Cholinergic modulation of dopaminergic reward areas: upstream and downstream targets of nicotine addiction
Introduction
Tobacco use in the western society is estimated to be the largest single cause of premature death (Peto et al., 1992). Nicotine is the main addictive component of tobacco that motivates continued use despite the harmful effects. Nicotinic acetylcholine receptors are widely distributed throughout the mammalian central nervous system, where they normally respond to acetylcholine and modulate neuronal excitability and synaptic communication. Nicotinic receptors are structurally diverse and mediate a variety of physiological effects. Presynaptic and preterminal nicotinic acetylcholine receptors enhance neurotransmitter release MacDermott et al., 1999, McGehee et al., 1995, McGehee and Role, 1995, Wonnacott, 1997. Postsynaptic and somatic nicotinic acetylcholine receptors mediate a small proportion of fast excitatory transmission and modulate cytoplasmic second messenger systems. Although the impact of nicotine obtained from tobacco is not completely understood, a considerable portion of nicotine's addictive power is attributable to actions ventral tegmental area into the nucleus accumbens is considered to be an important component in the reinforcement of rewarding behaviours, and nicotine along with other drugs of abuse usurp this process to motivate drug seeking and other behaviours associated with addiction. Physiologically relevant nicotine concentrations have been shown to activate both pre- and postsynaptic nicotinic acetylcholine receptors MacDermott et al., 1999, McGehee et al., 1995, McGehee and Role, 1995, Wonnacott, 1997. Important extensions of this work indicate that both activation and desensitisation of diverse nicotinic acetylcholine receptors may be crucial factors underlying the effects of nicotine on the ventral tegmental area Mansvelder et al., 2002, Mansvelder and McGehee, 2000 and the nucleus accumbens (de Rover et al., 2002).
This perspective-report will outline what is currently known about nicotinic modulation of synaptic transmission in these reward areas. Given their reciprocal connection, we will attempt to integrate the different effects of nicotine exposure.
Our strongest insight into the cellular effects of first exposure to nicotine upstream of dopamine neurons comes from the recent studies on the ventral tegmental area Mansvelder et al., 2002, Mansvelder and McGehee, 2000, Pidoplichko et al., 1997. These findings indicate differential distribution of nicotinic acetylcholine receptor subtypes on γ-amino buteric acid (GABA) inputs, glutamate terminals, and dopaminergic neurons within this nucleus and highlight the importance of carefully delineating potential differences in receptor activation and desensitisation when investigating the effects of nicotine.
Downstream of the dopaminergic projection in the nucleus accumbens, nicotinic acetylcholine receptors are also expressed, and a recent study on the endogenous cholinergic modulation of the feed-forward inhibition of GABA output neurons in this brain area from our lab (de Rover et al., 2002) puts new insight into how shifting the balance between GABA and glutamatergic synaptic transmission may further contribute to alterations in reward behaviour. These studies provide a base for future studies elucidating the synaptic mechanisms underlying the onset of nicotine addiction.
Section snippets
Nicotinic receptors in brain reward areas
Nicotinic receptors are pentameric membrane proteins that include two or more agonist binding sites and a central aqueous pore. Agonist binding results in a conformational change that leads to ion flux through the pore, inducing a depolarisation and increased excitability. Pharmacological and ligand-binding studies have demonstrated considerable diversity in neuronal nicotinic acetylcholine receptor subtypes. To date, 12 neuronal nicotinic acetylcholine receptor subunit genes have been
The addictive power of nicotine
In survey studies of human adolescents, the initial symptoms of nicotine dependence can be present after smoking of only a few cigarettes (DiFranza et al., 2000), i.e. before the onset of daily smoking. This demonstrates that human adolescents may become nicotine-dependent after occasional use of nicotine for a short period of time. These findings are consistent with the observation from cellular studies that profound changes in the synaptic physiology of the brain reward system can be observed
Synaptic mechanisms underlying nicotine addiction
Like humans, rodents readily self-administer nicotine when the opportunity is presented in the laboratory. Despite the widespread expression of nicotinic acetylcholine receptors throughout the brain, the activation of nicotinic acetylcholine receptors within the ventral tegmental area is critically important in the rewarding effect of nicotine Nisell et al., 1994, Schilstrom et al., 1998b.
It is remarkable that while a single exposure to nicotine increases dopamine release in the nucleus
First nicotine exposure of the ventral tegmental area
Nicotinic receptors are present on the presynaptic glutamatergic terminals in the ventral tegmental area (Mansvelder and McGehee, 2000). When nicotine arrives in the ventral tegmental area, it stimulates these glutamatergic terminals directly, in addition to activation of postsynaptic nicotine effects on dopamine neurons, thereby favouring conditions of paired electrical stimulation of the pre- and postsynaptic partners. In fact, in our experiments, nicotine could replace presynaptic
Nicotine effects in the nucleus accumbens
The nucleus accumbens contain acetylcholine-releasing interneurones, presumed to play a regulatory role in the electrical activity of medium spiny output neurons. In our lab, it was found recently that GABA-mediated inhibition of the output neurons is facilitated by activation of nicotinic acetylcholine receptors and suppressed via activation of muscarinic acetylcholine receptors (de Rover et al., 2002). The physiological significance of this finding was substantiated by recording from pairs of
Downstream effects of cigarette smoking?
However, what will happen when nicotine arrives in the nucleus accumbens following cigarette smoking? Without doubt, it will facilitate the so-called feed-forward inhibition while leaving the excitatory input to the output neurons relatively unaffected. Initially, nicotine exposure may therefore lead to a reduction of the GABA output coming from the nucleus accumbens. Whether this in turn would reinforce or prolong the initial dopamine surge from the ventral tegmental area needs to be
Downstream cholinergic modulation in behavioural sensitization
As mentioned above, a common feature of many addictive drugs, including nicotine is that they increase dopamine levels in the nucleus accumbens via an initial effect in the ventral tegmental area. Although some drugs of abuse alter dopamine metabolism or reuptake to increase dopamine levels in the nucleus accumbens, nicotine (Mansvelder and McGehee, 2000) and also cocaine (Ungless et al., 2001) appear to alter primarily the activity of ventral tegmental area neurons to enhance dopamine release.
Concluding remarks
Nicotinic receptors have been implicated in a variety of brain functions, including neuronal development, learning and memory formation, and reward. Although there are substantial data indicating that nicotinic acetylcholine receptor subunits are found in many brain regions, until recently, the precise cellular roles of these subunits in neuronal functions have remained elusive. While nicotinic acetylcholine receptors are still thought to primarily serve a modulatory role in the brain by
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