Interplay of β2*nicotinic receptors and dopamine pathways in the control of spontaneous locomotion

Acetylcholine (ACh) is a known modulator of the activity of dopaminergic (DAergic) neurons through the stimulation of nicotinic ACh receptors (nAChRs). Yet, the subunit composition and specific location of nAChRs involved in DA-mediated locomotion remain to be established in vivo. Mice lacking the beta 2 subunit of nAChRs (beta 2KO) display striking hyperactivity in the open field, which suggests an imbalance in DA neurotransmission. Here, we performed the selective gene rescue of functional beta 2*-nAChRs in either the substantia nigra pars compacta (SNpc) or the ventral tegmental area (VTA) of beta 2KO mice. SNpc rescued mice displayed normalization of locomotor activity, both in familiar and unfamiliar environments, whereas restoration in the VTA only rescued exploratory behavior. These data demonstrate the dissociation between nigrostriatal and mesolimbic beta 2*-nAChRs in regulating unique locomotor functions. In addition, the site-directed knockdown of the beta 2 subunit in the SNpc by RNA interference caused hyperactivity in wild-type mice. These findings highlight the crucial interplay of nAChRs over the DA control of spontaneous locomotion.