Dopamine D2 Receptors in Dopaminergic Neurons Modulate Performance in a Reversal Learning Task in Mice

Neuroimaging studies in animal models and human subjects have each revealed that relatively low striatal dopamine D2-like receptor binding potential is associated with poor impulse control and with vulnerability for addiction-related behaviors. These studies cannot, however, disambiguate the roles for various pools of D2 receptors found in the striatum (e.g., those expressed on medium spiny striato-pallidal neurons vs on dopamine-releasing nerve terminals) in these behavioral outcomes. To clarify the role of the latter pool, namely, D2 autoreceptors, we studied mice carrying a conditional DRD2 gene, with or without Cre-recombinase expressed under the transcriptional control of the dopamine transporter gene locus (autoDrd2-KO, n = 19 and controls, n = 21). These mice were tested for locomotor response to cocaine, and spatial reversal learning was assessed in operant conditioning chambers. As predicted, compared to control mice, autoDrd2-KO animals demonstrated heightened sensitivity to the locomotor stimulating effect of cocaine (10 mg/kg, i.p.), confirming previous research using a similar genetic model. In the spatial reversal learning task, autoDrd2-KO mice were slower to reach a learning criterion and had difficulty sustaining a prolonged nose poke response, measurements conceptually related to impaired response inhibition. Rate of learning of the initial discrimination and latencies to collect rewards, to initiate trials and to produce a response were unaffected by genetic deletion of D2 autoreceptors, discarding possible motor and motivational factors. Together, these findings confirm the role of D2 autoreceptors in reversal learning and suggest a broader involvement in behavioral inhibition mechanisms.