The major focus of the proposed experiments is to provide a systematic analysis of the interaction of D-1 and D-2 receptor stimulation in striatum and nucleus accumbens. These methods will be applied to define the activity of the atypical neuroleptic clozapine in all cases. Experiments utilizing in vivo and in vitro preparations will be run in parallel and direct comparison between the two will be made using null pharmacological models. In vitro preparations include DA-modulated efflux of cyclic AMP from striatal and accumbens slices. In vivo measurements include stereotypic behavior and locomotor activity. Three major experiments will be conducted corresponding to three null models. a) An analysis of competitive antagonis, will be made and estimates of effective in vivo and in vitro dissociation constants derived using non-linear least-squares analysis. b) The effect of both increases and decreases in receptor number will be analyzed using the null model for receptor occlusion. This experiment will provide estimates of effective dissociation constants for DSA agonists and allow evaluation of the degree to which alteration in receptor density accounts for observed changes in dose-response curves in the in vivo and in vitro preparations. c) The interaction between D-1 and D-2 receptor stimuation will be tested directly using the null pharmacological model for functional interaction. Dose-response curves for D-1 agonists in the presence of different concentrations of D-2 agonists will be obtained in the behavioral and the striatal cAMP efflux. Analysis of the null model will describe the type of interaction involved and provide estimates of functional affinity constants for the D-1 and D-2 receptors.
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| Mayfield, R D; Randall, P K; Spirduso, W W et al. (1993) Selective D1 and D2 dopamine receptor antagonists produce differential effects on reaction time in the rat. Pharmacol Biochem Behav 46:759-68 |
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