1. ¹Behavioral Neuroscience Branch, National Institute on Drug Abuse, IRP, NIH, DHHS, Baltimore, MD, USA
2. ²Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain
3. ³Cellular Neurobiology Branch, National Institute on Drug Abuse, IRP, NIH, DHHS, Baltimore, MD, USA

Correspondence: Dr S Ferré, Behavioral Neuroscience Branch, National Institute on Drug Abuse, IRP, NIH, DHHS, 5500 Nathan Shock Dr., Baltimore, MD 21224, USA. Tel: +1 410 550 1586; Fax: +1 410 550 1648; E-mail: sferre@intra.nida.nih.gov

Received 27 December 2005; Revised 24 March 2006; Accepted 4 April 2006; Published online 17 May 2006.

Abstract

In the striatum, dopamine and acetylcholine (ACh) modulate dopamine release by acting, respectively, on dopamine D₂ autoreceptors and nicotinic ACh (nACh) heteroreceptors localized on dopaminergic nerve terminals. The possibility that functional interactions exist between striatal D₂ autoreceptors and nACh receptors was studied with in vivo microdialysis in freely moving rats. Local perfusion of nicotine in the ventral striatum (shell of the nucleus accumbens) produced a marked increase in the extracellular levels of dopamine, which was completely counteracted by co-perfusion with either the non-₇ nACh receptor antagonist dihydro--erythroidine or the D_2-3 receptor agonist quinpirole. Local perfusion of the D_2-3 receptor antagonist raclopride produced an increase in the extracellular levels of dopamine, which was partially, but significantly, counteracted by coperfusion with dihydro--erythroidine. These findings demonstrate a potent crosstalk between G protein-coupled receptors and ligand-gated ion channels in dopaminergic nerve terminals, with the D₂ autoreceptor modulating the efficacy of non-₇ nACh receptor-mediated modulation of dopamine release. We further demonstrate physical interactions between ₂ subunits of non-₇ nicotinic acetylcholine receptors and D₂ autoreceptors in co-immunoprecipitation experiments with membrane preparations from co-transfected mammalian cells and rat striatum. These results reveal that striatal non-₇ nicotinic acetylcholine receptors form part of heteromeric dopamine autoreceptor complexes that modulate dopamine release.