The dopamine (DA) hypothesis of schizophrenia suggests that at least some of the symptoms of schizophrenia are related to a functional DA over- activity in some forebrain area (s) . Antischizophrenic agents produce both their therapeutic and adverse effects through the blockade of DA receptors. Conversely, the motor and cognitive deficits seen in Parkinson's disease are linked to the loss of forebrain DA and are attenuated by DA replacement therapy. Yet the effects of DA and dopaminergic agents on the functional output of DA-innervated forebrain neurons remains largely uninvestigated. Neurons containing the tachykinin neuropeptides substance P and neurokinin A (substance K) are intimately associated with forebrain DA systems, both as afferents to DA cells and as targets of DA innervation. The proposed research will determine the transcriptional and/or post-transcriptional mechanism(s) underlying the observed DAmediated changes in basal ganglia preprotachykinin (PPT, i.e. tachykinin peptide-encoding) mRNA. Since multiple PPT mRNAs encode different combinations of tachykinins with different biological activities, the effects of altered DA output on the proportion of the various PPT mRNAs, as well as the PPT gene primary transcript levels and the rate of PPT gene transcription, will be studied. Parallel experiments will determine the effects of altered DA transmission on PPT gene expression in limbic brain nuclei receiving dense DA innervations. Acutely dissociated cell preparations will help to establish whether or not the multiple DA receptors which alter PPT mRNAs are located directly on striatal tachykinin neurons. Further experiments using primary neuronal cultures will reveal the signal transduction mechanisms underlying PPT gene regulation and its modulation by DA receptors. Thus the proposed experiments will elucidate the cell and molecular biology of PPT gene expression and its regulation by DA, and will clarify whether alterations in PPT gene expression are potentially involved in the pathologies and therapeutic responses seen in Parkinson's disease and schizophrenia.
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