Cholinergic Modulation of Locomotion and Striatal Dopamine Release Is Mediated by 6 4* Nicotinic Acetylcholine Receptors
Year: 2010
Type: article
Abstract: 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 alpha6* nAChRs, which show high ACh and nicotine sensitivity. To help identify nAChR subtypes that control DA transmission, we studied transgenic mice expressing hypersensitive alpha6(L9'S)* receptors. alpha6(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 alpha6alpha4* pentamers, as alpha6(L9'S) mice lacking alpha4 subunits displayed essentially normal behavior. In alpha6(L9'S) mice, receptor numbers are normal, but loss of alpha4 subunits leads to fewer and less sensitive alpha6* receptors. Gain-of-function nicotine-stimulated DA release from striatal synaptosomes requires alpha4 subunits, implicating alpha6alpha4beta2* nAChRs in alpha6(L9'S) mouse behaviors. In brain slices, we applied electrochemical measurements to study control of DA release by alpha6(L9'S) nAChRs. Burst stimulation of DA fibers elicited increased DA release relative to single action potentials selectively in alpha6(L9'S), but not WT or alpha4KO/alpha6(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 alpha6(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 alpha6alpha4beta2* nAChRs in cholinergic control of DA transmission, and strongly suggest that these receptors are candidate drug targets for disorders involving the DA system.
Source: Journal of Neuroscience
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Funders: Ellison Medical Foundation, Gordon and Betty Moore Foundation, Tobacco-Related Disease Research Program, California Institute of Technology, National Institutes of Health, National Institute on Aging, National Institute of Mental Health, National Institute on Drug Abuse, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke
Awards: Chronic nicotine: cell-specific receptor and circuit alterations in basal ganglia, Molecular, Cellular and Systems Neuroscience, Nicotinic Ligands for Smoking Cessation, G2460519735, Alpha4 Nicotinic Receptor in Addiction: Mouse Models, Studies with Nicotinic Null Mutant Mice, G4663214355, Conus Peptides and Their Receptor Targets: Towards Constellation Pharmacology., Nicotinic ACh Receptors and Noradrenergic Neurotransmission in Nicotine Addiction, Novel nAChR-Targeted Peptides, Genetics of Nicotine Tolerance: Role of Receptors, G542420881, NOVEL NEURONAL NACHR-TARGETED PEPTIDES, Alpha-Conotoxin MII: A Selective Nicotinic Receptor Probe, G9000105786, G9000167852
OpenAlex ID: W2010309382