Studies conducted over the past nine years of the MERIT award established synaptic inputs to mesolimbic dopaminergic neurons in the ventral tegmental area (VTA) and their targets in the nucleus accumbens (NAc) that are critical for psychostimulant and antipsychotic drug actions. Most importantly, the results show that these neurons receive monosynaptic input from terminals containing neurotensin or serotonin (5-HT) and from excitatory prefrontal cortical afferents. Synaptic transmission depends, however, on vesicular packaging and plasmalemmal reuptake of monoamines and on the activation of functionally relevant receptors, whose subcellular distributions are largely unknown. To determine these sites, three studies are proposed using quantitative electron microscopic immunocytochemistry for the localization of sequence-specific antipeptide antisera against recently cloned transporters and receptors. These will be examined in brain tissue from normal adult rats and from animals receiving chronic treatment with haloperidol, a typical antipsychotic drug that blocks dopamine D2 receptors. Study I will test the hypotheses that (1) the levels of the vesicular monoamine transporter (VMAT2) and dopamine transporter (DAT) differ in dendrites of mesolimbic and mesocortical dopaminergic neurons, suggesting differences in their capacity for dendritic dopaminergic transmission. The potential functional sites for neurotensin and dopamine D3 receptor activation also will be examined in relation to neurons that contain dopamine, D2 receptors or gamma-aminobutyric acid (GABA), the neurotransmitter present in non-dopaminergic neurons in the VTA and in most targets of dopaminergic terminals in the NAc. Study II will test the hypothesis that 5-HT2A receptors, which are major binding sites for certain atypical antipsychotic drugs, are present in dendrites of dopaminergic neurons in the VTA and/or GABAergic neurons in NAc. The localization of the serotonin transporter (SERT) will be examined in the limbic shell and motor core of the NAc to determine whether there are regional variations that may affect local availability of extracellular serotonin. Study III will determine whether dopamine D2 and/or D3 receptors are present in axon terminals derived from the prefrontal cortex or their postsynaptic targets in the NAc. This study will also test the hypotheses that (1) N-methyl-D-aspartate (NMDA) glutamate receptors and D2 receptors are present in the same dendritic spines, and (2) chronic treatment with haloperidol produces selective changes in NMDA containing spines of GABAergic neurons in the motor striatum. Together, the results will contribute to our understanding of the pathophysiology and treatment of hyperkinetic movement disorders and schizophrenia.
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