Cholinergic modulation of dopaminergic reward areas: upstream and downstream targets of nicotine addiction

https://doi.org/10.1016/j.ejphar.2003.08.099Get rights and content

Abstract

Nicotine reinforces smoking behaviour by activating nicotinic acetylcholine receptors in the midbrain dopaminergic reward centres. Upstream of the dopaminergic neurons nicotine induces long-term potentiation of the excitatory input to dopamine cells in the ventral tegmental area, and depresses inhibitory inputs. Both effects of nicotine were shown to last much longer than the nicotine exposure and together will activate the dopaminergic ventral tegmental area projection toward the nucleus accumbens. However, downstream of dopamine, effects of nicotine are also likely to occur. Cholinergic interneurons within the nucleus accumbens are important in the tonic control of the γ-amino buteric acid (GABA) nucleus accumbens output neurons, which project back to the ventral tegmental area. The nicotinic acetylcholine receptors that mediate this control are likely to desensitise upon preexposure to the nicotine concentrations found in the blood of smokers. Thus, synaptic mechanisms both upstream and downstream of dopamine release are potentially important factors contributing to the etiology 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

References (47)

  • I. Walaas et al.

    Biochemical evidence for gamma-aminobutyrate containing fibres from the nucleus accumbens to the substantia nigra and ventral tegmental area in the rat

    Neuroscience

    (1980)
  • S. Wonnacott

    Presynaptic nicotinic ACh receptors

    Trends Neurosci.

    (1997)
  • M. Zoli et al.

    Volume transmission in the CNS and its relevance for neuropsychopharmacology

    Trends Pharmacol. Sci.

    (1999)
  • M. Alkondon et al.

    Diversity of nicotinic acetylcholine receptors in rat hippocampal neurons: I. Pharmacological and functional evidence for distinct structural subtypes

    J. Pharmacol. Exp. Ther.

    (1993)
  • N. Champtiaux et al.

    Distribution and pharmacology of alpha 6-containing nicotinic acetylcholine receptors analyzed with mutant mice

    J. Neurosci.

    (2002)
  • E. Charpantier et al.

    Nicotinic acetylcholine subunit mRNA expression in dopaminergic neurons of the rat substantia nigra and ventral tegmental area

    NeuroReport

    (1998)
  • M. de Rover et al.

    Cholinergic modulation of nucleus accumbens medium spiny neurons

    Eur. J. Neurosci.

    (2002)
  • G. Di Chiara et al.

    Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats

    Proc. Natl. Acad. Sci. U. S. A.

    (1988)
  • J.R. DiFranza et al.

    Initial symptoms of nicotine dependence in adolescents

    Tob. Control

    (2000)
  • C.D. Fiorillo et al.

    Cholinergic inhibition of ventral midbrain dopamine neurons

    J. Neurosci.

    (2000)
  • C.J. Frazier et al.

    Synaptic potentials mediated via alpha-bungarotoxin-sensitive nicotinic acetylcholine receptors in rat hippocampal interneurons

    J. Neurosci.

    (1998)
  • M. Garzon et al.

    Cholinergic axon terminals in the ventral tegmental area target a subpopulation of neurons expressing low levels of the dopamine transporter

    J. Comp. Neurol.

    (1999)
  • S. Hefft et al.

    Synaptic transmission at nicotinic acetylcholine receptors in rat hippocampal organotypic cultures and slices

    J. Physiol.

    (1999)
  • Cited by (117)

    • Critical Role of Cannabinoid CB1 Receptors in Nicotine Reward and Addiction

      2016, Neuropathology of Drug Addictions and Substance Misuse
    View all citing articles on Scopus
    View full text