A role for α4(non-α6)* nicotinic acetylcholine receptors in motor behavior

NEUROPHARMACOLOGY

卷:73

Article

Soll, Lindsey G.¹  Grady, Sharon R.²  Salminen, Outi³  Marks, Michael J.²  Tapper, Andrew R.¹ 

[1] Univ Massachusetts, Sch Med, Dept Psychiat, Brudnick Neuropsychiat Res Inst, Worcester, MA 01604 USA

[2] Univ Colorado, Inst Behav Genet, Boulder, CO 80309 USA

[3] Univ Helsinki, Fac Pharm, Helsinki, Finland

关键词: Nicotinic acetylcholine receptor;    Motor behavior;    Basal ganglia;    Dopamine;   

DOI  :  10.1016/j.neuropharm.2013.05.001

来源: Elsevier

【 摘 要 】

Nicotinic acetylcholine receptors (nAChRs) containing either the alpha 4 and/or alpha 6 subunit are robustly expressed in dopaminergic nerve terminals in dorsal striatum where they are hypothesized to modulate dopamine (DA) release via acetylcholine (ACh) stimulation from cholinergic interneurons. However, pharmacological blockade of nAChRs or genetic deletion of individual nAChR subunits, including alpha 4 and alpha 6, in mice, yields little effect on motor behavior. Based on the putative role of nAChRs containing the alpha 4 subunit in modulation of DA in dorsal striatum, we hypothesized that mice expressing a single point mutation in the alpha 4 nAChR subunit, Leu9'Ala, that renders nAChRs hypersensitive to agonist, would exhibit exaggerated differences in motor behavior compared to WT mice. To gain insight into these differences, we challenged WT and Leu9'Ala mice with the alpha 4 beta 2 nAChR antagonist dihydro-beta-erythroidine (DH beta E). Interestingly, in Leu9'Ala mice, DH beta E elicited a robust, reversible motor impairment characterized by hypolocomotion, akinesia, catalepsy, clasping, and tremor; whereas the antagonist had little effect in WT mice at all doses tested. Pre-injection of nicotine (0.1 mg/kg) blocked DH beta E-induced motor impairment in Leu9'Ala mice confirming that the phenotype was mediated by antagonism of nAChRs. In addition, SKF82958 (1 mg/kg) and amphetamine (5 mg/kg) prevented the motor phenotype. DH beta E significantly activated more neurons within striatum and substantia nigra pars reticulata in Leu9'Ala mice compared to WT animals, suggesting activation of the indirect motor pathway as the circuit underlying motor dysfunction. ACh evoked DA release from Leu9'Ala striatal synaptosomes revealed agonist hypersensitivity only at alpha 4(non-alpha 6)* nAChRs. Similarly, alpha 6 nAChR subunit deletion in an alpha 4 hypersensitive nAChR (Leu9'Ala/alpha 6 KO) background had little effect on the DH beta E-induced phenotype, suggesting an alpha 4(non-alpha 6)* nAChR-dependent mechanism. Together, these data indicate that alpha 4(non-alpha 6)* nAChR have an impact on motor output and may be potential molecular targets for treatment of disorders as ociated with motor impairment. (C) 2013 Elsevier Ltd. All rights reserved.

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