Methylphenidate-induced gene expression in the cortex

Rosalind Franklin Univ Of Medicine &Sci, North Chicago IL

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Abstract

DESCRIPTION (provided by applicant): Interactions between the basal ganglia and cortex are critical for normal goal-directed behavior. Dopamine in the striatum regulates these interactions. Deficiencies in striatal dopamine function are associated with neuropathologies such as schizophrenia, Parkinson's Disease, and drug addiction. Psychostimulants, including methylphenidate, are widely used in the treatment of Attention Deficit Hyperactivity Disorder, but are also increasingly abused for recreational purposes. Methylphenidate increases extracellular levels of dopamine in the striatum, an effect implicated in its abuse liability. Recent studies have demonstrated that methylphenidate treatment alters gene expression in striatal output neurons in a manner similar to the psychostimulant cocaine. Such molecular changes seem to preferentially occur in the D1 dopamine receptor-regulated "direct" striatal output pathway. Our preliminary experiments show that methylphenidate treatment affects striatal and cortical immediate-early gene (lEG) expression. The proposed research will test the hypothesis that stimulation of striatal D1 receptors contributes to methylphenidate-induced lEG expression in the cortex. This hypothesis will be tested by using intrastriatal infusion of a D1 receptor antagonist. These studies will further our understanding of methylphenidate effects on gene regulation.