Pathway-specific modulation of nucleus accumbens in reward and aversive behavior via selective transmitter receptors

摘要

The basal ganglia-thalamocortical circuitry plays a central role in selecting actions that achieve reward-seeking outcomes and avoid aversive ones. Inputs of the nucleus accumbens (NAc) in this circuitry are transmitted through two parallel pathways: the striatonigral direct pathway and the striatopallidal indirect pathway. In the NAc, dopaminergic (DA) modulation of the direct and the indirect pathways is critical in reward-based and aversive learning and cocaine addiction. To explore how DA modulation regulates the associative learning behavior, we developed an asymmetric reversible neurotransmission-blocking technique in which transmission of each pathway was unilaterally blocked by transmission-blocking tetanus toxin and the transmission on the intact side was pharmacologically manipulated by local infusion of a receptor-specific agonist or antagonist. This approach revealed that the activation of D1 receptors and the inactivation of D2 receptors postsynaptically control reward learning/cocaine addiction and aversive learning in a direct pathway-specific and indirect pathway-specific manner, respectively. Furthermore, this study demonstrated that aversive learning is elicited by elaborate actions of NMDA receptors, adeno-sine A2a receptors, and endocannabinoid CB1 receptors, which serve as key neurotransmitter receptors in inducing long-term po-tentiation in the indirect pathway. Thus, reward and aversive learning is regulated by pathway-specific neural plasticity via selective transmitter receptors in the NAc circuit.