Nicotinic acetylcholine receptors and the ascending dopamine pathways

Abstract

Nicotinic acetylcholine receptors (nAChRs) are widely expressed in midbrain dopamine neurons that project to dorsal striatum, nucleus accumbens and prefrontal cortex. Thus nAChRs can influence the functions of these three pathways; notably motor control, 'reward' and executive function, respectively. Diverse subtypes of nAChRs have been identified on dopamine cell bodies and terminals as well as on neighbouring afferents and interneurons. Here we review the molecular and cellular mechanisms through which nAChRs exert their influence on these pathways in rodents. Page 4 of 40A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t 5 IntroductionThe association of nicotine with tobacco addiction has stimulated particular interest in how nicotine interacts with the 'reward' pathways of the brain. Most attention has been given to the ascending dopaminergic pathways that arise in the midbrain and project to aspects of the basal ganglia and prefrontal cortex (PFC; Fig. 1). In addition to mediating the reinforcing properties of addictive substances, dopamine is also central to the fine control of movement governed by the basal ganglia, whereas its actions in the PFC are critically important to 'executive' function [1,2]. This includes working memory, behavioural flexibility and decision making, and the PFC is also involved with the anticipation of reward [3,4]. FIGURE ONE NEAR HERENicotine interacts with the dopamine systems via nicotinic acetylcholine receptors (nAChRs), a family of ligand-gated pentameric cation channels constituted from at least nine α and β subunits (α2-7 and β2-4) expressed in the mammalian brain [5]. nAChR subtypes can differ in their sensitivities to nicotine or acetylcholine (ACh), their channel characteristics (including their propensity to desensitise) and their cellular distribution. A high relative permeability to Ca 2+ , a notable characteristic of the α7 nAChR subtype, enables nAChRs to interface with a variety of intracellular Ca 2+ -dependent mechanisms [6]. The localisation of nAChRs on dopamine cell bodies in the ventral tegmental area (VTA) or substantia nigra pars compacta (SNc) allows nicotine to directly modulate dopaminergic cell firing. Additionally, nAChRs on dopamine terminals can influence transmitter release. nAChRs present on afferents projecting to the VTA and SNc or to the terminal fields can also influence the activity of dopaminergic neurons. The nicotinic modulation of dopamine release has generated interest in nAChRs as therapeutic targets for conditions involving dopaminergic dysfunction, including schizophrenia, attention deficit hyperactivity disorder, Parkinson's disease, Alzheimer's disease and age-related cognitive impairment [7][8][9][10].In this review we focus on the mechanisms through which nAChRs modulate the activity of dopamine neurones of the principal ascending pathways (Fig. 1). We will considerPage 6 of 40A c c e p t e d M a n u s c r i p t 6 nicotinic influences on somatodendritic and terminal fields, with the aim of integratin...

Frequency-Dependent Modulation of Dopamine Release by Nicotine and Dopamine D1 Receptor Ligands: An In Vitro Fast Cyclic Voltammetry Study in Rat Striatum

“…The present study also suggests that D1R ligands do not affect action potential dependent dopamine release. However, it must be considered if single or multiple nAChR subtypes play this essential and complex role in the bidirectional effect of nicotine on dopamine release [24]. Besides desensitization of the β2-containing nAChR, it has been suggested that there is an important role for functional α7*nAChRs [25] and this may depend upon endogenous ACh levels evoked by the stimulation.…”

Two Distinct Allosteric Binding Sites at α4β2 Nicotinic Acetylcholine Receptors Revealed by NS206 and NS9283 Give Unique Insights to Binding Activity-associated Linkage at Cys-loop Receptors

“…Aligning pharmacological actions for a range of PAMs (literature and current study) with their proposed binding sites, it appears that binding in ECD interfaces mostly result in agonist CRR left shifts, whereas TMD binding can further result in increased agonist-evoked peak currents, delayed desensitization characteristics, and direct agonist independent receptor activation. 7,8,9-tetrahydro-1H-benzo[g]indole-5-sulfonamide (NS206) was synthesized at NeuroSearch A/S according to methods described in patent WO 01/55110. 3-(3-(Pyridine-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (NS9283) was likewise synthesized at NeuroSearch A/S as described by Timmermann et al (9).…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…A remarkable diversity of b2* nAChR subtypes modulates DA release in these projections Gotti et al, 2009;Livingstone and Wonnacott, 2009). These projections, in particular those to the NAc and ventral striatum, are likely involved in reward pathways and the reinforcing properties of nicotine contributing to addiction.…”

“…This burst firing is thought to be mediated by activation of NMDARs on DAergic cell bodies by glutamatergic afferents from the PFC (Chergui et al, 1993;Tong et al, 1996). It is proposed that stimulation of presynaptic a7 nAChRs on glutamatergic afferents (Jones and Wonnacott, 2004) releases glutamate activating NMDARs on DAergic cell bodies to produce the burst firing (Livingstone and Wonnacott, 2009). The activation of NMDARs not only induces acute changes in firing but can induce long-lasting presynaptic facilitation and postsynaptic NMDAR-dependent LTP, resulting in sustained increases in the sensitivity of the DAergic neurons to burst firing (Mansvelder and McGehee, 2000;Mansvelder et al, 2002).…”