Striatopallidal adenosine A2A receptors in the nucleus accumbens confer motivational control of goal-directed behavior

Abstract

The ability to learn the reward-value and action-outcome contingencies in dynamic environment is critical for flexible adaptive behavior and development of effective pharmacological control of goal-directed behaviors represents an important challenge for improving the deficits in goal-directed behavior which may underlie seemingly disparate symptoms across psychiatric disorders. Adenosine A_2A receptor (A_2AR) is emerging as a novel neuromodulatory target for controlling goal-directed behavior for its unique neuromodulatory features: the ability to integrate dopamine and glutamate signaling, the "brake" constraint of various cognitive processes and the balanced control of goal-directed and habit actions. However, the contribution and circuit mechanisms of the striatopallidal A_2ARs in nucleus accumbens (NAc) to control of goal-directed behavior remain to be determined. Here, we employed newly developed opto-A_2AR and the focal A_2AR knockdown strategies to demonstrate the causal role of NAc A_2AR in control of goal-directed behavior. Furthermore, we dissected out multiple distinct behavioral mechanisms underlying which NAc A_2ARs control goal-directed behavior: (i) NAc A_2ARs preferentially control goal-directed behavior at the expense of habit formation. (ii) NAc A_2ARs modify the animals' sensitivity to the value of the reward without affecting the action-outcome contingency. (iii) A_2AR antagonist KW6002 promotes instrumental actions by invigorating motivation. (iv) NAc A_2ARs facilitate Pavlovian incentive value transferring to instrumental action. (v) NAc A_2ARs control goal-directed behavior probably not through NAc-VP pathway. These insights into the behavioral and circuit mechanisms for NAc A_2AR control of goal-directed behavior facilitate translational potential for A_2AR antagonists in reversal of deficits in goal-directed decision-making associated with multiple neuropsychiatric disorders.

Keywords: Adenosine A(2A) receptors; Goal-directed behavior; Instrumental learning; Motivation; Nucleus accumbens; Pavlovian–instrumental transfer.