CNS Drugs

, Volume 22, Issue 9, pp 705–724 | Cite as

Role of the Glutamatergic System in Nicotine Dependence

Implications for the Discovery and Development of New Pharmacological Smoking Cessation Therapies
Leading Article

Abstract

Preclinical research findings in laboratory animals indicate that the glutamatergic system is critically involved in nicotine dependence. In animals, compounds that decrease glutamatergic neurotransmission, such as antagonists at postsynaptic NMDA receptors, antagonists at excitatory postsynaptic metabotropic glutamate (mGlu) 5 receptors, or agonists at inhibitory presynaptic mGlu2 and mGlu3 receptors, decreased nicotine self-administration or reinstatement of nicotine-seeking behaviour. These findings suggest that medications that decrease glutamatergic transmission overall may reduce the reinforcing effects of tobacco smoking and prevent relapse to tobacco smoking in humans. Furthermore, compounds that increase glutamate release, such as antagonists at mGlu2 and mGlu3 receptors, ameliorated reward deficits associated with nicotine withdrawal in animals, and thus may alleviate the depression-like symptoms associated with nicotine withdrawal in humans. Animal studies also showed that α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate receptors did not appear to be involved in mediating the primary reinforcing effects of nicotine but that they may be involved in the development of nicotine dependence and withdrawal.

Taken together, the preclinical data indicate that different glutamatergic receptors are involved in the mediation of different aspects of nicotine dependence. These findings have implications for the discovery and development of new pharmacotherapies that target the glutamatergic system to aid in smoking cessation. At present, very few clinical studies have addressed the effects of glutamatergic compounds on cigarette smoking. Clinical studies involving compounds that have actions at ionotropic glutamate receptors are briefly discussed in this review and suggest the potential of glutamatergic compounds as pharmacotherapies to aid in smoking cessation. Medications that target mGlu receptors have recently been tested in human phase II trials for various indications; however, the potential of these mGlu compounds as medications for nicotine dependence remains to be evaluated in humans. The preclinical data evaluated in this review indicate that such clinical trials for smoking cessation with mGlu compounds are clearly warranted and may reveal novel treatments for nicotine dependence.

1. Brain Circuits Involved in Nicotine Dependence: Emphasis on Glutamate

Nicotine is one of the primary psychoactive components of tobacco smoke that promotes the tobacco smoking habit.[1] Nicotine activates nicotinic acetylcholine receptors (nAchRs), which are widely distributed throughout the CNS.[2, 3, 4, 5] Much emphasis has been placed on the critical role that the mesocorticolimbic dopaminergic system plays in mediating the incentive motivational properties of all drugs of abuse, including nicotine.[6, 7, 8, 9, 10, 11] Nevertheless, there are accruing data indicating a crucial role of glutamatergic transmission in the incentive motivational properties of nicotine, as well as various other aspects of nicotine dependence.[12, 13, 14] Indeed, there are close interactions between the glutamatergic and dopaminergic neurotransmitter systems that, together with other neurotransmitter systems such as the GABA system, form brain circuits that mediate the various aspects of nicotine dependence.

Figure 1 depicts some of these brain circuits, with an emphasis on glutamatergic and dopaminergic systems, as well as the localization of nAChRs, which are the target for nicotine. Many nAChRs are located presynaptically and positively regulate the release of various neurotransmitters, including glutamate.[15, 16, 17] One primary site of action of nicotine that has been studied extensively is the excitation of dopamine and glutamate neurons by nicotine in the ventral tegmental area (VTA).[18, 19, 20, 21, 22] Nicotine directly activates α4β2 nAChRs on dopamine neurons in the VTA,[22, 23, 24] but also acts on α7 nAChRs on glutamate neurons[17,19,20] and leads to the release of glutamate. This nicotine-induced release of glutamate in the VTA stimulates dopaminergic neurons that project to the nucleus accumbens (NAc), the prefrontal cortex (PFC) and the amygdala.[6, 7, 8, 9, 10,25] The mesocorticolimbic dopamine system also receives excitatory glutamatergic input from various brain areas. The VTA receives excitatory glutamatergic projections from the PFC, NAc, habenula, amygdala, pedunculopontine tegmentum and laterodorsal tegmentum.[25, 26, 27, 28, 29] The NAc receives glutamatergic input from the PFC, amygdala, hippocampus and thalamus (figure 1).[26,30,31] Direct glutamate-dopamine interactions have been described in the VTA, NAc, PFC and amygdala.[28,32]

Fig. 1

Diagram of a sagittal section of a rodent brain showing brain sites involved in the neurochemical and behavioural effects of nicotine, with an emphasis on glutamate-dopamine interactions. Nicotine binds to nicotinic acetylcholine receptors that are located throughout the brain and presynaptically regulate the release of several neurotransmitters, including that of glutamate. There are several interacting cortical and subcortical brain circuits that consist of several brain sites interconnected by glutamatergic and dopaminergic projections. Major glutamatergic and dopaminergic projections are depicted in the figure. Amy = amygdala; Hab = habenula; Hipp = hippocampus; LDT = laterodorsal tegmentum; NAc = nucleus accumbens; PFC = prefrontal cortex; PPT = pedunculopontine tegmentum; Thal = thalamus; VTA = ventral tegmental area.

In summary, there is increasing evidence to suggest that there is an important role for the glutamate system, including its interaction with the mesocorticolimbic dopamine system, in the neurobiological processes underlying dependence on nicotine[12, 13, 14] and other drugs of abuse.[33, 34, 35, 36] However, it should be noted that other neurotransmitter systems, such as GABA,[8,37] and other brain sites, such as the insula,[38] may also participate in the mediation of the various effects of nicotine that are relevant to nicotine dependence. In this review, we summarize recent preclinical research in laboratory animals that investigated the role of the glutamatergic system in nicotine dependence. Furthermore, we discuss the implications of these findings for the discovery and development of new glutamatergic compounds as treatments for smoking cessation in the context of recently reported clinical studies in humans with glutamatergic receptor ligands.

