Certain symptoms of schizophrenia appear to be associated with abnormalities in central nervous system dopamine transmission. Based on in vitro brain homogenate studies, there are at least two subclasses of brain dopamine receptors, D1 and D2. In vivo receptor binding studies have demonstrated pharmacologically separable D1 and D2 sites in rat striatum with kinetic properties different from those measured in vitro. A major finding of in vitro ligand-receptor assays is the development of increased ligand binding following denervation, produced either by anatomical lesions or chronic pharmacological blockade with neuroleptics. This phenomenon has been postulated as one mechanism for the development of tardive dyskinesia in patients treated with neuroleptics. However, in vivo binding of 3H- Spiperone, a D2 antagonist, and 3H-SCH 23390, a D1 antagonist, to lesion-denervated rat striata is not increased. Kinetic and pharmacological analysis of 3H-Spiperone and 3H-SCH 23390 binding to intact striata suggests that high affinity sites found in vitro are not detectable in vivo. Homogenization of brain tissue appears to alter the kinetic but not pharmacological proprieties of D1 and D2 ligand binding. Experiments in this proposal will examine further the in vivo properties of D1 and D2 receptors in the striatum, nucleus accumbens and frontal cortex using the techniques of in vivo receptor binding assays and in vivo intracerebral dialysis. Additionally, the effects of acute and chronic neuroleptic administration on D1 and D2 receptor numbers and DA metabolism in nigrostriatal, mesolimbic and mesocortical pathways will be investigated in detail using these in vivo techniques.
| Leslie, C A; Robertson, M W; Jung, A B et al. (1994) Effects of prenatal cocaine exposure upon postnatal development of neostriatal dopaminergic function. Synapse 17:210-5 |
| Leslie, C A; Robertson, M W; Cutler, A J et al. (1991) Postnatal development of D1 dopamine receptors in the medial prefrontal cortex, striatum and nucleus accumbens of normal and neonatal 6-hydroxydopamine treated rats: a quantitative autoradiographic analysis. Brain Res Dev Brain Res 62:109-14 |
| Robertson, M W; Leslie, C A; Bennett Jr, J P (1991) Apparent synaptic dopamine deficiency induced by withdrawal from chronic cocaine treatment. Brain Res 538:337-9 |
