Prefrontal Dopamine D ₁ and D ₂ Receptors Regulate Dissociable Aspects of Decision Making via Distinct Ventral Striatal and Amygdalar Circuits

Mesocortical dopamine (DA) regulates a variety of cognitive functions via actions on D1 and/or D2 receptors. For example, risk/reward decision making is modulated differentially by these two receptors within the prefrontal cortex (PFC), with D2 receptors enabling flexible decision making and D1 receptors promoting persistence in choice biases. However, it is unclear how DA mediates opposing patterns of behavior by acting on different receptors within the same terminal region. We explored the possibility that DA may act on separate networks of PFC neurons that are modulated by D1 or D2 receptors and in turn interface with divergent downstream structures such as the basolateral amygdala (BLA) or nucleus accumbens (NAc). Decision making was assessed using a probabilistic discounting task in which well trained male rats chose between small/certain or large/risky rewards, with the odds of obtaining the larger reward changing systematically within a session. Selective disruption of D1 or D2 modulation of separate PFC output pathways was achieved using unilateral intra-PFC infusions of DA antagonists combined with contralateral inactivation of the BLA or NAc. Disrupting D2 (but not D1) modulation of PFC→BLA circuitry impaired adjustments in decision biases in response to changes in reward probabilities. In contrast, disrupting D1 modulation of PFC→NAc networks reduced risky choice, attenuating reward sensitivity and increasing sensitivity to reward omissions. These findings reveal that mesocortical DA can facilitate dissociable components of reward seeking and action selection by acting on different functional networks of PFC neurons that can be distinguished by the subcortical projection targets with which they interface. SIGNIFICANCE STATEMENT Prefrontal cortical dopamine regulates a variety of executive functions governed by the frontal lobes via actions on D1 and D2 receptors. These receptors can in some instances mediate different patterns of behavior, but the mechanisms underlying these dissociable actions are unclear. Using a selective disconnection approach, we reveal that D1 and D2 receptors can facilitate diverse aspects of decision making by acting on separate networks of prefrontal neurons that interface with distinct striatal or amygdalar targets. These findings reveal an additional level of complexity in how mesocortical DA regulates different forms of cognition via actions on different receptors, highlighting how it may act upon distinct cortical microcircuits to drive different patterns of behavior.

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