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UBC Theses and Dissertations

Characterization and manipulation of prefrontal cortex D2 dopamine receptors in the rat Alexander John, MacLennan


A radioligand binding assay was developed to measure possible D2 dopamine receptors in the medial prefrontal cortex (mpfc) of the rat. It was demonstrated with competition studies at pH 7.9 that these candidate sites are, in fact, D2 receptors. All compounds without activity on dopaminergic systems were ineffective competitors at nanomolar concentrations. Dopamine was more potent than noradrenaline which was more potent than serotonin. At nanomolar concentrations, all dopamine receptor antagonists that were tested competed for the D2 binding. The IC50's of the dopamine receptor antagonists correlated with their in vivo potencies. The IC50's of all compounds tested with mpfc tissue correlated highly with their IC50's in an identical assay of the striatum. However, the dopamine receptor agonists, apomorphine and ADTN, were significantly more potent in the mpfc. The competition curves of the dopamine receptor agonists suggested that the mpfc, when compared to the striatum, contains a higher proportion of receptors with a high affinity for dopamine receptor agonists. Reducing the pH of the assay from pH 7.9 to pH 6.2 eliminated the difference in agonist affinity but did not affect the IC50 correlations between brain regions or the correlations with in vivo potencies. The reduction in pH increased the percent of D2 binding in the mpfc assay by presumably reducing spirodecanone binding. Consequently the pH 6.2 assay displayed a higher sensitivity to changes in D2 binding. Chronic haloperidol administration for 21 weeks increased the D2 binding in the mpfc (as measured at pH 6.2) by approximately 50% compared to approximately 70% in the striatum. Footshock stress increased the D2 binding measured at pH 6.2 by approximately 13% in the mpfc and had no effect in the striatum. Footshock stress increased the Bmax of the D2 binding measured at pH 7.9 by approximately 100% in the mpfc and reduced the affinity by approximately 70%. The striatal D2 binding was unaffected by footshock stress as measured at pH 7.9.

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