Stimulation of Adenosine A1 Receptors in the Nucleus Accumbens Reduces Dopamine D1 Receptor-Induced Reinstatement of Cocaine Seeking by Antagonizing D1-Mediated Enhancements in Glutamate Transmission

Cocaine is a psychostimulant that can lead to dependence following continuous use, resulting in an addiction that negatively affects the individual’s physical, mental, and social health. The continuous potential for relapse in addicts makes treatment of cocaine addiction especially difficult. These studies seek to understand the neurobiological factors contributing to relapse using a rodent model of addiction. Stimulation of either AMPA glutamate or dopamine D₁ receptors in the nucleus accumbens (NAc) is sufficient to induce reinstatement of cocaine seeking.  Identifying strategies to reduce the activity of these systems may provide insight into effective treatments. Adenosine A₁ receptors co-localize with D₁ receptors on post-synaptic terminals of medium spiny (NAc) neurons where they counteract D₁ receptor activity through opposing intracellular signaling. 

Here, we investigate the interaction between dopamine and glutamate receptors and explore how A₁ receptor stimulation in the NAc may reduce D₁-induced facilitation of AMPA receptors and cocaine seeking.  Specifically, we investigate the role of AMPA receptors in D₁-induced reinstatement using viral-mediated gene transfer to bi-directionally modulate AMPA receptor activity in the NAc. We also determined whether stimulating A₁ receptors in the NAc would inhibit D₁-induced reinstatement and GluA1^S845 phosphorylation using a synaptoneurosome prep and subsequent western blot analysis.  Our results demonstrate that stimulation of A₁ receptors decreases D₁-induced cocaine seeking as well as GluR1^S845 phosphorylation.  These findings suggest that A₁ receptor stimulation reduces the activity dependent AMPA receptor trafficking that drives D₁ receptor-mediated reinstatement.