A large body of literature exists supporting a role for central dopamine systems in mental illness. The identification of the neuropeptides - cholecystokinin and neurotensin - in sub-populations of mesolimbic dopamine neurons provides possible targets for future, more selective, drug therapy. The broad objective of this proposal is to elucidate the functional significance of the co-existence phenomenon as it pertains to the dopamine neurons in order that such drug development can proceed in a logical fashion. The focus is on understanding the interactions between these three transmitters both at the pre-synaptic level in terms of the regulation of their co-release and post-synaptically in relation to the integration of their actions once released into the synapse. The approach taken - that of measuring neurotransmitter release directly from discrete brain regions in vivo and in tissue culture - takes advantage of recent developments in the P.I.'s laboratory allowing such measurements to be extended to neuropeptides. Thus, the techniques of microdialysis, in vivo voltammetry and dopamine cell culture will be applied in concert to achieve the following specific aims: 1. To test the hypothesis that, in regions where they are co-localized within the same neurons, dopamine, neurotensin and cholecystokinin are differentially released in vivo under specific patterns of neuronal stimulation. 2. To test the hypothesis that the in vivo release of dopamine, cholecystokinin and neurotensin from terminals in the forebrain is differentially controlled by autoreceptors for these transmitters on the cells of origin in the midbrain. That is: a)Does dopamine somatodendritic autoreceptor stimulation or blockade differentially modulate coexisting neuropeptide release? b)Is the release of the neuropeptides similarly under the control of somatodendritic neuropeptide autoreceptors? 3. To elucidate the functional terminal presynaptic interactions between dopamine, cholecystokinin and neurotensin in the mesolimbic and nigrostriatal pathways at the level of transmitter release by addressing the following questions: a)Is dopamine release and turnover controlled by activation of terminal receptors for these peptides? b)Is the release of neurotensin and cholecystokinin influenced by terminal dopamine receptors? c)Is neurotensin and cholecystokinin release self-regulated by terminal autoreceptors for these peptides? 4. To test the hypothesis that co-released dopamine, neurotensin and cholecystokinin in the nucleus accumbens can act independently at the post- synaptic level to differentially modulate enkephalin and GABA release in this region and in the ventral pallidum.
| Anton, R; Kordower, J H; Maidment, N T et al. (1994) Neural-targeted gene therapy for rodent and primate hemiparkinsonism. Exp Neurol 127:207-18 |
