Nicotine Dependence Perpetuating Tobacco Smoking May Be Treatable by Drugs Acting at Glutamate Receptors
Abstract: On average, tobacco smoking leads to a loss of 8 years in lifespan. 70% of smokers have tried to quit but only 6% succeeded. Two separate groups of receptors in the brain govern the sensory stimulation by nicotine and depression-like symptoms of nicotine withdrawal. Drugs targeting both groups may help smokers quit.
By the year 2020 tobacco smoking will become the single largest health problem worldwide leading to approximately 8.4 million deaths annually. In the USA alone, tobacco smoking leads to serious illness in an estimated 8.6 million people, causing roughly 440,000 deaths annually, and approximately $157 billion in health-related economic costs. On average, smoking leads to a loss of 12 healthy years and reduces the lifespan by 8 years. Almost a quarter of the USA population are tobacco smokers. The percentage of smokers is even higher in some other countries, and there is an alarming increase of tobacco use in the developing countries.
The cost of tobacco smoking to society is tremendous in terms of health problems that frequently lead to death, medical costs and human suffering. In the USA and Europe, 70% of all smokers have considered quitting smoking at least once, and 35% try to quit at least once a year. Yet only approximately 6% succeed in maintaining abstinence. Therefore, there is a great need for the discovery and development of new treatments to assist people in achieving and maintaining abstinence from tobacco smoking.
Nicotine and the Harmful Health Effects of Tobacco Smoking
Overwhelming evidence indicates that nicotine is the main chemical ingredient in tobacco responsible for addiction. Nicotine stimulates nicotinic acetylcholine receptors (nAchR) found throughout the brain. These nicotinic receptors are normally activated by acetylcholine, a chemical found naturally in the brain. Such activation of nicotinic receptors by acetylcholine is involved in the chemical communication among neurons in the brain. In addition to nicotine, there are over 4,000 other chemicals in tobacco and cigarette smoke, many of which also could contribute to the maintenance of the tobacco smoking habit either through their own pharmacological properties or interactions with nicotine. Sensory stimulation from the smoke, the acquired “taste” for cigarettes, and the habitual behavioral patterns of smokers, such as having a cigarette with the morning coffee, also contribute to the tobacco smoking habit.
Nevertheless, the pharmacological actions of nicotine are the ones that primarily lead to dependence and addiction. Therefore, much research is directed towards investigating the neurobiology of nicotine dependence to understand what maintains the tobacco smoking habit as a first step towards identifying therapeutic targets for smoking cessation. Currently, the most widely used treatments to aid smoking cessation are nicotine replacement therapies that enable the smoker to substitute the nicotine from cigarettes with other safer nicotine formulations, such as chewing gum, transdermal (skin) patches, lozenges and inhalers. Another therapy that is not nicotine-based is the atypical antidepressant bupropion (Zyban). Unfortunately, first year relapse rates with these treatments are as high as 80%, further emphasizing the need for additional and alternative treatments for smoking.
Two Fundamental Aspects of Addiction
The currently available treatments for tobacco smoking are not as effective as desired because each treatment may not deal with all the factors that lead to the maintenance of the tobacco smoking habit. In humans, nicotine produces positive effects including mild euphoria, increased energy, heightened arousal, an increased ability to concentrate and focus, reduced stress and anxiety, and appetite suppression. Some of these positive effects of nicotine are experienced after the person has developed tolerance to the initial aversive effects of nicotine, which include a dislike for the smoke taste and nausea. In contrast to the acute pleasant effects of nicotine, smoking cessation leads to an aversive withdrawal syndrome comprised of affective symptoms, such as depressed mood, dysphoria (emotional discomfort), craving, anxiety, irritability and difficulty concentrating. In other words, nicotine addiction is characterized by a nicotine-induced positive affect, followed by a withdrawal-associated negative affect, such as depressed mood. Therefore, it is not surprising that habitual smokers tend to seek the pleasurable effects of tobacco smoking and want to avoid the discomfort and distress associated with withdrawal from tobacco smoking. Such nicotine-induced positive and negative affective states provide crucial sources of motivation that drive compulsive drug consumption in the form of tobacco smoking. Consequently, both the positive mildly euphoric properties of nicotine and the desire to avoid the aversive negative effect of nicotine withdrawal contribute to the perpetuation of the tobacco smoking habit.
Accordingly, treatments that block the positive euphoria induced by nicotine and/or treat the negative affects of nicotine withdrawal are likely to be effective, as long as they are administered at the relevant times. That is, some treatments may be effective in blocking the mildly positive euphoria induced by nicotine, making tobacco smoking not pleasurable and not worth engaging in. Other treatments may soothe the mild depression-like symptoms of nicotine withdrawal. The discovery of such new treatments requires thorough evaluation in experimental animals before the new drugs are tested in humans.
