Soll_2013_Neuropharmacol_73_19

Nicotinic acetylcholine receptors (nAChRs) containing either the alpha4 and/or alpha6 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 alpha4 and alpha6, in mice, yields little effect on motor behavior. Based on the putative role of nAChRs containing the alpha4 subunit in modulation of DA in dorsal striatum, we hypothesized that mice expressing a single point mutation in the alpha4 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 alpha4beta2 nAChR antagonist dihydro-beta-erythroidine (DHbetaE). Interestingly, in Leu9'Ala mice, DHbetaE 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 DHbetaE-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. DHbetaE 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 alpha4(non-alpha6)* nAChRs. Similarly, alpha6 nAChR subunit deletion in an alpha4 hypersensitive nAChR (Leu9'Ala/alpha6 KO) background had little effect on the DHbetaE-induced phenotype, suggesting an alpha4(non-alpha6)* nAChR-dependent mechanism. Together, these data indicate that alpha4(non-alpha6)* nAChR have an impact on motor output and may be potential molecular targets for treatment of disorders associated with motor impairment.