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Differential response of cortical-limbic neuropotentiated compulsive mice to dopamine D1 and D2 receptor antagonists
K M Campbell1, M J McGrath, F H Burton
1Department of Pharmacology, University of Minnesota, Minneapolis 55455, USA.
Abstract:
We previously created transgenic mice in which dopamine D1 receptor-expressing (D1+) neurons in regional subsets of the cortex and amygdala express a neuropotentiating cholera toxin (CT) transgene. These 'D1CT' mice engage in complex biting, locomotor and behavioral perseverance-repetition abnormalities that resemble symptoms of human compulsive disorders associated with cortical-limbic hyperactivity. Because excessive cortical-limbic stimulation of striatal motor pathways may play a critical role in causing compulsive disorders, we examined the responsiveness of D1CT mice to dopamine D1 and D2 receptor antagonists. D1CT mice were found to be largely resistant to the cataleptic action of the D1 receptor antagonist SCH23390. The abnormal repetitive leaping of D1CT mice was similarly unaffected by SCH23390. In contrast, the D1CT mice displayed supersensitivity to cataleptic induction by the D2 receptor antagonist sulpiride. These data are consistent with the hypothesis that complex compulsions are mediated by chronic excessive corticostriatal (and/or amygdalostriatal) glutamatergic stimulation of the striatal direct and indirect motor pathways.
Insights
Transgenic mice with enhanced dopamine D1 receptor activity exhibited compulsive behaviors. These mice showed resistance to D1 antagonists but heightened sensitivity to D2 antagonists, suggesting a role for dopamine pathways in compulsive disorders.
Area of Science:
- Neuroscience
- Behavioral Neuroscience
- Molecular Psychiatry
Background:
- Compulsive disorders are linked to hyperactivity in cortical-limbic circuits.
- Dopamine D1 receptor-expressing neurons in the cortex and amygdala are implicated in these behaviors.
- Transgenic D1CT mice model compulsive disorders through specific neural alterations.
Purpose of the Study:
- To investigate the role of dopamine D1 and D2 receptors in the compulsive behaviors of D1CT mice.
- To examine the effects of dopamine receptor antagonists on D1CT mouse behavior.
- To test the hypothesis linking corticostriatal glutamatergic stimulation to compulsive disorders.
Main Methods:
- Creation of D1CT transgenic mice with a cholera toxin (CT) transgene in dopamine D1 receptor-expressing neurons.
- Administration of dopamine D1 receptor antagonist (SCH23390) and D2 receptor antagonist (sulpiride).
- Assessment of cataleptic effects and abnormal repetitive behaviors (leaping, biting) in response to antagonists.
Main Results:
- D1CT mice were resistant to the cataleptic effects of SCH23390.
- Abnormal repetitive behaviors in D1CT mice were not affected by SCH23390.
- D1CT mice showed supersensitivity to catalepsy induced by the D2 antagonist sulpiride.
Conclusions:
- The findings support the hypothesis that compulsive disorders involve excessive corticostriatal glutamatergic stimulation.
- Dopamine D2 receptor pathways appear critical in modulating the compulsive behaviors observed in D1CT mice.
- These results offer insights into the neurobiological mechanisms underlying human compulsive disorders.