Medications currently marketed for smoking cessation act through nAchRs and/or activate the monoamine neurotransmitter systems. These pharmacological treatments include nicotine replacement therapies, the nAChR α4β2 partial agonist varenicline[39] and the atypical antidepressant bupropion, an inhibitor of the dopamine and noradrenaline (norepinephrine) transporter and an antagonist at nAChRs at high doses.[40] Although most smokers wish to stop, few succeed. Relapse rates are as high as 80% 1 year after the quit date, even with the help of the available medications and additional nonpharmacological therapies.[41, 42, 43] Therefore, despite the availability of currently approved medications for smoking cessation, there is still a great need to develop and test alternative therapies, including non-nicotinic and non-dopaminergic agents, which will facilitate smoking cessation and assist in maintaining abstinence. Glutamate receptors, particularly metabotropic glutamate (mGlu) receptors, are potential targets for new smoking cessation medications.

1.1 Glutamate Receptors

Glutamate is the most abundant excitatory neurotransmitter in the brain. Glutamate activates ionotropic (iGlu) and metabotropic glutamate (mGlu) receptors.[44] iGlu receptors are ligand-gated ion channels that mediate fast excitatory neurotransmission. iGlu receptors are located postsynaptically and include the NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate receptor subtypes. mGlu receptors are located pre- and postsynaptically, as well as on glial cells.[45]

mGlu receptors are classified into three groups (I–III) based on sequence homology, transduction mechanisms and pharmacology.[46] Group I mGlu receptors (mGlu1 and mGlu5) are coupled via Gq proteins to phospholipase C, and are located primarily postsynaptically, where they positively mediate the excitatory effects of glutamate on NMDA receptors.[45,47, 48, 49] Accordingly, it was shown that blockade of mGlu5 receptors decreases glutamate neurotransmission.[49] In contrast, mGlu1 receptor stimulation in the NAc releases glutamate from presynaptic terminals.[50] Group II (mGlu2 and mGlu3) receptors are coupled to Gi proteins and inhibit adenylate cyclase activity. Group III (mGlu4, mGlu6, mGlu7 and mGlu8) receptors are also coupled to Gi proteins and also inhibit adenylate cyclase activity. mGlu2 and mGlu3 receptors are of particular interest because of their hypothesized role in several psychiatric disorders and the potential availability of mGlu2 and mGlu3 receptor agonists for clinical use (see section 5.2). mGlu2 and mGlu3 receptors function as inhibitory autoreceptors that regulate glutamate release or presynaptic heteroceptors that control the release of neurotransmitters other than glutamate.[45] Activation of mGlu2 and mGlu3 receptors reduces evoked glutamate release and decreases glutamate-mediated excitation of postsynaptic receptors.[45] mGlu2 and mGlu3 receptors are highly expressed in forebrain regions and are mainly located presynaptically outside the active axon terminal.[45] The extrasynaptic location suggests that mGlu2/mGlu3 receptors regulate and prevent high glutamate excitation, which could be pathological, but may not interfere with physiological transmission.[45,51]

In summary, mGlu receptors are slow acting, modulate glutamate transmission and are widely, but differentially, expressed in the mammalian brain.

2. Preclinical Models of Nicotine Dependence

In humans, nicotine dependence, similar to dependence on other drugs of abuse, is characterized by different phases, including acquisition and maintenance of nicotine-taking despite adverse consequences, early withdrawal characterized by negative affective withdrawal symptoms and physical signs upon cessation of nicotine taking, and prolonged abstinence characterized by vulnerability to relapse to nicotine-taking upon exposure to stress or stimuli or contexts previously associated with nicotine-seeking and -taking (table I).[52]

Table I

Stages of nicotine addiction, corresponding preclinical animal models and potential effects of metabotropic glutamate (mGlu) receptor ligands

Preclinical procedures have been developed that model these aspects of nicotine dependence. The reinforcing effects of nicotine can be studied during acquisition and/or maintenance of intravenous nicotine self-administration, a procedure with good construct and face validity for human smoking.[53,54] Early nicotine withdrawal can be studied after long-term nicotine administration is stopped (e.g. by removing an osmotic minipump delivering nicotine to the animal over an extended period of time). Nicotine withdrawal in rodents is associated with somatic abstinence signs.[55] In addition, brain reward function can be assessed during withdrawal using the intracranial self-stimulation (ICSS) procedure. In this procedure, animals are prepared with electrodes placed into specific brain regions that support ICSS behaviour; they learn to perform an operant behaviour to self-administer small amounts of electrical currents that have rewarding effects.[56] ICSS thresholds serve as a measure of brain reward function. Acute nicotine administration results in lowering of ICSS thresholds, while withdrawal from nicotine is associated with elevations in ICSS reward thresholds.[57, 58, 59] The nicotine-induced lowering of ICSS thresholds reflects an enhancement by nicotine of the rewarding effects of ICSS. This property of nicotine to enhance the rewarding properties of other rewarding stimuli has been hypothesized to play a critical role in the perpetuation of nicotine dependence. People may continue to smoke to experience both the primary rewarding effects of nicotine, as well as the nicotine-induced enhancement of other rewards.[57,60, 61, 62, 63] By contrast, the elevation in ICSS thresholds during nicotine withdrawal reflects an anhedonic, depression-like state.

In addition, recent data indicated that nicotine withdrawal in rats is associated with enhanced sensitivity to a stressor. Specifically, rats undergoing nicotine withdrawal exhibited enhanced light-potentiated startle, while startle under baseline conditions was unchanged compared with controls.[64] Prolonged abstinence characterized by increased reactivity to nicotine-associated cues and stress is followed by relapse to nicotine taking. Nicotine-, stress- and cue-induced reinstatement of nicotine-seeking behaviour is a putative animal model of relapse to nicotine taking.[65,66] In this procedure, nicotine-seeking behaviour is induced by stimuli that have previously been associated with the availability of nicotine, or by administration of nicotine or a stressor by the person conducting the experiment. For example, a light above the active lever is usually paired with the delivery of the nicotine infusion during the nicotine self-administration procedure. The contingent or noncontingent presentation of such cues induces nicotine-seeking behaviour after abstinence from nicotine and/or extinction training.[61,67, 68, 69, 70, 71, 72, 73]

Finally, sensory stimuli that are present in tobacco smoke also play an important role in the maintenance of tobacco smoking.[74] Such stimuli become conditioned reinforcers through their association with nicotine, and nicotine further enhances their conditioning reinforcing effects, resulting in a positive feedback loop that maintains nicotine-taking.

