Modulation of Striatal Neural Activity by Nitric Oxide and Dopamine: Implications for Tourette Syndrome

Grant Type
Grant Year
Institution Location
Institution Organization Name
University of Pittsburgh
Investigators Name
West, Anthony, PhD

A substantial amount of research has focused on the role of the neurotransmitter dopamine in regulating the activity of brain regions involved in voluntary movement. Recent clinical and animal studies suggest that a dysfunction in dopaminergic neurotransmission within a brain region known as the striatum may be involved in the basic causes of Tourette Syndrome (TS) symptoms. However, the exact role that dopamine plays in integrating neuronal signals in this subcortical brain region remains poorly understood. Having said that, it is known that the spiny projection cells within the striatum are the primary targets of dopaminergic inputs. These neurons are also believed to be the central processing units responsible for regulating the flow of information from the cortex to premotor areas in the brainstem. Additionally, these neurons are known to produce multiple subtypes of dopamine receptor proteins which are thought to play important roles in modulating cell activity. Given that drugs which act to block the actions of dopamine in the striatum have been shown to be useful for the treatment of some of the symptoms of TS, it is likely that a better understanding of the neurophysiological and neurochemical interactions of dopamine with intrinsic striatal neurotransmitter systems will aid in the development of novel pharmacotherapies for the treatment of this condition. Our recent studies suggest that the subclass of neurons in the striatum that produce the neurotransmitter nitric oxide (NO) may play an important role in regulating the excitability of striatal systems involved in modulating movement. We believe these NO-producing cells may regulate information flow within the striatum via their ability to maintain a homeostatic balance between specific temporal modes of dopamine neurotransmission termed “tonic” and “phasic.” Thus striatal NO signaling may function to enhance tonic (i.e. steady state) extracellular dopamine levels and suppress phasic (i.e. a brief burst) dopamine transmission during conditions of minimal sensory stimulation or behavioral demands (i.e. when the animal is not presented with novel or appetitive stimuli). Potentially, a disruption of the NO-mediated regulation of this striatal dopaminergic homeostasis could result in inappropriate selection of motor programs and some of the symptoms of TS. The aim of our work is to characterize the interaction between NO-producing interneurons and dopamine inputs involved in modulating the activity of striatal spiny projection neurons in anesthetized rats. In order to examine these interactions at the cellular, network, and system levels, we will perform intracellular and extracellular electrophysiological recordings in conjunction with cell labeling techniques. Additionally, during these recordings local striatal NO levels will be manipulated via intrastriatal infusions of drugs known to block or augment NO transmission. We hypothesize that dopamine will modulate striatal neuron activity differentially depending on the level of striatal NO tone. We believe that these studies will produce valuable insights into mechanisms involved in the integration of dopaminergic signaling in striatal systems. Moreover, these studies may suggest novel molecular targets which could aid in the development of more efficacious treatment strategies for patients with TS. Anthony R. West, Ph.D. University of Pittsburgh, Pittsburgh, PA Award: $25,000 Tourette Association of America Inc. – Research Grant Award 2000-2001