Although assessing affect and emotion is difficult to accomplish in experimental animals, there are techniques that allow animals to communicate to us how they “feel” through their behavior in sophisticated experimental tasks. The behavior of experimental animals in some of these tasks closely resembles the way people behave when immersed in a similar environment. Specifically, the positive euphoria induced by nicotine and the effects of pharmacological treatments on this nicotine-induced euphoria can be evaluated in laboratory animals using the intravenous nicotine self-administration procedure (see Figure 1A). The negative emotional depression-like actions of nicotine withdrawal can be evaluated in
laboratory animals using the intracranial self-stimulation procedure (see Figure 2A).
Ionotropic and Metabotropic Glutamate Receptors
Glutamate is the major excitatory neurotransmitter in the central nervous system of mammals. Like acetylcholine, glutamate is involved in the chemical communication between neurons. The actions of glutamate are regulated by ionotropic and metabotropic glutamate (mGlu) receptors. Ionotropic glutamate receptors are primarily located postsynaptically, that is, at the site on the neuron that receives information from other neurons via a synapse (space between two neurons across which a signal is passed by a neurotransmitter). These receptors are ion channels that when activated increase neuron excitability. Ionotropic receptors consist of the following receptor subtypes: NMDA (N-methyl-D-aspartate), AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate) and kainate. The metabotropic receptors are classified into three groups: Group I, Group II and Group III. These receptors act on a downstream effector via a signaling pathway rather than being the effector (e.g., an ion channel) as ionotropic receptors are. Group I metabotropic receptors include the mGlu1 and mGlu5 receptors, and are predominately located postsynaptically. Group II metabotropic receptors consist of mGlu2 and mGlu3 receptors. These receptors are found mostly presynaptically, that is, at the site of the neuron that sends chemical information to other neurons. Finally, Group III metabotropic receptors consist of mGlu4, mGlu6, mGlu7 and mGlu8 receptors, and are also predominately located presynaptically.
Due to their localization at the presynaptic site, Group II and III metabotropic receptors regulate the amount of glutamate that is released by the neuron based on how much glutamate is already in the space (synaptic cleft) between the two neurons. When there is too much glutamate in the synapse, the presynaptic metabotropic receptors are activated and communicate to the presynaptic neuron to decrease glutamate release. Therefore, these presynaptic receptors are inhibitory and provide a negative feedback mechanism to control glutamate levels to keep them within a normal range (see Figure 4).
Interestingly, there are also presynaptic nicotinic acetylcholine receptors on glutamate neurons. These presynaptic nicotinic receptors are excitatory and increase glutamate release when activated. Hence, there is a delicate balance in the signal communicated by glutamate between neurons. This balance is regulated by excitatory presynaptic nicotinic receptors, inhibitory presynaptic metabotropic glutamate receptors, and excitatory postsynaptic glutamate receptors.
When nicotine is administered by smoking tobacco it acts on these presynaptic excitatory nicotinic receptors and there is an increase in glutamate release, which in turn activates postsynaptic neurons to release the neurotransmitter dopamine. Dopamine is another neurotransmitter system in the brain that is strongly implicated in brain reward mechanisms. This increase in glutamate and dopamine partly leads to the mild euphoric effects of tobacco smoking. However, long-term disruption of this delicate balance through daily tobacco smoking forces the glutamate receptors to change their activity to maintain glutamate levels within the normal homeostatic range. It is this change in neurotransmitter function that occurs with chronic nicotine exposure that leads to addiction and the affective depression-like aspects of nicotine withdrawal. When tobacco smoking stops and nicotine is no longer available to activate the glutamate neuron, the altered function of both presynaptic and postsynaptic glutamate receptors leads to decreased glutamate communication between neurons. Such decreased glutamate transmission likely mediates, at least partly, the depression-like aspects of nicotine withdrawal (see Figure 4).
Consequently pharmacological treatments acting at glutamate receptors may alter both the positive effects of tobacco smoking and reverse the negative aspects of nicotine withdrawal when smoking stops. Drugs acting at metabotropic glutamate receptors may be better targets for drug discovery and development than ionotropic glutamate receptors. Ionotropic glutamate receptors mediate “fast” glutamate transmission, and their excitation can lead to severe toxic effects. By contrast, metabotropic glutamate receptors mediate “slow” glutamatergic transmission. Their activation does not appear to lead to toxic effects, and their effects are more subtle and modulatory than those of ionotropic receptors. Further, metabotropic glutamate receptors exhibit a more restricted, site-specific localization in the mammalian brain than ionotropic receptors. Finally, the metabotropic receptors are located both presynaptically and postsynaptically, while the ionotropic receptors are located only postsynaptically. As such, the various metabotropic glutamate receptors are likely, albeit diverse, targets for the development of new pharmacological therapeutics that will modulate glutamate function in more subtle and specific ways than ionotropic receptors.
