Cholinergic Modulation of Locomotion and Striatal Dopamine Release Is Mediated by α6α4*Nicotinic Acetylcholine Receptors

Dopamine (DA) release in striatum is governed by firing rates of midbrain DA neurons, striatal cholinergic tone, and nicotinic ACh receptors (nAChRs) on DA presynaptic terminals. DA neurons selectively express alpha 6* nAChRs, which show high ACh and nicotine sensitivity. To help identifyn AChR subtypes that control DA transmission, we studied transgenic mice expressing hypersensitive alpha 6(L9'S)* receptors. alpha 6(L9'S) mice are hyperactive, travel greater distance, exhibit increased ambulatory behaviors such as walking, turning, and rearing, and show decreased pausing, hanging, drinking, and grooming. These effects were mediated by alpha 6 alpha 4* pentamers, as alpha 6(L9'S) mice lacking similar to 4 subunits displayed essentially normal behavior. In alpha 6(L9'S) mice, receptor numbers are normal, but loss of alpha 4 subunits leads to fewer and less sensitive similar to 6* receptors. Gain-of-function nicotine-stimulated DA release from striatal synaptosomes requires alpha 4 subunits, implicating alpha 6 alpha 4 beta 2* nAChRs in alpha 6(L9'S) mouse behaviors. In brain slices, we applied electrochemical measurements to study control of DA release by alpha 6(L9'S) nAChRs. Burst stimulation of DA fibers elicited increased DA release relative to single action potentials selectively in alpha 6(L9'S), but not WT or alpha 4KO/alpha 6(L9'S), mice. Thus, increased nAChR activity, like decreased activity, leads to enhanced extracellular DA release during phasic firing. Bursts may directly enhance DA release from alpha 6(L9'S) presynaptic terminals, as there was no difference in striatal DA receptor numbers or DA transporter levels or function in vitro. These results implicate alpha 6 alpha 4 beta 2* nAChRs in cholinergic control of DA transmission, and strongly suggest that these receptors are candidate drug targets for disorders involving the DA system.