Dysfunctions of dopaminergic systems are thought to play a role in the etiology of several neurological and psychiatric disorders, such as Parkinson's disease and schizophrenia. However, models of these disorders to date have often failed to take into account the large amount of homeostatic regulation that comes into play whenever these systems are perturbed, and which serve to reset the system towards normality. Another possible approach to investigating the normal functions of this system and its role in disease would be to examine in detail the modes of autoregulation that modulate the activity of dopamine-containing neurons, with a predisposition to examining how deficits in these processes could precipitate dysfunctional states. We have been investigating the membrane processes involved in the self-regulation of dopamine neuron activity using the in vitro rat brain slice preparation, in which confounding environmental or afferent influences can be better controlled. In this proposal, we plan to extend this investigation into dopamine neuron regulation by studying five processes believed to play a role in their function: 1) identifying the spike generating zones within dopamine neurons and their morphological correlates, and in this way enable the study of dopamine neuron regulation in terms of its functional subcompartments; 2) testing the involvement of glutamatergic afferents in the regulation of dopamine neuron firing pattern; 3) examining the functional mechanism of autoreceptor stimulation and factors involved in regulating its sensitivity, for the purpose of studying the autonomous control exerted by the dopamine neuron on its responsivity to its own neurotransmitter; 4) determining the important factors which play a role in controlling dopamine release from dendritic stores, and thus elucidating whether this release is an autoregulatory process or is mediated, as it is in the striatum, by glutamatergic afferent processes; and 5) analyzing the functional implications of the different peptidergic cotransmitters contained within subpopulations of dopamine neurons, detailing their involvement in cell firing and how their co-release may influence autoreceptor sensitivity and peptide interactions in identified subsets of dopamine neurons, which will be classified by combining retrograde labelling from their projection sites and intracellular staining. The validity of the results to the in situ cell class will be determined by carrying out parallel experiments in vivo, when feasible. This type of combined functional and morphological analysis of individual dopamine neurons may thus facilitate the development of models concerning states of psychiatric dysfunction. Furthermore, by examining in detail how these regulatory processes differ between identified subpopulations of dopamine neurons, it may be possible to derive new therapeutic approaches by pharmacologically targeting these regulatory sites, and thereby avoid the debilitating side effects often associated with the use of direct-acting drugs.
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