Blockade of mGlu5 Receptors Blocks the Positive Mild Euphoric Effects of Nicotine
Based on the neurobiology of the glutamate system described above and the influence of nicotine on glutamate function, it is not surprising that there is accumulating evidence strongly suggesting that modulation of glutamate transmission through actions at metabotropic glutamate receptors alters nicotine’s effects on the brain and behavior. Some of this evidence involves the use of the intravenous nicotine self-administration procedure in rodents. This procedure involves surgically preparing rats or mice with a catheter in the jugular vein and allowing them to press a lever to self-administer small doses of nicotine for one hour daily (Figure 1A). Voluntary self-administration of nicotine indicates that nicotine has reinforcing properties that likely reflect the positive euphoric effects of nicotine. Accordingly, this technique provides a reliable, valid and robust model of human nicotine consumption. The patterns of intravenous nicotine self-administration in non-human primates, rodents and humans tested in the laboratory are very similar. As one would expect, administration of a drug that counteracts the effects of nicotine at nicotinic acetylcholine receptors (called an antagonist; whereas a drug that mimics the effects of nicotine on the receptor is known as an agonist) before nicotine is administered, decreases nicotine self-administration in rats. This reflects the blockade of the reinforcing properties of nicotine by preventing nicotine from activating nicotinic acetylcholine receptors.
Another way of decreasing the indirect effects of nicotine on glutamate transmission is by blocking the effects of glutamate at postsynaptic glutamate receptors. Indeed, using the intravenous nicotine self-administration procedure, it was shown that administration of the mGlu5 receptor antagonist MPEP (2-methyl-2[phenyl-ethenyl]-pyridine) decreased self-administration of either of two different doses of nicotine, without altering the responding for food rewards in rats and mice (see Figure 1B). These results are consistent with other data demonstrating that mice in which the gene for the mGlu5 receptor was deleted would not self-administer cocaine. However, responding for food was unchanged in these same mice.
Taken together, the above data indicate that the diminished or absence of responding for nicotine or cocaine was not due to deficits in learning and cognitive ability, or motor effects of the manipulation. Consistent with the above findings, the mGlu5 receptor antagonist MPEP also decreased cocaine self-administration in wild-type mice and rats, and decreased alcohol self-administration in mice. These observations suggest that mGlu5 receptors play a crucial role in regulating self-administration of most major drugs of abuse, including self-administration of nicotine. Thus, mGlu5 receptor blockade may lead to a voluntary reduction in tobacco smoking in humans with no cognitive or motor side-effects.
Blockade of mGlu2/3 Receptors Reverses the Anhedonia of Nicotine Withdrawal
As discussed above, with chronic nicotine administration through tobacco smoking there are adaptations in glutamate receptor activity to counteract the stimulatory effects of nicotine on the glutamate system. When tobacco smoking ceases, these adaptations remain unopposed leading to decreased glutamate levels and the negative effect of nicotine withdrawal. Thus, pharmacological treatments acting at metabotropic glutamate receptors that increase glutamate activity without toxic effects are likely to reverse the depression-like symptoms of withdrawal.
One way to assess the negative effect of nicotine withdrawal is with the intracranial self-stimulation procedure in rodents. In the 1950’s, it was discovered that brief electrical pulses of specific brain sites is extremely reinforcing for animals, including humans, probably because these electrical pulses activate the brain’s reward circuits (see Figure 2A). This procedure involves surgically preparing rats with an electrode in part of the brain’s reward pathways, such as the lateral hypothalamus, and assessing the function of the brain’s reward systems (see Figure 2A and Figure 3).
The extraordinary strength of the hedonic (pleasurable) effect produced by intracranial self-stimulation is indicated by the rapid learning and vigorous execution of the stimulation-producing behavior, as well as by the competitive preference for intracranial self-stimulation over other rewards, such as food and water. This high reward value suggests that the stimulation directly activates the same neuronal circuits that are activated by natural reinforcers, and thus provides a direct measure of brain reward function. Reward thresholds are measured by recording the subject’s responses as the current intensity of the electrical stimulus is varied. Elevations in thresholds indicate that higher current intensities are required for the rat to perceive the stimulation as rewarding, and therefore reflect decreased brain reward function and a general anhedonic (depressive) effect.
Anhedonia is defined as deriving decreased pleasure from stimuli and situations that induced pleasure previously. Anhedonia is a core symptom of depression, and is also seen during nicotine withdrawal. Withdrawal from chronic administration of all major drugs of abuse, including nicotine, results in elevated reward thresholds reflecting an anhedonic depression-like state (see Figure 3). Similar elevations in reward thresholds are seen when nicotine-dependent rats are injected with nicotinic acetylcholine receptor antagonists, which elicit a nicotine withdrawal syndrome. Thus, although negative affective states are difficult to measure and quantify in animals, the intracranial self-stimulation procedure provides a quantitative measure of brain reward function in animals that can reflect the negative affective depression-like state of nicotine withdrawal.