3. NMDA Receptors and Nicotine

3.1 Preclinical Findings

Stimulation of NMDA receptors is hypothesized to play a key role in several of the neurochemical and behavioural effects of nicotine. Much support for this notion is provided by studies demonstrating that NMDA receptor antagonists block such nicotine-induced neurochemical and behavioural effects. Nicotine-induced dopamine release in the NAc was blocked by intra-VTA administration of the competitive NMDA receptor antagonists 2-amino-5-phosphonopentanoic acid (AP-5) or cis-4-phophonomethyl-2-piperidine carboxylic acid (CGS-19755; selfotel),[18,75] or systemic administration of the NMDA receptor antagonist CGP-39551.[76] In addition, the noncompetitive NMDA receptor antagonist dizocilpine (MK-801) attenuated sensitization to the dopamine-releasing effects of nicotine in the NAc.[77,78] In behavioural experiments, dizocilpine blocked sensitization to the locomotor-activating effects of nicotine in rats.[77, 78, 79] Furthermore, a competitive NMDA receptor antagonist, LY-235959, administered systemically or directly into the VTA, decreased intravenous nicotine self-administration.[80] Systemic administration of the NMDA receptor antagonist LY-235959 also decreased the reward-enhancing effects of nicotine, reflected in the lowering of ICSS thresholds in rats.[80]

Finally, nicotine self-administration produced neuroadaptive changes in iGlu receptors in mesocorticolimbic areas. Nicotine self-administration increased NMDA receptor subunit levels (NR2A and NR2B) in the PFC, and AMPA receptor subunit GluR2/GluR3 levels in the VTA.[81] Kenny and colleagues also found an increase in NR2A levels in the VTA, but a decrease in NR2A, NR2B and GluR2 subunits in the PFC in nicotine-treated versus control rats.[80]

Taken together, these preclinical findings suggest that the stimulatory action of nicotine on the mesocorticolimbic dopamine system and the primary rewarding effects of nicotine partly depend on NMDA receptor activation in areas such as the VTA, and that these NMDA receptors undergo adaptive changes as a result of long-term nicotine exposure.

Functional NMDA receptor antagonists that bind to the NMDA receptor glycine site may also be potential candidates for treatments of nicotine dependence. For example, the glycine site partial agonist 1-aminocyclopropanecarboxylic acid (ACPC) blocked nicotine-induced acquisition and expression of conditioned place preference,[82] and the partial agonist cycloserine facilitated extinction of cocaine-induced conditioned place preference in rats.[83] In addition, the NMDA glycine site antagonists (+)-HA-966 or ACPC decreased alcohol consumption in rats.[84] Furthermore, the NMDA glycine site antagonist L-701324 attenuated cue-induced reinstatement of cocaine seeking.[85] Studies that focus on the effects of such functional NMDA receptor antagonists on nicotine self-administration, reinstatement of nicotine seeking and nicotine withdrawal are needed to better evaluate the potential benefit of these compounds in smoking cessation.

3.2 Potential Clinical Use

Although these preclinical findings point to a role of NMDA receptors in the mediation of nicotine reward, NMDA receptors may not be ideal drug targets because they are ubiquitously involved in fast synaptic transmission throughout the CNS and are associated with severe adverse effects, including neurotoxicity and psychotogenicity.[86,87] Therefore, nonselective, high-affinity NMDA receptor antagonists are unlikely to be used in humans, although newer NMDA receptor subtype-selective compounds may be better tolerated.[44] Indeed, a few antagonists with moderate affinity for NMDA receptors, including memantine and amantadine,[86] are in clinical use. Memantine is a noncompetitive NMDA receptor antagonist, but also a nicotinic receptor blocker,[88] used in the treatment of dementia.[89] In mice, memantine prevented the acquisition of nicotine, but not cocaine, self-administration.[90] In humans, a recent small study investigated the effect of a 14-day treatment with memantine or placebo on cigarette consumption, cigarette craving and the subjective effects of an intranasal nicotine application. Memantine did not facilitate instructed smoking reduction, had no effect on cigarette craving (‘wanting’) and did not influence ratings of pleasantness of an intranasal nicotine application.[91] There is also little support for a role of memantine in the treatment of dependence on other drugs of abuse. Memantine pretreatment did not decrease the effects of cocaine in humans[92, 93, 94] and only modestly decreased the subjective, but not the reinforcing, effects of diamorphine (heroin).[95] While memantine reduced alcohol withdrawal[96] and cue-induced alcohol craving,[97] it failed to decrease alcohol drinking behaviour in alcohol-dependent patients compared with placebo in a controlled clinical trial.[98]

Acamprosate is another compound with antagonistic modulatory action at NMDA receptors, but also possible actions at GABA receptors.[99,100] Acamprosate is widely used for relapse prevention in alcohol-dependent patients.[101] It is hypothesized to restore dysregulations in glutamatergic neurotransmission induced by long-term alcohol consumption.[102] The effects of acamprosate on cocaine use in humans are currently being investigated.[103] We are not aware of any studies that assessed the effects of acamprosate in preclinical models of nicotine dependence or in tobacco smokers.

