1. ¹Divisions of Neurology, Barrow Neurological Institute, St Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA
2. ²Department of Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

Correspondence: Jie WU, MD, PhD, E-mail Jie.Wu@chw.edu

Received 1 March 2009; Accepted 10 April 2009.

Abstract

Neuronal nicotinic acetylcholine receptors (nAChRs) are the superfamily of ligand-gated ion channels and widely expressed throughout the central and peripheral nervous systems. nAChRs play crucial roles in modulating a wide range of higher cognitive functions by mediating presynaptic, postsynaptic, and extrasynaptic signaling. Thus far, nine alpha (2-10) and three beta (2, 3, and 4) subunits have been identified in the CNS, and these subunits assemble to form a diversity of functional nAChRs. Although 42- and 7-nAChRs are the two major functional nAChR types in the CNS, 6*-nAChRs are abundantly expressed in the midbrain dopaminergic (DAergic) system, including mesocorticolimbic and nigrostriatal pathways, and particularly present in presynaptic nerve terminals. Recently, functional and pharmacological profiles of 6*-nAChRs have been assessed with the use of 6 subunit blockers such as -conotoxin MII and PIA, and also by using 6 subunit knockout mice. By modulating DA release in the nucleus accumbens (NAc) and modulating GABA release onto DAergic neurons in the ventral tegmental area (VTA), 6*-nAChRs may play important roles in the mediation of nicotine reward and addiction. Furthermore, 6*-nAChRs in the nigrostriatal DAergic system may be promising targets for selective preventative treatment of Parkinson's disease (PD). Thus, 6*-nAChRs may hold promise for future clinical treatment of human disorders, such as nicotine addiction and PD. In this review, we mainly focus on the recent advances in the understanding of 6*-nAChR function, pharmacology and pathophysiology.