This laboratory is interested in the development of new therapies for human brain diseases that can be controlled by drugs selective for m1, m2, m3, m4, or m5 muscarinic receptors. At present many groups are interested in the potential use of an m1 agonist for memory disorders, based largely on the prevalence of m1 receptors in the cortex and hippocampus, the amnesic effects of scopolamine, and the loss of acetylcholine in Alzheimer's disease (AD). In reality, we don't know how new selective agonists or antagonists for m1-m5 receptors might work, because we have not had these drugs to study. In fact, the field of muscarinic neurotransmission is still at the stage where the most pressing need is to understand how individual receptor subtypes regulate the functions of neurons, circuits and specific behaviors. This lab has discovered the only specific antagonists for m1 and m4 receptors, m1-toxin and m4-toxin. These toxins now permit, and we propose to carry out, precise and coordinated anatomical, physiological, biochemical and behavioral experiments to establish the cells and circuits at which new m4- and m1-selective drugs may be use to modify movement, memory and pain. Studies of the striatum begin with the premise that an m4 antagonist will be useful for hypokinetic disorders (e.g., Parkinson's disease) and an m4 agonist for hyperkinetic disorders (e.g., tardive dyskinesia), based on the exceptional prevalence of striatal m4 receptors, 5-fold lower levels elsewhere, and the effects of scopolamine on movement. Fluorescent toxins and laser scanning confocal microscopy (LSCM) will be used to test the idea that m4 receptors are located preferentially on rat striatal projection neurons in the direct pathway, plus or minus nigrostriatal lesions. Collaborative electrophysiological studies with both toxins will establish to cells and currents that can be regulated. Both toxins will be used in vivo to study the agonist-induced turning responses of rats having unequal dopaminergic or cholinergic receptor levels in the right and left striata. These studies should provide a rational basis for testing m4-selective drugs for the treatment of movement disorders. Studies of hippocampus are based on the exceptional prevalence of m1 receptors and the importance of acetylcholine for memory. LSCM will be used to test the idea that m1 and m4 receptors are on different neurons. Both toxins will be used in collaborative studies to establish how m1 and m4 activation modulate hippocampal excitation and inhibition. These studies should help validate the idea of using m1 agonists for memory, and disclose some potential clinical effects of m4-selective drugs. Studies of nociception are based on evidence that muscarinic agonists for m1 or m4 receptors diminish nociception in rats by a mechanism unaffected by naloxone. LSCM will be used to test the idea that the key receptors are m4 in the dorsal spinal cord and rostral ventral medulla, and both toxins will be used to establish which receptor modulates analgesia. These studies should provide a rational basis for the development of new non-opioid analgesics. Further biochemical studies are designed to disclose new features of the structure of m1 receptors from normal and AD brains.
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