Nigrostriatal Dopamine: Synaptic and Nonsynaptic Actions

Grant Type
Grant Year
Institution Location
Institution Organization Name
University of Pittsburgh
Investigators Name
Bernath, Sandor, PhD

Although the pathophysiological process underlying Tourette Syndrome is not fully understood, an abnormal functioning of the dopaminergic systems within the brain has been implicated. Drugs which reduce the effectiveness of dopaminergic transmission have been used for clinical treatment of Tourette Syndrome. Conversely, drugs which increase dopaminergic activity aggravate the symptoms. In addition, withdrawal of chronic neuroleptic treatment can result in Tourette-like responses indicating an increased sensitivity of dopamine receptors. Involuntary hyperkinetic movements occuring in Huntington’s chorea resemble those of Tourette Syndrome, and although Huntington’s chorea is attributed to a dysfunction of cholinergic and GABAergic innervation mainly in striatum, they can be alleviated by decreasing dopaminergic activity with neuroleptic treatment. These clinical observations are consistent with the idea that involuntary movements may result from either an overproduction of, or an oversensitivity to, dopamine. Pathological changes in dopaminergic transmission occurring in Tourette Syndrome are expected to influence striatal functions. The neostriatum, the most important subcortical center for sensory-motor integration, is innervated by dopaminergic afferents originating in the substantia nigra. Whereas dopamine containing neurons comprise one of the most important input systems in the striatum, information received and processed in this brain region is transmitted to other brain regions mainly by GABAergic projecting neurons. Therefore, an increased dopaminergic neurotransmission can be expected to alter striatal output via the GABAergic system. The traditional view is that interactions among neurons are mediated by receptors as a result of synaptic activity. Recent studies, however, suggest that neuronal communication may be mediated via Na+-dependent carrier proteins as well. Effects mediated via carrier proteins can eventually influence the way that information is processed in, and transmitted from, the striatum, and this fact may be of great significance both in normal and pathological conditions. Therefore, we propose to study both conventional and non-conventional interactions between dopamine and GABA by utilizing electrophysiological and neurochemical techniques to explore how dopamine influences GABAergic activity in the striatum. Sandor Bernath, Ph.D. University of Pittsburgh, Pittsburgh, PA Award $15,000 Tourette Association of America Inc. – Research Grant Award 1992