Modulation by Nitric Oxide of Dopamine Neuronal Excitability in Rat

Grant Type
Grant Year
Institution Location
Institution Organization Name
Oregon Health Sciences University
Investigators Name
Cox, Barbara, PhD

Neuroleptics used for the treatment of Tourette Syndrome (TS) block dopamine receptors suggesting that dopamine neurons have increased activity in patients with TS. As these neuroleptics often have adverse effects, a novel approach to the treatment of TS might be to diminish dopamine neuronal activity by increasing synaptic release of the inhibitory neurotransmitter GABA or by reducing the synaptic release of the excitatory amino acid glutamate onto dopamine neurons. However, this is not practical without a thorough knowledge of how dopamine neurons are normally regulated by synaptic inputs. In freely moving animals, dopamine neurons of the ventral tegmental area change from single spike firing to firing in bursts. The switch to burst firing increases the release of dopamine at the neuronal projection sites, one being the prefrontal cortex. It is the excitatory (glutamate) synaptic inputs from the prefrontal cortex that are thought to induce this burst firing by activating NMDA receptors on the dopamine neurons. In TS there may be increased dopamine neuronal activity due to alterations in the interdependence between these two regions. Burst firing is not seen in vitro, presumably due to the loss of the cortical afferents. However, previous work from our group has shown that activation of NMDA receptors by application of NMDA to rat brain slice will induce burst firing of dopamine neurons. Activation of NMDA receptors can also, via calcium entry, stimulate production of nitric oxide, a readily diffusable messenger molecule with diverse roles. Nitric oxide synthase, the enzyme which produces nitric oxide from L-arginine, is found in the ventral tegmental area. Nitric oxide has been implicated in the oscillatory activity of other neurons and may, therefore, regulate the burst firing of ventral tegmental dopamine neurons. Nitric oxide also has been shown to increase dopamine release and inhibit uptake of glutamate and dopamine. We have found, when recording from dopamine neurons in the ventral tegmental area of rat brain slice, that the application of the substrate for endogenous nitric oxide production, L-arginine, potentiates GABAB synaptic currents. Additionally, application of GABABreceptor agonist will cause NMDAinduced bursting dopamine neurons to switch to single spike firing. One interpretation could be that glutamate, via activation of NMDA receptors, not only can produce burst firing of dopamine neurons, but also can stimulate production of nitric oxide thereby potentiating GABA release or inhibiting uptake of GABA at GABABreceptor sites resulting in a conversion from burst firing to that of single spikes. For my proposed work, I will use electrophysiologic techniques to explore the effects of the L-arginine/nitric oxide pathway on dopamine neuronal excitability in the ventral tegmental area of rat brain slice. Direct effects of nitric oxide on NMDA receptor-activated burst firing of dopamine neurons will be examined, as well as indirect actions of nitric oxide on synaptic transmission mediated by excitatory and inhibitory inputs. An understanding of these regulatory mechanisms could lead to better treatment strategies for Tourette Syndrome. Barbara A. Cox, Ph.D. Oregon Health Sciences University, Portland, OR Award $20,000 Tourette Association of America Inc. – Research Grant Award 1995