Patterns of gene expression and behavior induced by chronic dopamine treatments.

Chronic administration of drugs that increase dopaminergic neurotransmission produces long-lasting changes in gene regulation and behavior. Evidence suggests that several conditions in which the serial ordering and coordination of motor actions are disrupted following dopaminergic treatment share common underlying neurobiological mechanisms. The induction of high-intensity motor stereotypies by dopamine D1- and D2-class receptor agonists, the sensitized behavioral responsiveness to psychostimulant drugs in normal animals, and the progressive sensitization of dyskinesias after intermittent treatment with dopamine agonists following dopamine depletion are all correlated with persistent changes in gene induction in the striatum. These changes, as measured by the induction of immediate-early genes, consist of a relative enhancement in the autoregulatory activity of the striosomal pathway and the disinhibitory activity of the direct output pathway. We hypothesize that long-term modifications in the activity of these pathways result in persistent adaptations in striatum-centered motor loops linking the basal ganglia and cortex, as well as long-lasting disruption of the timing and segmentation of motor behavior.