| The subthalamic nucleus (STN) is an important modulator of movement. Many pathological movements are accounted for by models describing abnormal modulation of motor related thalamocortical pathways that derive input from the STN indirectly, via its efferents to the basal ganglia output nuclei. Excitatory, glutamatergic afferents from the cerebral cortex and inhibitory, GABA-ergic inputs from the external globus pallidus play a prominent role in modulating the STN in these models. Converging lines of evidence suggest that dopamine also acts as an excitatory neurotransmitter within the STN via presynaptic D1 receptor mediated release of glutamate, and that this action contributes to orofacial dyskinesias in rats. The source of this dopaminergic innervation, the cellular loci at which it acts, and its potential import in modulating normal and pathological movement are poorly understood.; This dissertation investigates the anatomy, physiology, and behavioral correlates of dopamine innervation of the subthalamic nucleus. We investigated dopaminergic projections to the STN using retrograde tracing combined with immunocytochemistry for tyrosine hydroxylase and identified a dopaminergic projection from the substantia nigra pars compacta to the STN. Studies combining systemic drug administration with in vivo extracellular recording of STN neurons demonstrated that a D1 agonist induced increase in STN firing rates is attentuated by an AMPA receptor antagonist in intact animals, and an NMDA receptor antagonist in dopamine denervated animals. The cellular localization of D1 receptors was investigated using immunoreactivity at the electroni microscopic level, which demonstrated predominantly post-synaptic localization in cell bodies and dendrites. Behavioral studies investigated using local infusion of dopaminergic agents demonstrated elicitation of oral dyskinesias is anatomically limited to the STN. This response could not be further characterized pharmacologically.; These results are a first step in elucidating the nigro-subthalamic pathway and pharmacology of this dopamine innervation. This potentially important aspect of dopaminergic innervation should be considered in models of basal ganglia function which generally emphasize the well established nigro-striatal pathway. The behavioral relevance of dopaminergic innervation to the STN in the rodent remains unclear and demands further exploration. |
