title: Chronic Nicotine Mitigates Aberrant Inhibitory Motor Learning Induced by Motor Experience under Dopamine Deficiency.
abstract: Although dopamine receptor antagonism has long been associated with impairments in motor performance, more recent studies have shown that dopamine D2 receptor (D2R) antagonism, paired with a motor task, not only impairs motor performance concomitant with the pharmacodynamics of the drug, but also impairs future motor performance once antagonism has been relieved. We have termed this phenomenon "aberrant motor learning" and have suggested that it may contribute to motor symptoms in movement disorders such as Parkinson's disease (PD). Here, we show that chronic nicotine (cNIC), but not acute nicotine, treatment mitigates the acquisition of D2R-antagonist-induced aberrant motor learning in mice. Although cNIC mitigates D2R-mediated aberrant motor learning, cNIC has no effect on D1R-mediated motor learning. β2-containing nicotinic receptors in dopamine neurons likely mediate the protective effect of cNIC against aberrant motor learning, because selective deletion of β2 nicotinic subunits in dopamine neurons reduced D2R-mediated aberrant motor learning. Finally, both cNIC treatment and β2 subunit deletion blunted postsynaptic responses to D2R antagonism. These results suggest that a chronic decrease in function or a downregulation of β2-containing nicotinic receptors protects the striatal network against aberrant plasticity and aberrant motor learning induced by motor experience under dopamine deficiency.
  
  
  
  Increasingly, aberrant plasticity and aberrant learning are recognized as contributing to the development and progression of movement disorders. Here, we show that chronic nicotine (cNIC) treatment or specific deletion of β2 nicotinic receptor subunits in dopamine neurons mitigates aberrant motor learning induced by dopamine D2 receptor (D2R) blockade in mice. Moreover, both manipulations also reduced striatal dopamine release and blunt postsynaptic responses to D2R antagonists. These results suggest that chronic downregulation of function and/or receptor expression of β2-containing nicotinic receptors alters presynaptic and postsynaptic striatal signaling to protect against aberrant motor learning. Moreover, these results suggest that cNIC treatment may alleviate motor symptoms and/or delay the deterioration of motor function in movement disorders by blocking aberrant motor learning.
authors.affiliation: Department of Neurobiology and korandajl@uchicago.edu jbeeler@qc.cuny.edu.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Koranda
authors.affiliation: Department of Neurobiology and.
authors.forename: Anne C
authors.initials: AC
authors.lastname: Krok
authors.affiliation: Department of Physiology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, and.
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Physiology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, and.
authors.forename: Anis
authors.identifier: 0000-0002-5131-2536
authors.initials: A
authors.lastname: Contractor
authors.affiliation: Department of Anesthesia, University of Chicago, Chicago, Illinois 60637.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: McGehee
authors.affiliation: Department of Psychology, Queen's College, City University of New York, Queens, New York 11367 korandajl@uchicago.edu jbeeler@qc.cuny.edu.
authors.forename: Jeff A
authors.initials: JA
authors.lastname: Beeler
authors.affiliation: Department of Neurobiology and.
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Zhuang
mesh_terms: D000818:Animals; D004298:Dopamine / Q000172:deficiency* / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D005260:Female; D007858:Learning / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity; D009538:Nicotine / Q000008:administration & dosage / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D055366:Synaptic Potentials
chemical_list: D004298:Dopamine; D009538:Nicotine; D018722:Nicotinic Agonists; D017448:Receptors, Dopamine D2; D011978:Receptors, Nicotinic
keywords: Beta2 nAChR; aberrant plasticity; dopamine D2 receptor; dopamine release; inhibitory learning