Overall, despite the strong preclinical data indicating that blockade of NMDA receptors blocks the neurochemical and behavioural effects of nicotine that appear to have relevance to nicotine addiction, there is currently no clinical evidence that NMDA receptor antagonists would be effective as aids in smoking cessation. In addition, compounds with NMDA antagonistic activity that are in clinical use for other indications, such as memantine and acamprosate, also bind to nicotinic or GABAergic receptors that are known to be involved in the actions of nicotine. It is possible that subtype-specific NMDA receptor antagonists[44] may be effective; however, more potent NMDA receptor antagonists are also likely to interfere with normal excitatory neurotransmission and may not be well tolerated by humans.[86] Therefore, an alternative approach involves indirectly modulating NMDA receptor activity by targeting slow-acting postsynaptic mGlu5 receptors that are functionally linked to NMDA receptors[49] or by targeting presynaptic mGlu2/mGlu3 receptors that are involved in the regulation of synaptic glutamate release.[45] The various mGlu receptor subtypes are also expressed more differentially in corticolimbic brain areas involved in reward processes[13,104,105] compared with the more general distribution of iGlu receptors. Thus, the mGlu receptors may offer more selective targets than iGlu receptors. Several relatively selective mGlu receptor ligands have been developed[44,106,107] and have recently been tested in preclinical models of nicotine dependence (see section 5).

4. α-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionic Acid (AMPA)/Kainate Receptors and Nicotine

Little is known about the role of AMPA/kainate receptors in nicotine dependence. The AMPA receptor antagonist ZK200775 {[1,2,3,4-tetrahydro-7-morpholinyl-2,3-dioxo-6-(fluoromethyl) quinoxalin-1-yl] methyl-phosphonate} decreased nicotine-induced dopamine release in the NAc.[108] However, the AMPA/kainate receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX) had no effect on nicotine self-administration,[80] indicating that AMPA/kainate receptors are not involved in the primary rewarding effects of nicotine. In contrast, NBQX administration induced nicotine withdrawal-like ICSS threshold elevations in nicotine-dependent, but not control, rats,[109] suggesting a possible role for these receptors in the development of nicotine dependence and the depression-like aspects of nicotine withdrawal.

Topiramate is a nonselective AMPA/kainate receptor antagonist,[110] but also a GABA receptor agonist, used clinically as an antiepileptic drug and in the treatment of alcohol, cocaine and opioid dependence.[111, 112, 113] In experimental animals, topiramate decreased nicotine-induced dopamine release in the NAc.[114] In human smokers, acute topiramate pretreatment enhanced the pleasurable subjective effects of an intravenous nicotine injection, including ‘good effects’ and ‘drug liking’, and attenuated the nicotine-induced increase in heart rate.[115] Topiramate also enhanced the rewarding effects of smoking a cigarette, increased subjective ratings of withdrawal, and did not affect cue-induced cigarette craving.[116] In contrast, in preliminary studies, long-term treatment with topiramate was found to facilitate smoking cessation.[117,118] In a subset of a larger trial comparing topiramate versus placebo in alcohol-dependent patients,[111] topiramate significantly increased 12-week smoking cessation rates to 16.7% compared with 6.9% in the placebo group in these dually-addicted individuals.[117] In a small and uncontrolled study in 13 smokers with various co-morbidities, treatment with topiramate resulted in smoking abstinence in six of the smokers after 2 months.[118] In another study, topiramate nonsignificantly increased smoking quit rates, but only in men.[119]

A randomized controlled trial with such compounds in a representative population of smokers remains to be conducted. It is unclear whether the effects of topiramate are mediated via its GABAergic action or its effects on AMPA/kainate receptors.[120] Accordingly, the available preclinical and clinical data indicate the lack of a role for AMPA/kainate receptors in the acute effects of nicotine, but a potential role for these receptors in nicotine dependence, particularly in the depression-like aspects of nicotine withdrawal (see earlier in this section). The latter notion is supported by recent evidence that led to the hypothesis that AMPA receptors are involved in major depression and in the mode of action of antidepressant drugs.[121] Positive modulators of AMPA receptors (AMPA receptor potentiators) exhibited antidepressant-like effects in animals.[122, 123, 124] Compounds that increase signalling through AMPA receptors may therefore ameliorate both major depression and the depression-like aspects of nicotine withdrawal. These preliminary clinical data appear promising and suggest that further evaluation of AMPA receptor ligands in additional preclinical animal models of nicotine dependence and in randomized controlled clinical trials is warranted.

5. Metabotropic Glutamate (mGlu) Receptors and Nicotine

The role of mGlu receptors in drug dependence has been investigated extensively over the past few years.[12,125, 126, 127, 128, 129, 130] Postsynaptic mGlu5 and presynaptic mGlu2/mGlu3 receptors may be of particular interest as potential medications in the treatment of drug dependence, including nicotine dependence.[12,13,67,131]

5.1 Modulation of the Effects of Nicotine by Ligands Acting on mGlu5 Receptors

A critical role for mGlu5 receptors in the mediation of the rewarding effects of drugs of abuse was initially demonstrated by the fact that mice lacking the mGlu5 receptor did not acquire intravenous cocaine self-administration, although they readily learned to respond for food.[132] In addition, the mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) was shown to decrease cocaine[132,133] and nicotine[134,135] self-administration in rats and mice. MPEP also decreased the breakpoint for nicotine reinforcement on a progressive ratio schedule of reinforcement, indicating reduced incentive motivation for nicotine.[136] The role of mGlu5 receptors was also evaluated in the reinstatement procedure, a putative animal model of relapse (see section 2). MPEP attenuated nicotine-[137] as well as cue- and schedule-induced[70] reinstatement of nicotine-seeking behaviour in rats, indicating that mGlu5 receptors may also be involved in relapse to nicotine-seeking. Similarly, mGlu1 receptor blockade attenuated cue- and nicotine-induced reinstatement of nicotine-seeking in rats.[69] However, although MPEP attenuated the ICSS threshold-lowering effect of acute nicotine, indicating blockade of the reward-enhancing effects of nicotine, MPEP also elevated reward thresholds when administered alone.[58] Thus, MPEP nonspecifically decreased brain reward function. MPEP also aggravated brain reward deficits and somatic signs associated with nicotine withdrawal.[131]