To investigate which glutamate receptors exhibit changes in their activity with the development of nicotine dependence, rats were chronically exposed to nicotine or saline through the implantation of osmotic minipumps beneath the skin, and then treated with drugs that probe ionotropic and metabotropic glutamate receptors. If withdrawal-like elevations in reward thresholds are seen in nicotine-dependent, but not control, rats after administration of a glutamate drug, then this would be an indication that there are changes in the function of the particular receptor with the development of nicotine dependence. Such a finding would be analogous to eliciting nicotine withdrawal with a nicotinic receptor antagonist.
Administration of the agonist drug LY314582 ([±]-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid), which excites presynaptic mGlu2/3 receptors, elevated reward thresholds in nicotine-dependent, but not control, rats. Considering that mGlu2/3 receptors are located presynaptically, activation of these receptors decreases glutamate transmission. These findings indicate that there is an increased activity of the mGlu2/3 receptors with the development of nicotine dependence to counteract the nicotine-induced increases in glutamate transmission. Based on these observations, it was predicted that administration of an mGlu2/3 receptor antagonist would reverse the reward threshold elevations seen during spontaneous withdrawal when nicotine administration is stopped abruptly. Indeed, this prediction was shown to be accurate. Administration of the mGlu2/3 receptor antagonist LY341495 (2S-2-amino-2-[1S,2S-2-carboxycyclopropan-1-yl]-3-[xanth-9-yl]propionic acid) reversed the negative affective aspects of nicotine withdrawal in rats (see Figure 2B).
These observations suggest that during the development of nicotine dependence there is an increase in the activity of presynaptic mGlu2/3 receptors to counteract the stimulatory effects of nicotine on glutamate transmission. When nicotine administration ceases, this increased activity in presynaptic mGlu2/3 receptors results in decreased glutamate release that leads to the depression-like aspects of nicotine withdrawal. Administration of an mGlu2/3 receptor antagonist restores glutamate levels and the normal functioning of the brain’s reward circuits, and thus reverses the anhedonic state of nicotine withdrawal (Figure 4). Therefore, it appears that antagonism at mGlu2/3 receptors would be an effective treatment for the negative affective depression-like aspects of nicotine withdrawal. Amelioration of the depression-like aspects of nicotine withdrawal would decrease the discomfort of nicotine withdrawal and make it easier for people to maintain their abstinence state and resist a relapse to tobacco smoking.
Summary and Conclusions
Tobacco smoking is the largest preventable cause of illness and death. Nicotine is the main chemical ingredient in tobacco smoking responsible for addiction. Once dependence develops, tobacco smoking is maintained both by the desire to experience the positive euphoric effects of nicotine and the motivation to avoid the aversive affective aspects of nicotine withdrawal. Glutamate is a neurotransmitter system that participates in the chemical communication between neurons via actions at metabotropic and ionotropic glutamate receptors. Evidence has shown that an antagonist at metabotropic glutamate 5 receptors blocked the euphoric effects of nicotine, while an antagonist at metabotropic glutamate 2/3 receptors reversed the depression-like symptoms of nicotine withdrawal. Thus, sequential pharmacological treatment first with a metabotropic glutamate 5 receptor antagonist and then with a metabotropic glutamate 2/3 receptor antagonist would first decrease tobacco smoking, and then ameliorate the negative affective aspects of nicotine withdrawal. Both of these actions would assist people in quitting smoking, maintaining abstinence and reducing the risk of relapse to smoking.
The author’s laboratory is funded by research grants from the National Institutes of Health, the State of California, and Novartis Pharma AG.
References and Further Readings
Cryan JF, Gasparini F, van Heeke G, Markou A. Non-nicotinic neuropharmacological strategies for nicotine dependence: beyond bupropion. Drug Discovery Today 8(22):1025-1034, 2003.
Kenny PJ, Markou A. The ups and downs of addiction: Role of metabotropic glutamate receptors. Trends in Pharmacological Sciences 25:265-272, 2004.
Markou A, Kenny PJ. Neuroadaptations to chronic exposure to drugs of abuse: Relevance to depressive symptomatology seen across psychiatric diagnostic categories. Neurotoxicity Research 4(4):297-313, 2002.
Paterson NE, Semenova S, Gasparini F, Markou A. The mGluR5 antagonist MPEP decreased nicotine self-administration in rats and mice. Psychopharmacology 167:257-264, 2003.
[Discovery Medicine, 4(23):246-254, 2004]