title: Mice lacking the alpha4 nicotinic receptor subunit fail to modulate dopaminergic neuronal arbors and possess impaired dopamine transporter function.
abstract: Neuronal nicotinic acetylcholine receptors (nAChRs) at presynaptic sites can modulate dopaminergic synaptic transmission by regulating dopamine (DA) release and uptake. Dopaminergic transmission in nigrostriatal and mesolimbic pathways is vital for the coordination of movement and is associated with learning and behavioral reinforcement. We reported recently that the D2 DA receptor plays a central role in regulating the arbor size of substantia nigra dopaminergic neurons. Given the known effects of nAChRs on dopaminergic neurotransmission, we assessed the ability of the alpha4 nAChR subunit to regulate arbor size of dopaminergic neurons by comparing responses of wild-type and alpha4 nAChR subunit knockout [alpha4(-/-)] mice to long-term exposure to cocaine, amphetamine, nicotine, and haloperidol, and after substantia nigra neurotoxic lesioning. We found that dopaminergic neurons in adult drug-naive alpha4(-/-) mice had significantly larger terminal arbors, and despite normal short-term behavioral responses to drugs acting on pre- and postsynaptic D2 DA receptors, they were unable to modulate their terminal arbor in response to pharmacological manipulation or after lesioning. In addition, although synaptosome DA uptake studies showed that the interaction of the D2 DA receptor and the dopamine transporter (DAT) was preserved in alpha4(-/-) mice, DAT function was found to be impaired. These findings suggest that the alpha4 subunit of the nAChR is an independent regulator of terminal arbor size of nigrostriatal dopaminergic neurons and that reduced functionality of presynaptic DAT may contribute to this effect by impairing DA uptake.
authors.affiliation: Howard Florey Institute of Experimental Physiology and Medicine, The University of Melbourne, Parkville, 3010, Victoria, Australia.
authors.forename: C L
authors.initials: CL
authors.lastname: Parish
authors.forename: J
authors.initials: J
authors.lastname: Nunan
authors.forename: D I
authors.initials: DI
authors.lastname: Finkelstein
authors.forename: F N
authors.initials: FN
authors.lastname: McNamara
authors.forename: J Y
authors.initials: JY
authors.lastname: Wong
authors.forename: J L
authors.initials: JL
authors.lastname: Waddington
authors.forename: R M
authors.initials: RM
authors.lastname: Brown
authors.forename: A J
authors.initials: AJ
authors.lastname: Lawrence
authors.forename: M K
authors.initials: MK
authors.lastname: Horne
authors.forename: J
authors.initials: J
authors.lastname: Drago
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002452:Cell Count; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism; D003342:Corpus Striatum / Q000166:cytology*; D004298:Dopamine / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000502:physiology*; D009474:Neurons / Q000166:cytology*; D016627:Oxidopamine; D011978:Receptors, Nicotinic / Q000032:analysis / Q000502:physiology*; D013378:Substantia Nigra / Q000166:cytology*; D009435:Synaptic Transmission; D013574:Synaptosomes / Q000378:metabolism
chemical_list: C486720:Chrnb4 protein, mouse; D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic; C069723:2beta-carbomethoxy-3beta-(4-iodophenyl)tropane; D016627:Oxidopamine; D003042:Cocaine; D004298:Dopamine