Patterns of gene expression and behavior induced by chronic dopamine treatments

Chronic administration of drugs that increase dopaminergic neurotransmissio n produces long-lasting changes in gene regulation and behavior. Evidence s uggests that several conditions in which the serial ordering and coordinati on of motor actions are disrupted following dopaminergic treatment share co mmon underlying neurobiological mechanisms. The induction of high-intensity motor stereotypies by dopamine D1- and D2-class receptor agonists, the sen sitized behavioral responsiveness to psychostimulant drugs in normal animal s, and the progressive sensitization of dyskinesias after intermittent trea tment with dopamine agonists following dopamine depletion are all correlate d with persistent changes in gene induction in the striatum. These changes, as measured by the induction of immediate-early genes, consist of a relati ve enhancement in the autoregulatory activity of the striosomal pathway and the disinhibitory activity of the direct output pathway. We hypothesize th at long-term modifications in the activity of these pathways result in pers istent adaptations in striatum-centered motor loops linking the basal gangl ia and cortex, as well as long-lasting disruption of the timing and segment ation of motor behavior.