Taken together, the preclinical results indicate that mGlu5 receptor antagonists may be effective in the phases of nicotine dependence associated with increased glutamate transmission (see table I). Thus, they may reduce the primary rewarding effects of nicotine in humans and prevent relapse to tobacco smoking after a period of abstinence by blocking the increases in glutamate transmission induced by nicotine administration or by the presentation of situations or stimuli that lead to relapse,[67] similar to reinstatement to cocaine-seeking.[85,138,139] However, mGlu5 receptor antagonism can be expected to worsen symptoms of early withdrawal from tobacco smoking, based on the preclinical data discussed earlier in this section, which showed an aggravation of affective and somatic signs of nicotine withdrawal in rats, and the hypothesized decreased glutamate transmission characterizing early nicotine withdrawal[12] and withdrawal from other psychomotor stimulant drugs.[140,141]

The authors are not aware of clinical trials that assessed the effects of mGlu5 receptor antagonists or modulators in tobacco smokers or other drug users. An mGlu5 receptor negative allosteric modulator (ADX-10059, Addex Pharmaceuticals, Geneva, Switzerland) has been used in a series of phase II proof-of-concept studies in patients with gastro-oesophageal reflux disease and migraine (www.addexpharma.com). In addition, another negative allosteric modulator of the mGlu5 receptor (ADX-48621, Addex Pharmaceuticals) has entered a clinical phase I trial and is proposed as a novel compound for the treatment of depression, anxiety disorder and pain (www.addexpharma.com). Therefore, it appears that agents with antagonistic actions at mGlu5 receptors are well tolerated by humans and have good toxicity profiles, and thus may be used clinically. In particular, allosteric modulation of mGlu receptors may provide an attractive approach to facilitate or attenuate receptor function in a more physiological way compared with the global activation or inhibition induced by administration of orthosteric ligands.

5.2 Modulation of the Effects of Nicotine by Ligands Acting on mGlu2/mGlu3 Receptors

5.2.1 Preclinical Findings with mGlu2/mGlu3 Receptor Agonists and Antagonists

A considerable number of recent preclinical studies have used mGlu2/mGlu3 receptor agonists and antagonists to evaluate the function of mGlu2/mGlu3 receptors in drug dependence,[125, 126, 127, 128, 129,140,142, 143, 144, 145, 146, 147] including dependence on nicotine.[12,67] We conducted a series of experiments that investigated the effects of mGlu2/mGlu3 receptor activation, which leads to decreased glutamatergic transmission, on the rewarding effects of nicotine in rats.[67] Acute systemic as well as intra-VTA or intra-NAc administration of the mGlu2/mGlu3 receptor agonist LY-379268 decreased nicotine self-administration in rats (figure 2).[67] Furthermore, nicotine self-administration downregulated mGlu2/mGlu3 receptor function in corticolimbic rat brain sites, including the VTA and the NAc, demonstrated by decreased coupling of mGlu2/mGlu3 receptors to G proteins in the [35S]GTPγS binding assay (figure 3).[67]

Fig. 2

The metabotropic glutamate (mGlu) 2/3 receptor agonist LY-379268 decreased nicotine self-administration in rats. (a) The black columns represent the number of nicotine infusions earned during a 1-hour intravenous nicotine self-administration test session (n = 7). A fixed-ratio 5 timeout 20 s (FR5TO20 s) schedule of reinforcement was used. The white columns represent the number of food pellets earned during a similar 1-hour test session (n = 8) when rats had access to food under a FR5TO210 s schedule of reinforcement. This schedule of reinforcement was used for food because it better equated response rates for nicotine under the FR5TO20 s schedule because of the longer timeout period used in the food session. LY-379268 dose-dependently decreased nicotine self-administration, while it decreased food administration only at the highest dose. LY-379268 also significantly decreased nicotine self-administration when injected directly into the nucleus accumbens (NAc) [n = 9] (b), or the ventral tegmental area (VTA) [n = 9] (c). In contrast, nicotine self-administration was not decreased when LY-379268 was injected as an anatomical control (Co) 2 mm above the NAc into the lateral septal nucleus [n = 9] (b), or when it was injected 2 mm above the VTA into the red nucleus [n = 7] (c). LY-379268, administered systemically [n = 8] (d), or into the NAc [n = 9] (e) or the VTA [n = 9] (f), did not decrease food self-administration under an FR5TO20 s schedule of reinforcement at doses that significantly decreased nicotine self-administration. SEM = standard error of the mean; * p < 0.05, ** p < 0.01, *** p < 0.001 vs LY-379268 0 mg/kg; + p < 0.05 vs LY-379268 1 mg/kg. p-Values were calculated using Neuman-Keuls tests based on significant main effects of the drug in repeated measures of analysis of variances (reproduced from Liechti et al.,[67] with permission. Copyright 2007 by the Society for Neuroscience).

Fig. 3

Nicotine self-administration downregulated metabotropic glutamate (mGlu) 2/3 receptor function in rat brains. In vitro stimulation of [35S]GTPγS binding by the mGlu2/mGlu3 receptor agonist LY-354740 (eglumetad) was significantly decreased in rats self-administering nicotine compared with animals responding to food, suggesting mGlu2/mGlu3 receptor downregulation in all assessed brain areas (factorial analysis of variance: LY-354740 × reward interactions, # p < 0.05, ### p < 0.001; * p < 0.05, ** p < 0.01, *** p < 0.001 vs food). Repeated LY-379268 administration also decreased [35S]GTPγS binding in the prefrontal cortex and increased [35S]GTPγS binding in the nucleus accumbens and amygdala, indicating the plasticity of these receptors (LY-354740 × LY-379268 interactions, ° p < 0.05, ° p < 0.001; + p < 0.05, ++ p < 0.01, +++ p < 0.001 vs food). Data are expressed as mean ± standard error of the mean (n = 6) [reproduced from Liechti et al.,[67] with permission. Copyright 2007 by the Society for Neuroscience].

