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...

Nicotine enhances attentional and working memory aspects of executive function in the prefrontal cortex (PFC) where dopamine plays a major role. Here, we have determined the nicotinic acetylcholine receptor (nAChR) subtypes that can modulate dopamine release in rat PFC using subtype-selective drugs. Nicotine and 5-Iodo-A-85380 (beta2* selective) elicited [(3)H]dopamine release from both PFC and striatal prisms in vitro and dopamine overflow from medial PFC in vivo. Blockade by dihydro-beta-erythroidine supports the participation of beta2* nAChRs. However, insensitivity of nicotine-evoked [(3)H]dopamine release to alpha-conotoxin-MII in PFC prisms suggests no involvement of alpha6beta2* nAChRs, in contrast to the striatum, and this distinction is supported by immunoprecipitation of nAChR subunits from these tissues. The alpha7 nAChR-selective agonists choline and Compound A also promoted dopamine release from PFC in vitro and in vivo, and their effects were enhanced by the alpha7 nAChR-selective allosteric potentiator PNU-120596 and blocked by specific antagonists. DNQX and MK801 inhibited [(3)H]dopamine release evoked by choline and PNU-120596, suggesting crosstalk between alpha7 nAChRs, glutamate and dopamine in the PFC. In vivo, systemic (but not local) administration of PNU-120596, in the absence of agonist, facilitated dopamine overflow in the medial PFC, consistent with the activation of extracortical alpha7 nAChRs by endogenous acetylcholine or choline. These data establish that both beta2* and alpha7 nAChRs can modulate dopamine release in the PFC in vitro and in vivo. Through their distinct actions on dopamine release, these nAChR subtypes could contribute to executive function, making them specific therapeutic targets for conditions such as schizophrenia and attention deficit hyperactivity disorder.

The Erythrina alkaloids erysodine and dihydro-␤-erythroidine (DH␤E) are potent and selective competitive inhibitors of ␣4␤2 nicotinic acetylcholine receptors (nAChRs), but little is known about the molecular determinants of the sensitivity of this receptor subtype to inhibition by this class of antagonists. We addressed this issue by examining the effects of DH␤E and a range of aromatic Erythrina alkaloids on [ 3 H]cytisine binding and receptor function in conjunction with homology models of the ␣4␤2 nAChR, mutagenesis, and functional assays. The lactone group of DH␤E and a hydroxyl group at position C-16 in aromatic Erythrina alkaloids were identified as major determinants of potency, which was decreased when the conserved residue Tyr126 in loop A of the ␣4 subunit was substituted by alanine. Sensitivity to inhibition was also decreased by substituting the conserved aromatic residues ␣4Trp182 (loop B), ␣4Tyr230 (loop C), and ␤2Trp82 (loop D) and the nonconserved ␤2Thr84; however, only ␣4Trp182 was predicted to contact bound antagonist, suggesting ␣4Tyr230, ␤2Trp82, and ␤2Thr84 contribute allosterically to the closed state elicited by bound antagonist. In addition, homology modeling predicted strong ionic interactions between the ammonium center of the Erythrina alkaloids and ␤2Asp196, leading to the uncapping of loop C. Consistent with this, ␤2D196A abolished sensitivity to inhibition by DH␤E or erysodine but not by epierythratidine, which is not predicted to form ionic bonds with ␤2Asp196. This residue is not conserved in subunits that comprise nAChRs with low sensitivity to inhibition by DH␤E or erysodine, which highlights ␤2Asp196 as a major determinant of the receptor selectivity of Erythrina alkaloids.

A recently developed ␣-conotoxin, ␣-conotoxin Arenatus IB-[V11L,V16D] (␣-CtxArIB[V11L,V16D]), is a potent and selective competitive antagonist at rat recombinant ␣7 nicotinic acetylcholine receptors (nAChRs), making it an attractive probe for this receptor subtype. ␣7 nAChRs are potential therapeutic targets that are widely expressed in both neuronal and nonneuronal tissues, where they are implicated in a variety of functions. In this study, we evaluate this toxin at rat and human native nAChRs.

The aim of this study was to explore the modulation by alpha7 nicotinic receptors (nAChRs) of dopamine and glutamate release in the rat prefrontal cortex where these receptors are implicated in attentional processes and are therapeutic targets for cognitive deficits. The presence of presynaptic alpha7 nAChRs on glutamate terminals is supported by the ability of the subtype-selective agonist Compound A to evoke [(3)H]D-aspartate release from synaptosomes: This response was potentiated by the selective allosteric potentiator PNU-120596 and blocked by alphabungarotoxin. Compound A also evoked dopamine overflow in the prefrontal cortex in vivo, and this was potentiated by PNU-120596. alpha7 nAChR-evoked [(3)H]dopamine release from tissue prisms in vitro was blocked by antagonists of NMDA and AMPA receptors. These data are consistent with a model in which alpha7 nAChRs present on glutamate terminals increase glutamate release that (1) contributes to presynaptic facilitation and synaptic plasticity and (2) co-ordinately enhances dopamine release from neighbouring boutons.

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