John A. Dani

Nicotine activates and desensitizes midbrain dopamine neurons

Tobacco use in developed countries is estimated to be the single largest cause of premature death. Nicotine is the primary component of tobacco that drives use, and like other addictive drugs, nicotine reinforces self-administration and place preference in animal studies. Midbrain dopamine neurons normally help toshape behaviour by reinforcing biologically rewarding events, but addictive drugs such as cocaine can inappropriately exert a reinforcing influence by acting upon the mesolimbic dopamine system. Here we show that the same concentration of nicotine achieved by smokers activates and desensitizes multiple nicotinic receptors thereby regulating the activity of mesolimbic dopamine neurons. Initial application of nicotine can increase the activity of the dopamine neurons, which could mediate the rewarding aspects of tobacco use. Prolonged exposure to even these low concentrations of nicotine, however, can cause desensitization of the nicotinic receptors, which helps to explain acute tolerance to nicotines effects. The effects suggest a cellular basis for reports that the first cigarette of the day is the most pleasurable, whereas the effect of subsequent cigarettes may depend on the interplay between activation and desensitization of multiple nicotinic receptors.

Molecular and Cellular Aspects of Nicotine Abuse

A simplistic hypothesis can be put forward as a working basis for research (Figure 2Figure 2). Upon smoking a cigarette, a small pulse of nicotine activates nAChRs that directly or indirectly induce DA release that provides a pleasurable effect. It is likely that the mesolimbic dopaminergic system mediates at least part of this reward. With continued use, nicotine builds up to a low steady-state concentration that causes significant nAChR desensitization and (over time) longer-term inactivation. There is evidence that nicotinic receptor turnover decreases following inactivation, leading to an increased number of nAChRs, which subsequently may lead to nicotinic cholinergic systems that are pathological. In between cigarettes, during sleep, or under conditions of abstinence while attempting to stop smoking, nicotine levels drop and a portion of the inactive nAChRs recover to a responsive state. Because of the increased number of nAChRs that have now become responsive in this pathological condition, some cholinergic systems other than the reward pathways become hyperexcitable to synaptically released ACh, contributing to the drive for the next cigarette. Thus, smokers medicate themselves with nicotine to regulate the number of functional nAChRs.Figure 2A Hypothetical Cycle for Perpetuating Nicotine UseThe increased number of nAChRs and the subsequent pathology of nicotinic cholinergic function is hypothesized to develop after chronic use of nicotine. The simplified scheme is described in the text.View Large Image | View Hi-Res Image | Download PowerPoint SlideSuperimposed on this simplistic cycle of nicotine exposure, there may be long-term synaptic changes that result in the learned behaviors that are associated with smoking and with the context in which smoking takes place. Because these behaviors are reinforced by repeated variable rewards from cigarettes (especially after abstinence) and by associated sensory cues, the desire for cigarettes extinguishes slowly and sometimes incompletely. These factors coupled to the easy access of cigarettes and constant advertising contribute to the difficulty in breaking the nicotine habit.

Mice Deficient in the α7 Neuronal Nicotinic Acetylcholine Receptor Lack α-Bungarotoxin Binding Sites and Hippocampal Fast Nicotinic Currents

The α7 subunit of the neuronal nicotinic acetylcholine receptor (nAChR) is abundantly expressed in hippocampus and is implicated in modulating neurotransmitter release and in binding α-bungarotoxin (α-BGT). A null mutation for the α7 subunit was prepared by deleting the last three exons of the gene. Mice homozygous for the null mutation lack detectable mRNA, but the mice are viable and anatomically normal. Neuropathological examination of the brain revealed normal structure and cell layering, including normal cortical barrel fields; histochemical assessment of the hippocampus was also normal. Autoradiography with [3H]nicotine revealed no detectable abnormalities of high-affinity nicotine binding sites, but there was an absence of high-affinity [125I]α-BGT sites. Null mice also lack rapidly desensitizing, methyllycaconitine-sensitive, nicotinic currents that are present in hippocampal neurons. The results of this study indicate that the α-BGT binding sites are equivalent to the α7-containing nAChRs that mediate fast, desensitizing nicotinic currents in the hippocampus. These mice demonstrate that the α7 subunit is not essential for normal development or for apparently normal neurological function, but the mice may prove to have subtle phenotypic abnormalities and will be valuable in defining the functional role of this gene product in vivo.

Calcium modulation and high calcium permeability of neuronal nicotinic acetylcholine receptors

Two properties were found to distinguish neuronal from muscle nicotinic acetylcholine receptors (nAChRs). First, neuronal nAChRs have a greater Ca2+ permeability. The high Ca2+ flux through neuronal nAChRs activates a Ca(2+)-dependent Cl- conductance, and the Ca2+ to Cs+ permeability ratio (PCa/PCs) is 7 times greater for neuronal than for muscle nAChRs. A second difference between the receptor types is that neuronal nAChRs are potently modulated by physiological levels of external Ca2+. Neuronal nAChR currents are enhanced by external Ca2+ in a dose-dependent manner. The results indicate that changes in extracellular Ca2+ modulate neuronal nAChRs and may modulate cholinergic synapses in the CNS. Also, activation of neuronal nAChRs produces a significant influx of Ca2+ that could be an important intracellular signal.