Taken together, these findings indicate an important role for glutamate, particularly mGlu2/mGlu3 receptors, in the VTA and the NAc shell, in the mediation of the primary rewarding effects of nicotine. Consistent with the effects of LY-379268 on nicotine self-administration, this agent also decreased cocaine self-administration,[142,146] suggesting that increased glutamate transmission mediates the primary reinforcing effects of psychostimulants, including nicotine. However, repeated systemic administration of an LY-379268 dose, which reduced nicotine self-administration when administered once, led to tolerance, reflected in a gradual return of nicotine self-administration to baseline levels.[67] This observed tolerance to repeated LY-379268 administration indicates that treatment with an mGlu2/mGlu3 receptor agonist in a clinical setting in humans may lose its efficacy over time, although dose adjustments may overcome the tolerance effect. Similar to the findings with the mGlu5 receptor antagonist MPEP, the mGlu2/mGlu3 receptor agonist LY-314582 attenuated the ICSS threshold-lowering effect of acute nicotine,[58] but mGlu2/mGlu3 receptor activation with the mGlu2/mGlu3 receptor agonists LY-314582 or LY-379268 also elevated reward thresholds when administered alone.[58,148] Thus, mGlu2/mGlu3 receptor agonists nonspecifically decreased brain reward function.

The role of mGlu2/mGlu3 receptors in nicotine withdrawal has been evaluated in several studies that assessed deficits in brain reward function, measured by elevations in ICSS reward thresholds associated with nicotine withdrawal.[109] Similar to depression, stimulant withdrawal is associated with decreased dopamine and glutamate transmission.[12,141,149,150] Stimulation of mGlu2/mGlu3 receptors decreases both extracellular glutamate and dopamine levels, and blockade of mGlu2/mGlu3 receptors increases both extracellular glutamate and dopamine in the NAc.[147,151] Accordingly, an mGlu2/mGlu3 receptor agonist would be expected to worsen and an antagonist would be expected to improve deficits in brain reward function during nicotine withdrawal. Indeed, the mGlu2/mGlu3 receptor agonist LY-314582 {a racemic mixture of LY-354740 ([+]-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid])} induced nicotine withdrawal-like elevations in ICSS thresholds in nicotine-dependent, but not control, rats.[109]

In contrast, and as expected from the above data, the mGlu2/mGlu3 receptor antagonist LY-341495 (2S-2-amino-2-[1S,2S-2-carboxycyclopropan-1-yl]-3-[xanth-9-yl]propionic acid) attenuated the threshold elevations observed in rats undergoing spontaneous nicotine withdrawal.[109] These data demonstrate that mGlu2/mGlu3 receptors play an important role in the development of nicotine dependence and the reward deficits associated with nicotine withdrawal, and that mGlu2/mGlu3 receptor antagonists may be used in the treatment of the anhedonia seen during early nicotine withdrawal in humans.[152,153] It should be noted here that mGlu2/mGlu3 antagonists exacerbated, while mGlu2/mGlu3 receptor agonists ameliorated behavioural signs of morphine withdrawal.[154,155] This is opposite to what was observed during nicotine withdrawal, but consistent with increased extracellular glutamate levels during morphine withdrawal.[156] Thus, the effects of mGlu2/mGlu3 receptor ligands on withdrawal from drugs of abuse other than nicotine appear to depend on the type of abused drug.

Based on the above data and the fact that mGlu5 receptor blockade decreases nicotine reinforcement (see section 5.1), it was hypothesized that mGlu5 receptor antagonists may be used to decrease the rewarding effects of nicotine, while mGlu2/mGlu3 antagonists may be helpful in the treatment of the affective, depression-like aspects of nicotine withdrawal.[12,13] However, medication compliance issues in humans who may not always follow complicated instructions regarding when to switch medications, prompted us to evaluate the interactive effects of the mGlu5 receptor antagonist MPEP and the mGlu2/mGlu3 receptor antagonist LY-341495 on nicotine self-administration and the reward deficits associated with spontaneous nicotine withdrawal in rats.[131] The question posed was whether coadministration of an mGlu5 receptor antagonist that decreases glutamate transmission through postsynaptic mGlu5 receptors and an mGlu2/mGlu3 receptor antagonist that decreases the inhibitory actions of mGlu2/mGlu3 receptors, thus resulting in increased glutamate transmission through all postsynaptic glutamate receptors, would negate each other’s effects. As predicted, we found that coadministration of the mGlu2/mGlu3 receptor antagonist LY-341495 with the mGlu5 receptor antagonist MPEP attenuated the effectiveness of MPEP in decreasing nicotine intake, although MPEP was still effective. Furthermore, coadministration of the mGlu2/mGlu3 receptor antagonist LY-341495 reduced the MPEP-induced reward deficits in both nicotine- and saline-withdrawing rats, although the combined treatment did not ameliorate the nicotine-induced reward deficit (figure 4). Thus, increasing glutamate transmission via mGlu2/mGlu3 autoreceptor blockade decreased the effects of mGlu5 receptor blockade on nicotine self-administration, although the mGlu5 receptor antagonist still had statistically reliable effects and blocked MPEP-induced exacerbation of brain reward deficits associated with nicotine withdrawal. This set of findings suggests that co-treatment with mGlu5 and mGlu2/mGlu3 receptor antagonists may decrease the rewarding effects of tobacco smoking, thus facilitating abstinence from tobacco smoking without aggravating or ameliorating the negative effects of nicotine withdrawal.

Fig. 4

The effects of co-administration of the metabotropic glutamate (mGlu) 5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and the mGlu2/mGlu3 receptor antagonist LY-341495 on intracranial self-stimulation threshold elevations associated with spontaneous nicotine withdrawal in rats. Intracranial self-stimulation thresholds were assessed at 6, 12, 24, 48, 72, 96 and 120 hours after removal of subcutaneous osmotic minipumps delivering either nicotine or saline. There was a significant elevation in intracranial self-stimulation thresholds in the nicotine-withdrawing rats compared with control rats (factorial analysis of variance: pump content × time interaction: F6,300 = 7.93; p < 0.001), indicating a brain reward deficit during spontaneous nicotine withdrawal. Rats received a single co-administration of MPEP (3 mg/kg) and LY-341495 (1 mg/kg) or vehicle 30 minutes before testing at the 12-hour timepoint (indicated by a vertical arrow). The combined treatment with MPEP and LY-341495 had no effect on intracranial self-stimulation elevations induced by the removal of the nicotine-containing pumps, and did not affect intracranial self-stimulation thresholds in the control rats. Data are expressed as mean ± standard error of the mean percentage change from baseline thresholds prior to removal of nicotine- or saline-containing osmotic minipumps. * p < 0.05, ** p < 0.01 vs vehicle-treated control group (Dunnett’s tests) [reproduced from Liechti and Markou,[131] with permission from Elsevier].

