NICOTINIC CHOLINERGIC MECHANISMS CAUSING ELEVATED DOPAMINE RELEASE AND ABNORMAL LOCOMOTOR BEHAVIOR

Firing rates of dopamine (DA) neurons in substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) control DA release in target structures such as striatum and prefrontal cortex. DA neuron firing in the soma and release probability at axon terminals are tightly regulated by cholinergic transmission and nicotinic acetylcholine receptors (nAChRs). To understand the role of alpha 6(star) nAChRs in DA transmission, we studied several strains of mice expressing differing levels of mutant, hypersensitive (leucine 9' to serine [L9'S]) alpha 6 subunits. alpha 6 L9'S mice harboring six or more copies of the hypersensitive alpha 6 gene exhibited spontaneous home-cage hyperactivity and novelty-induced locomotor activity, whereas mice with an equal number of WT and L9'S alpha 6 genes had locomotor activity resembling that of control mice. alpha 6-dependent, nicotine-stimulated locomotor activation was also more robust in high-copy alpha 6 L9'S mice versus low-copy mice. In wheel-running experiments, results were also bimodal; high-copy alpha 6 L9'S animals exhibited blunted total wheel rotations during each day of a 9-day experiment, but low-copy alpha 6 L9'S mice ran normally on the wheel. Reduced wheel running in hyperactive strains of alpha 6 L9'S mice was attributable to a reduction in both overall running time and velocity. ACh and nicotine-stimulated DA release from striatal synaptosomes in alpha 6 L9'S mice was well-correlated with behavioral phenotypes, supporting the hypothesis that augmented DA release mediates the altered behavior of alpha 6 L9'S mice. This study highlights the precise control that the nicotinic cholinergic system exerts on DA transmission and provides further insights into the mechanisms and consequences of enhanced DA release. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.