Dopaminergic Modulation of Calcium Currents in Amygdaloid Pyramidal Neurons

Grant Type
Basic
Grant Year
1999-2000
Institution Location
TN
Institution Organization Name
University of Tennessee
Investigators Name
Foehring, Robert, PhD

Several lines of evidence suggest that an imbalance in dopamine (DA) neurotransmission underlies the symptoms of Tourette Syndrome (TS). Most investigations into the basis for TS have focused on the ventral striatum and associated nucleus accumbens because of the involvement of these structures in movement control and reward circuitry, their location at the limbic/motor interface, and their being the recipients of strong dopaminergic projections from the ventral tegmental area (VTA). It is likely that the frontal cortex is also involved through interactions with the striatum. However, less attention has been paid to the amygdaloid nuclei, a telencephalic complex thought to be involved in regulating anxiety and fear, learning and the emotional aspects of several behaviors. These nuclei provide a major input to the N. accumbens, and have strong connections with the striatum and prefrontal cortex. The amygdaloid nuclei also receive an extensive DA projection from the VTA. The interconnections of the amygdala and the N. accumbens suggest an important role for the amygdala in regulation systems of reward and motivation and in controlling the repetitive behaviors in TS. It is notable that people with TS commonly experience other neurological and behavioral conditions such as obsessive-compulsive disorder, anxieties, attention deficit disorder, impulse control problems, depression, and sleep disorders. Motor and vocal tics have emotional content, and tic severity and frequency of occurrence are sensitive to stress. DA cells in the VTA are activated by stress. The amygdala coordinates stress responses and projects back to the VTA. Based upon the anatomical connectivity, dopaminergic inputs and known functions of the amygdaloid nuclei, insight into the role of DA in controlling neuronal excitability in the amygdaloid nuclei should provide insight into the mechanisms underlying TS. Knowledge of the detailed mechanisms underlying DA’s action is essential for development of rational therapies for TS. As a first step, we propose to examine the physiological actions of DA on amygdaloid pyramidal neurons from the basolateral nucleus. Initial studies will focus on somatodendritic Ca2+ currents. We assume that (1) Ca2+ entry is essential for the normal function of amygdaloid pyramidal neurons, and (2) DA and Ca2+ channels in amygdaloid output neurons are involved in processes underlying TS. Ca2+ entry through voltage-gated channels is essential for triggering exocytosis in synaptic terminals, for regulating firing behavior of pyramidal cells, and for regulation of synaptic plasticity and gene activity. DA could modulate these processes via effects on Ca2+ entry through voltage-gated Ca2+ channels, leading to abnormal activity of pyramidal neurons in response to emotional or stressful conditions. Through projections to N. accumbens and prefrontal cortex, this abnormal firing could in turn influence tics and vocalizations. We will test which dopamine receptor and G protein subtypes are involved, which calcium channel subtypes are modulated, the involvement of second messengers, and whether the modulation is voltage-dependent. Robert C. Foehring, Ph.D. The University of Tennessee, Memphis, TN Award $38,761 Tourette Association of America Inc. – Research Grant Award 1999-2000