between subregions and receptor subtypes; higher D1 mRNA expression in the shell predicted greater impulsive action, whereas lower D2 mRNA expression in the core predicted greater impulsive action. We also observed a negative correlation between impulsive action and D2 mRNA expression in the prelimbic cortex. Interestingly, a similar relationship was present between impulsive choice and prelimbic cortex D2 mRNA, despite the fact that behavioral indices of impulsive action and impulsive choice were uncorrelated. Finally, we found that both high D1 mRNA expression in the insular cortex and low D2 mRNA expression in the infralimbic cortex were associated with willingness to exert effort for rewards. Notably, dopamine receptor mRNA in these regions was not associated with either facet of impulsivity. The data presented here provide novel molecular and neuroanatomical distinctions between different forms of impulsivity, as well as effort-based decision-making.

Individual Differences in Impulsive Action Reflect Variation in the Cortical Serotonin 5-HT2A Receptor System

“…Individual differences in impulsive action have now been associated with expression patterns of the dopamine D 1 receptor (Simon et al, 2013), D 2/3 receptor (Besson et al, 2013;Dalley et al, 2007;Simon et al, 2013), γ-aminobutyric acid (GABA), and dendritic markers (Caprioli et al, 2014) in the nucleus accumbens as well as the 5-HT 2A R (present results) and the 5-HT 2C R in mPFC ). The precise manner in which these systems coordinate at the level of the neuron and/or circuit remains poorly understood, and it is parsimonious to suggest that these neurobiological factors interact to fine-tune behavioral control afforded by the corticostriatal network (Jupp et al, 2013).…”

“…Given that the constitutive knockout of the 5-HT 2A R results in upregulation of 5-HT 2C R control over the excitability of mPFC neurons (Beique et al, 2007), these data suggest that a 5-HT 2A R/5-HT 2C R interaction at the level of the mPFC may rheostatically control impulsive action (Cunningham and Anastasio, 2014). Future studies will be required to intuit the coordinated serotonergic, dopaminergic, and GABAergic control of the corticostriatal circuitry that contributes to phenotypic impulsive action (Besson et al, 2013;Caprioli et al, 2014;Dalley et al, 2007;Jupp et al, 2013;Simon et al, 2013).…”

Affective and cognitive mechanisms of risky decision making

“…In support of such differences, available data regarding the neural basis of performance on the two tasks suggest both overlapping and distinct neural mechanisms. For example, although damage to the basolateral nucleus of the amygdala causes an increase in both risky and impulsive decision making (Orsini, Trotta, Bizon, & Setlow, submitted; Winstanley, Theobald, Cardinal, & Robbins, 2004), expression of D2 receptor mRNA in the striatum is inversely related to risky decision making, but appears to be unrelated to impulsive decision making (Loos et al, 2010; Mitchell, et al, 2014; Simon et al, 2013; Simon, et al, 2011). In light of these differences, a likely account for the fact that risky and impulsive decision making covary in neuropsychiatric conditions is that mechanisms common to both are altered (e.g., computations of outcome value).…”

Recent Insights into the Neurobiology of Impulsivity

“…Administration of d-amphetamine, which influences dopaminergic and noradrenergic function, may increase response impulsivity in rodents [63, 64]. D2-like receptor agonism has been reported to reduce response impulsivity in rats during the 5CSRTT [65], regardless of preexisting high or low impulsivity levels.…”