To further characterize the role of mGlu2/mGlu3 receptors in nicotine withdrawal, we assessed the effects of the mGlu2/mGlu3 receptor agonist LY-379268 on brain reward deficits associated with spontaneous nicotine withdrawal in rats.[148] Because the mGlu2/mGlu3 receptor antagonist LY-314582 attenuated nicotine withdrawal-induced reward deficits,[109] we hypothesized that the mGlu2/mGlu3 receptor agonist LY-379268 would worsen nicotine withdrawal. While LY-379268 administration induced reward deficits in animals ‘withdrawing’ from long-term saline administration, this agent only tended to aggravate nicotine withdrawal-induced reward deficits in rats previously treated with long-term nicotine.[148] Thus, mGlu2/mGlu3 receptor stimulation did not appear to significantly influence the affective depression-like aspects of nicotine withdrawal.[148] This finding is important because this mGlu2/mGlu3 receptor agonist decreased nicotine reward and also decreased cue-induced reinstatement of nicotine-seeking behaviour (figure 5).[67] The latter effect is consistent with previous findings showing that LY-379268 also reduces reinstatement of drug-seeking for cocaine,[125,128,140,146] alcohol[129,145] and heroin.[126,144] However, LY-379268 also reduced reinstatement of food-seeking behaviour;[67,125,143,146] thus, there appear to be nonspecific effects of LY-379268 on the motivational properties of conditioned reinforcers.

Fig. 5

Effects of the metabotropic glutamate (mGlu) 2/3 receptor agonist LY-379268 on cue-induced reinstatement of nicotine- and food-seeking behaviour in rats. LY-379268 blocked reinstatement for both nicotine-seeking [n = 32, within-subjects comparison] (a), and food-seeking [n = 10/dose, between-subjects comparison] (b). Responses are the total of active lever presses, including responses during the cue presentation. Ext = mean response during the last 3 days of extinction training; SEM = standard error of the mean. Neuman-Keuls tests based on significant main effects for dose in the analyses of variance: * p < 0.01 vs extinction; ** p < 0.001 vs LY-379268 0 mg/kg (reproduced from Liechti et al.,[67] with permission. Copyright 2007 by the Society for Neuroscience).

Overall, these studies contributed to our understanding of the role of mGlu2/mGlu3 receptors in reward processes and suggested a role for mGlu2/mGlu3 receptors and enhanced glutamate neurotransmission in nicotine reinforcement and the development of nicotine dependence. Furthermore, these studies indicated that adaptations in mGlu2/mGlu3 receptor function occur with the development of nicotine dependence, which are likely to contribute to the expression of the anhedonic depression-like aspects of early nicotine withdrawal, and eventually to relapse to nicotine-seeking behaviour after a period of extended abstinence and in response to stimuli previously associated with the acute effects of nicotine. Accordingly, these findings suggest that administration of an mGlu2/mGlu3 receptor agonist would facilitate a decrease in nicotine intake, would not aggravate the affective depression-like aspects of nicotine withdrawal, and would prevent relapse to nicotine-seeking and -taking. Thus, an mGlu2/mGlu3 receptor agonist could potentially be administered long term to tobacco-dependent individuals in order to assist with reducing tobacco smoking and preventing relapse without effects on depression-like signs of early nicotine withdrawal.

However, it should be noted that an mGlu2/mGlu3 receptor agonist may ameliorate the enhanced reactivity to stressors seen during early nicotine withdrawal;[64] such compounds have shown efficacy as anxiolytics in clinical trials (see section 5.2.2). However, the lack of specificity of the effects of mGlu2/mGlu3 receptor agonists on drug- and food-seeking behaviour, and the tolerance to the effects of long-term treatment with such compounds, may restrict the use of these agents as treatments for smoking cessation. Nevertheless, mGlu2/mGlu3 receptors may represent promising targets for new therapeutics for nicotine dependence and warrant further exploration in clinical trials.

5.2.2 Clinical Findings with mGlu2/mGlu3 Receptor Agonists

To our knowledge, the effects of mGlu2/mGlu3 receptor agonists on smoking have not yet been studied. mGlu2/mGlu3 receptor agonists, with similar properties to those examined in preclinical models of drug dependence described in this review, have been used in humans. LY-354740 was found to reduce both fear-potentiated startle[157] and provoked anxiety symptoms in patients with panic disorder[158,159] and in healthy volunteers.[160] LY-354740 was also tested in a small phase II study,[161] but had no effect on the number of panic attacks over a treatment period of several weeks. In contrast, in a large multicentre placebo- and lorazepam-controlled clinical study in patients with generalized anxiety disorder, LY-354740 significantly decreased anxiety scores compared with placebo and to a similar degree to lorazepam during a 5-week treatment phase.[162,163] LY-354740 was also reported to have a superior tolerability profile compared with lorazepam.[162] In addition, LY-544344, an LY-354740 prodrug that increases LY-354740 bioavailability, was efficient and well tolerated in the treatment of generalized anxiety disorder during an 8-week treatment phase.[162] However, it should be noted that this trial was terminated early because of findings of convulsions in preclinical toxicity studies in rats, mice and dogs, an adverse effect not confirmed in the available data from humans.[162] Furthermore, LY-354740 attenuated working memory disruptions induced by the NMDA antagonist ketamine in healthy volunteers.[164]

Another mGlu2/mGlu3 receptor agonist (LY-2140023, Eli Lilly, Indianapolis, IN, USA) has been evaluated in a placebo- and olanzapine-controlled clinical phase II trial in patients with schizophrenia.[165] Treatment with LY-2140023 was reported to be safe and well tolerated, and effectively decreased positive and negative symptoms of schizophrenia over a 28-day treatment phase.[165] Thus, in these clinical trials with up to 8 weeks of treatment, no tolerance to continued treatment with mGlu2/mGlu3 receptor agonist treatments was observed, suggesting that tolerance may be avoided in the treatment of some indications.

