• Addiction involves enduring neuroplasticity in the reward circuitry of the brain.
• Neuroplasticity is a result of glutamate-dependent long-term potentiation.
• Glutamate is an excitatory neurotransmitter.
• Glutamate release is involved in alcohol and drug relapse in response to drug cues.
• There are changes in glutamate receptor functioning in substance addiction.
• Medications that reduce glutamate tone may prevent alcohol and drug relapse.
Chronic substance use is thought to induce enduring pathological changes in the brain. One of these changes is a form of synaptic plasticity within neural circuits important for adaptive behavioural responding. This synaptic plasticity, particularly within dopamine midbrain and striatal regions, is dependent upon the excitatory neurotransmitter glutamate. Significantly, evidence points to similar glutamate-dependent processes involved in both learning and memory and in the development of substance addiction.
In this chapter, we will discuss the recruitment of glutamate over dopamine-dependent substrates in addiction and its implication for medications that treat addiction through the modulation of glutamate signalling in the brain.
9.1 The glutamate system
Glutamate is the primary excitatory neurotransmitter in the brain. The main glutamate projection neurons (see Figure 9.1) arise from a number of different nuclei, including the thalamus and prefrontal cortex (PFC). The transamination of α-ketoglutarate within the presynaptic nerve terminals of these nuclei produces glutamate, a small proportion of which is used as a neurotransmitter (most serves a metabolic function). The regions in receipt of these glutamate projection neurons are numerous and are known to include the midbrain ventral tegmental area (VTA) and the striatum.
When released from presynaptic projection neurons, glutamate binds with two types of receptors. These are ionotropic and metabotropic. N-methyl-D-aspartate (NMDA), kainate, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are ionotropic: when activated, they open ion channels that pass sodium and/or calcium ions across the neuronal membrane. The G-protein coupled glutamate receptors (mGluR) are metabotropic: when activated, they regulate intracellular adenylyl cyclase and cyclic adenosine monophosphate (cAMP) activity. There are three groups of the mGluR, which make up a total of eight receptor subtypes (mGluR1–8). Glutamate can also come from glutamine. When sequestered into nearby astrocytes, glutamate is converted to glutamine via glutamine synthase. Here, glutamine diffuses out of astrocytes and into the nearby nerve terminals where it is converted back into glutamate via glutaminase.
NMDA receptors are thought to play a significant role in the development of addiction. They are located on postsynaptic neurons (see Figure 9.2). Their stimulation is rapidly converted into a postsynaptic electrical signal and is involved in the processes of long-term potentiation (LTP) and long-term depression (LTD). LTP and LTD are long-lasting increases or decreases, respectively, in synaptic transmission. These cellular processes are hypothesized to underlie information storage in the brain as they are rapidly established and strengthened by repetition. NDMA receptors, therefore, are involved in synaptic plasticity—a strengthening of connections between neurons. This is an important neurochemical foundation of learning and memory.
The NMDA receptor has a number of recognition binding sites, including those for phencyclidine, MK-801 (dizocilpine), and ketamine. Alcohol blocks the NMDA receptor (see Figure 9.2). Consequentially, there is an upregulation in NDMA receptor functioning. Features of this upregulation include tolerance to the effects of alcohol as well as increased cortical excitability, withdrawal seizures, and withdrawal-related neurotoxicity. In animals and in humans, drugs that block NMDA glutamate receptors or reduce glutamate release appear to be effective in suppressing the alcohol abstinence syndrome (see 9.4 Treatment).
9.2 Substance addiction—VTA glutamate in the development of addiction
The first indication that glutamate was involved in stimulant addiction came from studies investigating the neurobiology of behavioural sensitization. Behavioural sensitization involves a progressive increase in the motor stimulatory effects of stimulants following their repeated and intermittent administration. Sensitization development has been hypothesized to represent a shift from drug ‘liking’ to drug ‘wanting’. It has also been hypothesized to underlie compulsive substance use in humans.
Behavioural sensitization has been demonstrated for a variety of substances, particularly those acting directly through the dopamine system, such as amphetamines, cocaine, and nicotine. It may potentially model elements of craving and relapse in humans. Antagonists at NMDA receptors in the VTA have been shown to block the development of this behavioural sensitization in animals.
The emergence of behavioural sensitization in response to substances of addiction is thought to involve glutamate-dependent LTP at NMDA receptors on dopamine neurons in the VTA. For example, a single exposure to cocaine has been found to potentiate excitatory synapses in the VTA, which is dependent upon NMDA receptors. In addition, enhanced synaptic transmission occurs via an increase in the number (or function) of postsynaptic AMPA receptors. This finding has also been shown for the development of drug self-administration in animals.
While it is less clear which glutamatergic afferents to the VTA are critical for the development of addiction, the role of glutamate-dependent LTP in the VTA appears to suggest that synaptic plasticity in midbrain dopamine neurons is essential. During repeated drug administration, neuroplasticity is also taking place in the PFC. Glutamate neurons in the PFC appear to be sensitized by substances, such as psychostimulants. This may be commensurate with the exaggerated release of glutamate in the ventral striatum (VS) during drug-seeking, as described in 9.3 Substance addiction.
