The affective and cognitive symptoms of Parkinson's Disease (PD) pose significant problem in the field of mental health. These symptoms could result from subthalamic nucleus hyperactivity, causing increased excitatory amino acid (EAA) release and EAA desensitization in the ventral pallidum (VP). If cholinergic neurons, which govern cognitive functions, are preferentially sensitive to AMPA, and GABAergic neurons, which influence affective states, are preferentially sensitive to NMDA, then perhaps specific therapy can be directed toward each sub-population. We hypothesize that changes consistent with increased EAA neurotransmission occur in the VP following a substantia nigra lesion. In a rat model of PD with a unilateral 6-hydroxydopamine-induced lesion of the substantia nigra, we will compare left and right pallidal regions to test the following hypothesis in three Specific Aims. Hypothesis 1: Dopamine deafferentation will increase spontaneous neuronal activity and decrease sensitivity to EAA agonists in the VP. Neuronal firing will be measured by extracellular single neuron electrophysiology. Microiontophoresis of receptor subtype-selective EAA agonists and antagonists will be used to measure EAA sensitivity and endogenous EAA-induced spontaneous firing, respectively. Hypothesis 2: dopamine deafferentation will reduce EAA-evoked c-fos/c-jun expression in the VP, and will differentially alter EAA receptor subtype-selective agonist-evoked c-fos/c-jun expression between cholinergic and GABAergic neurons.. Expression of C-fos/c-jun will be induced by microinjection of EAA receptor subtype-selective agonists into the VP. C-Fos/c-Jun and markers for cholinergic or GABAergic neurons will be detected by immunofluorescence. Hypothesis 3: destruction of neurons in the subthalamic nucleus will tend to normalize the changes in spontaneous neuronal activity and EAA-induced effects in the VP caused by dopamine deafferentation. Neurons in the subthalamic nucleus ipsilateral to the lesioned substantia nigra will be destroyed with ibotenic acid and the procedures outlined for specific Aims 1 and 2 will be repeated.
| Turner, Michael S; Mignon, Laurence; Napier, T Celeste (2002) Alterations in responses of ventral pallidal neurons to excitatory amino acids after long-term dopamine depletion. J Pharmacol Exp Ther 301:371-81 |
| Turner, M S; Lavin, A; Grace, A A et al. (2001) Regulation of limbic information outflow by the subthalamic nucleus: excitatory amino acid projections to the ventral pallidum. J Neurosci 21:2820-32 |
