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Patterns of gene expression and behavior induced by chronic dopamine treatments
1Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA.
Abstract:
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.
Insights
Long-term dopaminergic drug use causes lasting gene and behavior changes. These adaptations in brain pathways may disrupt motor control and coordination.
Area of Science:
- Neuroscience
- Neuropharmacology
- Molecular Biology
Background:
- Chronic dopaminergic drug administration induces persistent alterations in gene regulation and behavior.
- Disruptions in motor action sequencing and coordination following dopaminergic treatment suggest shared neurobiological underpinnings.
Purpose of the Study:
- To investigate the neurobiological mechanisms underlying long-lasting behavioral changes induced by dopaminergic drugs.
- To correlate persistent gene induction in the striatum with specific motor disruptions.
Main Methods:
- Examined gene induction, specifically immediate-early genes, in the striatum following chronic dopaminergic drug administration.
- Assessed motor stereotypies induced by dopamine receptor agonists and psychostimulant sensitization.
- Investigated progressive dyskinesias after intermittent dopamine agonist treatment in dopamine-depleted animals.
Main Results:
- Correlated motor stereotypies, psychostimulant sensitization, and dyskinesias with persistent changes in striatal gene induction.
- Observed enhanced autoregulatory activity in the striosomal pathway and disinhibitory activity in the direct output pathway.
- Identified these gene induction changes as persistent.
Conclusions:
- Hypothesize that long-term pathway modifications lead to persistent adaptations in basal ganglia-cortex motor loops.
- Conclude that these adaptations may cause long-lasting disruptions in motor behavior timing and segmentation.
- Suggest a neurobiological basis for motor control deficits associated with chronic dopaminergic stimulation.