Endogenous nicotinic cholinergic activity regulates dopamine release in the striatum

Dopamine is vital for coordinated motion and for association learning linked to behavioral reinforcement. Here we show that the precise overlap of striatal dopaminergic and cholinergic fibers underlies potent control of dopamine release by ongoing nicotinic receptor activity. In mouse striatal slices, nicotinic antagonists or depletion of endogenous acetylcholine decreased evoked dopamine release by 90%. Nicotine at the concentration experienced by smokers also regulated dopamine release. In mutant mice lacking the β2 nicotinic subunit, evoked dopamine release was dramatically suppressed, and those mice did not show cholinergic regulation of dopamine release. The results offer new perspectives when considering nicotine addiction and the high prevalence of smoking in schizophrenics.

Timing and location of nicotinic activity enhances or depresses hippocampal synaptic plasticity.

This study reveals mechanisms in the mouse hippocampus that may underlie nicotinic influences on attention, memory, and cognition. Induction of synaptic plasticity, arising via generally accepted mechanisms, is modulated by nicotinic acetylcholine receptors. Properly timed nicotinic activity at pyramidal neurons boosted the induction of long-term potentiation via presynaptic and postsynaptic pathways. On the other hand, nicotinic activity on interneurons inhibited nearby pyramidal neurons and thereby prevented or diminished the induction of synaptic potentiation. The synaptic modulation was dependent on the location and timing of the nicotinic activity. Loss of these synaptic mechanisms may contribute to the cognitive deficits experienced during Alzheimers diseases, which is associated with a loss of cholinergic projections and with a decrease in the number of nicotinic receptors.

Overview of nicotinic receptors and their roles in the central nervous system

Alzheimers disease is a complex disorder affecting multiple neurotransmitters. In particular, the degenerative progression is associated with loss within the cholinergic systems. It should be anticipated that both muscarinic and nicotinic mechanisms are affected as cholinergic neurons are lost. This review focuses on the basic roles of neuronal nicotinic receptors, some subtypes of which decrease during Alzheimers disease. Nicotinic acetylcholine receptors belong to a superfamily of ligand-gated ion channels that play key roles in synaptic transmission throughout the central nervous system. Neuronal nicotinic receptors, however, are not a single entity, but rather there are many different subtypes constructed from a variety of nicotinic subunit combinations. This structural diversity and the presynaptic, axonal, and postsynaptic locations of nicotinic receptors contribute to the varied roles these receptors play in the central nervous system. Presynaptic and preterminal nicotinic receptors enhance neurotransmitter release, and postsynaptic nicotinic receptors mediate a small minority of fast excitatory transmission. In addition, some nicotinic receptor subtypes have roles in synaptic plasticity and development. Nicotinic receptors are distributed to influence many neurotransmitter systems at more than one location, and the broad, but sparse, cholinergic innervation throughout the brain ensures that nicotinic acetylcholine receptors are important modulators of neuronal excitability.

Cellular mechanisms of nicotine addiction

In developed countries, tobacco use is estimated to be the largest single cause of premature death [Lancet 339 (1992) 1268]. Nicotine is the main addictive component of tobacco that motivates continued use despite the harmful effects. Nicotinic acetylcholine receptors (nAChRs) are widely distributed throughout the mammalian central nervous system (CNS), where they normally respond to acetylcholine (ACh) and modulate neuronal excitability and synaptic communication. Nicotinic receptors are structurally diverse and have varied roles. Presynaptic and preterminal nAChRs enhance neurotransmitter release. Postsynaptic and somal nAChRs 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 portion of nicotines addictive power is attributable to actions upon the dopaminergic systems, which normally help to reinforce rewarding behaviors. As obtained from tobacco, nicotine activates and desensitizes nAChRs, and both processes contribute to the cellular events that underlie nicotine addiction.

Differential Desensitization and Distribution of Nicotinic Acetylcholine Receptor Subtypes in Midbrain Dopamine Areas

Although many psychopharmacological factors contribute to nicotine addiction, midbrain dopaminergic systems have received much attention because of their roles in reinforcement and associative learning. It is generally thought that the mesocorticolimbic dopaminergic system is important for the acquisition of behaviors that are reinforced by the salient drives of the environment or by the inappropriate stimuli of addictive drugs. Nicotine, as obtained from tobacco, can activate nicotinic acetylcholine receptors (nAChRs) and excite midbrain neurons of the mesocorticolimbic system. Using midbrain slices from rats, wild-type mice, and genetically engineered mice, we have found differences in the nAChR currents from the ventral tegmental area (VTA) and the substantia nigra compacta (SNc). Nicotinic AChRs containing the α7 subunit (α7* nAChRs) have a low expression density. Electrophysiological analysis of nAChR currents, autoradiography of [125I]-α-bungarotoxin binding, and in situ hybridization revealed that α7* nAChRs are more highly expressed in the VTA than the SNc. In contrast, β2* nAChRs are move evenly distributed at a higher density in both the VTA and SNc. At the concentration of nicotine obtained by tobacco smokers, the slow components of current (mainly mediated by β2* nAChRs) become essentially desensitized. However, the minority α7* component of the current in the VTA/SNc is not significantly desensitized by nicotine in the range ≤100 nm. These results suggest that nicotine, as obtained from tobacco, can have multiple effects on the midbrain areas by differentially influencing dopamine neurons of the VTA and SNc and differentially desensitizing α7* and non-α7 nAChRs.

Nicotine addiction and comorbidity with alcohol abuse and mental illness

The World Health Organization estimates that one-third of the global adult population smokes. Because tobacco use is on the rise in developing countries, death resulting from tobacco use continues to rise. Nicotine, the main addictive component of tobacco, initiates synaptic and cellular changes that underlie the motivational and behavioral alterations that culminate in addiction. Nicotine addiction progresses rapidly in adolescents and is most highly expressed in vulnerable people who have psychiatric illness or other substance abuse problems.