5.2.3 Other Compounds Acting at mGlu2/mGlu3 Receptors

In addition to mGlu2/mGlu3 receptor agonists, other compounds also activate mGlu2 and/or mGlu3 receptors. Allosteric potentiators for the mGlu2 receptor have been developed that selectively potentiate the ability of glutamate and other receptor agonists to activate mGlu2 receptors.[166,167] The mGlu2 receptor selective positive allosteric modulator biphenyl-indanone A was recently shown to block effects in a hallucinogenic drug model of psychosis,[168] but no data on the effects of such modulators in models of drug dependence are available yet. Furthermore, N-acetyl-asparyl-glutamate (NAAG), the most abundant peptide neurotransmitter in the mammalian brain, also activates mGlu3 receptors.[169] NAAG is inactivated by N-acetylated-α-linked-acidic-dipeptidase (NAALADase). NAALADase inhibitors were found to prevent acquisition and expression of morphine- or cocaine-induced conditioned place preference,[170,171] and also attenuated the development of sensitization to the locomotor-activating effects of cocaine.[172] Similar to mGlu2/mGlu3 receptor agonists, NAALADase inhibitors may therefore be potential treatments for aspects of drug dependence, although their effects in preclinical models of the primary rewarding effects of drugs of abuse and models of nicotine dependence remain to be evaluated.

An alternative approach to pharmacologically regulate glutamate release involves the stimulation of mGlu2/mGlu3 autoreceptors by increasing extracellular glutamate levels using N-acetylcysteine, which is an amino acid and cysteine prodrug. In the brain, extracellular cysteine is exchanged for intracellular glutamate to maintain extracellular glutamate levels. While acute cocaine ingestion elevates extracellular levels of glutamate, withdrawal from long-term cocaine use, and possibly also nicotine withdrawal, is associated with decreased extracellular glutamate levels (table I).[12,141] In rats previously treated with cocaine or self-administering cocaine, administration of N-acetylcysteine restored extracellular glutamate levels in the NAc and prevented cocaine-seeking.[140,141,173] N-acetylcysteine similarly decreased heroin seeking.[174] In humans, N-acetylcysteine decreased cue-induced craving for cocaine[175, 176, 177] and pathological gambling,[178] indicating that this pharmacological manipulation of the glutamate system may help to decrease reward-seeking addictive and compulsive behaviours. These preliminary clinical data will need further confirmation from larger placebo-controlled trials. N-acetylcysteine is already used to treat paracetamol (acetaminophen) overdose and as a mucolytic agent. It has no significant adverse effects in humans, which may be an advantage over new glutamatergic compounds with unknown safety profiles. Because of the demonstrated role of the glutamate system in behaviours with relevance to nicotine dependence in rats, and the evidence of an effect of N-acetylcysteine on cocaine reward, the potential therapeutic benefit of N-acetylcysteine should be evaluated in both animal models of nicotine dependence and in human tobacco smokers.

6. Conclusion

The results from the experimental animal studies summarized in this review demonstrate a critical role for glutamate transmission in nicotine dependence and the involvement of several glutamatergic receptors in behaviours relevant to nicotine dependence.

Compounds that directly block iGlu receptors may not be well tolerated in humans because they also interfere with normal excitatory neurotransmission. Ligands at mGlu receptors have modulatory effects on glutamate neurotransmission and only decrease excessive glutamate transmission or subtly increase glutamate neurotransmission via indirect mechanisms and/or in specific brain areas. Such compounds may be more likely to have fewer adverse effects and to be clinically useful.

Based on the preclinical animal studies, potential candidate medications include postsynaptic mGlu5 receptor antagonists that indirectly modulate iGlu receptor activity,[49] and agonists and antagonists at presynaptic mGlu2/mGlu3 autoreceptors that inhibit excessive glutamate release and allow glutamate release, respectively.[45] Both mGlu5 receptor antagonists and mGlu2/mGlu3 receptor agonists may decrease the reinforcing effects of nicotine and decrease relapse to smoking by decreasing the increases in glutamate transmission induced by nicotine or the presentation of stimuli previously associated with the effects of nicotine or the availability of nicotine (table I). mGlu2/mGlu3 receptor antagonists may be useful in the treatment of the depression-like affective symptoms of nicotine withdrawal by reversing the decrease in glutamate transmission hypothesized to occur during early stages of nicotine withdrawal (table I). Clinical data on the effects of such mGlu compounds are needed to assess their potential as medications for nicotine dependence in humans.

Notes

Acknowledgements

This work was supported by National Institute on Drug Abuse grants DA11946 and DA023209, and Tobacco-Related Disease Research Program grant 15RT-0022 awarded to Athina Markou. Athina Markou’s laboratory was a recipient of a research grant from Novartis Pharma AG on metabotropic glutamate receptors. Athina Markou and colleagues have submitted a patent application regarding the use of metabotropic glutamate receptor compounds for smoking cessation. Matthias Liechti was supported by fellowship awards from the Swiss National Science Foundation (SNF-PBZHB-108501, SSMBS 1246 and F. Hofmann-La Roche Ltd, Basel, Switzerland). He has no other conflicts of interest to declare that are directly relevant to the content of this review. The authors would like to thank Mr Mike Arends for his editorial assistance.

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Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  1. 1.Division of Clinical Pharmacology and ToxicologyUniversity Hospital of BaselBaselSwitzerland
  2. 2.Department of Psychiatry, M/C 0603, School of MedicineUniversity of California San DiegoLa JollaUSA

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