Pharmacological treatment of repetitive behavior using the deer mouse model: targeting adenosine, dopamine, and glutamate heteromeric receptor complexes

Abstract

Event Abstract Back to Event Pharmacological treatment of repetitive behavior using the deer mouse model: targeting adenosine, dopamine, and glutamate heteromeric receptor complexes Amber M. Van Matre1* and Mark H. Lewis2 1 University of Florida, Department of Psychology, United States 2 University of Florida, Department of Psychiatry, United States Repetitive, stereotypic behaviors are extremely common in neurodevelopmental disorders. The deer mouse (Peromyscus maniculatus) model of this repetitive behavior is a particularly valid model because the stereotypy is spontaneously expressed (i.e. not induced by drugs, neuronal, or genetic insults). Preliminary evidence from our laboratory indicates that stereotypy is a result of a neurobiological imbalance of activation between the direct and indirect pathways of the basal ganglia [1,2]. This imbalance seems to be caused by decreased activation of the indirect pathway that allows direct pathway activation to over-excite the cortex. On neurons of the direct and indirect pathways there are heteromeric complexes of receptors that exhibit antagonistic relationships [3-6]. These receptor complexes include dopamine D1 and adenosine A1 receptors on direct pathway neurons and dopamine D2, adenosine A2A, and glutamate mGluR5 receptors on indirect pathway neurons. In this study we evaluated the efficacy of drugs that affect the heteromeric receptor complexes on the indirect pathway neurons to reduce repetitive behavior in deer mice. We examined the effects of an adenosine A2A agonist (CGS21680), a dopamine D2 antagonist (L-741,626), and a glutamate mGluR5 positive allosteric modulator (PAM; CDPPB) individually and in combination. Our data suggest that when administered individually the adenosine A2A agonist, the dopamine D2 antagonist, and the glutamate mGluR5 PAM do not significantly reduce stereotypy in deer mice. However, when co-administered, the adenosine A2A agonist and the dopamine D2 antagonist are effective at significantly decreasing the rate of stereotypy in deer mice. We are currently evaluating whether the addition of the glutamate mGluR5 PAM will further reduce stereotypy. In addition, we will explore whether the cell surface expression of these three receptor types differ between high and low stereotypy deer mice. We continue to explore the hypothesis that drug cocktails will be more effective than any of the treatments individually because of the nature of the heteromeric receptor complex. Our data suggest that targeting these receptor complexes may offer pharmacotherapeutic benefit for individuals with neurodevelopmental disorders who exhibit restrictive repetitive behavior.