The hallmark of Parkinson s disease is a dopamine deficiency in the basal ganglia due to degeneration of dopaminergic neurons in the substantia nigra pars compacta. Because of this, the physiology of the neurotransmitter dopamine in the basal ganglia has been extensively studied. However, none of the current models of basal ganglia function includes the novel cannabinergic neurotransmitter system. The recent cloning and mapping of a nervous cannabinoid receptor unveiled high levels of cannabinoid receptors in the basal ganglia where they are as abundant as the receptors for dopamine. Furthermore, cannabinoid receptor levels in the output nuclei of the basal ganglia, the globus pallidus and the substantia nigra pars reticulata, are the highest in the brain. In recent studies we have described a major modulatory role of cannabinoids in the basal ganglia where they act on both major excitatory (subthalamic) and major inhibitory (striatal) inputs to basal ganglia output nuclei. Cannabinoids block the activation of either input, and the effect observed would be to return the system to basal levels of activity. A complex interaction between the cannabinoid and the dopaminergie system was also observed, blocking each others effects in intact animals and synergizing in the 6-OHDA model. The major modulatory action of cannabinoids in the basal ganglia counteracting both the major source of excitation and the major source of inhibition depending on their level of activity is relevant to Parkinson s disease where the subthalamic nucleus becomes hyperactive. This proposal aims to determine wether cannabinoids could be used alone or in conjunctive therapy with ineffective levels or low doses of dopaminergic drugs to counteract the motor impairments induced by degeneration of the dopaminergic innervation of the basal ganglia. Behavioral, biochemical, and physiological studies will be conducted in parallel to test this possibility. It will also help integrate the cannabinergic system with the current knowledge of basal ganglia physiology.