9.3 Substance addiction—nucleus accumbens (NAcc) glutamate in the expression of addiction
There also appears to be a role for glutamate in the expression of addiction behaviour, particularly in the NAcc region of the VS. The reinstatement model of drug-seeking has been used extensively to examine the expression of addiction-related behaviour in animals. This model has also demonstrated a preferential role for the core region of NAcc (as opposed to the shell) in the expression of reinstatement. As described in Chapter 4, there are discrete hedonic ‘hotspots’ for substance ‘liking’, one of which is in the shell of the NAcc. Animals will learn to self-administer dopaminergic drugs (e.g. cocaine, D1R/D2R receptor agonists) more into the shell of the NAcc than the core. This may suggest that there are differential roles for the shell and core in substance ‘liking’ and ‘wanting’, respectively, the latter of which may occur following chronic substance use and which may be important for substance use reinstatement (i.e. relapse).
During the reinstatement model, animals will typically self-administer a drug (e.g. cocaine) under operant conditions for prolonged periods of time. This operant responding for the drug is intended to mimic chronic drug self-administration in humans. Following this chronic drug self-administration period, animals will then undergo extinction training—responding on the previous reinforced (i.e. active) operandum will no longer elicit primary reinforcement (i.e. drug delivery). This extinction training will gradually lead to a significant reduction in the level of responding on the drug-paired operandum. Following extinction, a conditioned cue, drug-priming injection, or a stressor will be introduced to trigger the reinstatement of drug-seeking behaviour—as indexed by a renewed increase in responding on the previously drug-paired operandum. The reinstatement of increased responding is thought to model relapse in humans.
The reinstatement of cocaine-seeking is associated with increased glutamate release into the core of the NAcc. Moreover, AMPA receptor blockade in the core prevents the reinstatement of responding to a drug or cue prime. The inhibition of glutamate PFC afferents into this region attenuates drug-seeking induced by cocaine, heroin, stress, and cues. The inhibition of amygdala glutamate afferents also blocks cue and heroin reinstatement in animals.
In addition to enhanced glutamate transmission in the NAcc core during the expression of drug-seeking or sensitization, there are also a number of glutamate-related cellular adaptations produced by chronic psychostimulant administration. Research points towards augmented AMPA sensitivity—AMPA stimulation induces motor activity or the reinstatement of drug-seeking.
Given the apparent role of glutamate in regulating both the development and expression of addictive behaviours in animal models, glutamate may be a potential pharmacotherapeutic target for substance addiction in humans. Figure 9.3 illustrates the putative glutamatergic mechanisms of action of eight anti-addiction medications. While these medications have very contrasting pharmacological mechanisms of action (that are not all specific to glutamate) their overall effect is to reduce glutamate tone in the brain.
The regulation of non-synaptic glial glutamate release by stimulating cystine-glutamate exchange (see xc– in the N-acetylcysteine section of Figure 9.3) has recently come to light as a potential medication target. xc− is involved in exchanging the uptake of one cystine in exchange for the release of one molecule of intracellular glutamate into the extracellular space. Cocaine self-administration in animals has been shown to downregulate the cystine–glutamate exchanger. Therefore, restoring the functional integrity of this exchanger may possess some efficacy in reducing substance use by increasing synaptic glutamate at mGluR2/3 regulating autoreceptors—thus reducing glutamate tone.
N-acetylcysteine (NAC) is an xc− agonist that has been shown to indirectly stimulate mGluR2/3 to reduce glutamate release in the NAcc and inhibit cocaine-seeking in animals (Amen et al. 2011). In parallel, preliminary clinical research indicates that repeated administration (4 days) of NAC (1200–2400 mg/day) in cocaine-dependent subjects produces a significant reduction in craving following acute cocaine (Amen et al. 2011).
NAC has also been shown to reduce cocaine-related withdrawal symptoms and craving (LaRowe et al. 2006). Cocaine use was either terminated or significantly reduced over a four week trial using NAC in cocaine abusers. NAC has also been shown to significantly reduce glutamate levels in the dorsal anterior cingulate of cocaine-dependent subjects (Schmaal et al. 2012). This may lend credence to the supposition that NAC-induced reductions in glutamate tone are involved in the clinical efficacy of this compound.
Other compounds that influence glutamate functioning may also possess some efficacy. Acamprosate (see Figure 9.3) is an NMDA antagonist (and possibly a GABAA receptor agonist). It has some clinical potential in alcohol dependence. Theories posit that acamprosate may restore an imbalance between excitatory and inhibitory neurotransmission that results from chronic alcohol consumption. Indeed, a recent study in detoxified alcoholics has shown that four weeks of acamprosate treatment significantly reduces glutamate in the anterior cingulate gyrus (Umhau et al. 2010). The overall bio-availability of acamprosate, however, remains poor (i.e. <20%) and requires doses in the range of 2–3 g per day in order to demonstrate clinical efficacy. The requirement for three doses per day, therefore, may act as a compliance barrier in some patients.
The partial NMDA agonist D-cycloserine (DCS—see Figure 9.2) has also been tested. DCS mimics the actions of glycine at the glycineB receptor. Both glycine and glutamate are necessary for NMDA receptor functioning (see Figure 9.1). NMDA receptor functioning is known to be blunted in alcohol-dependent patients, appearing to support the hypothesis that NMDA receptor upregulation increases tolerance to the effects of alcohol. DCS has been shown to reduce cocaine-induced conditioned place preference in animals. It has proved less favourable in cocaine-dependent humans—it actually increases cue-induced relapse. In alcoholics, it has shown some promise, but the wide range of craving responses in alcoholics precludes any firm conclusion regarding its potential clinical efficacy.
Gabapentin (see Figure 9.2) is an anticonvulsant medication. It has a general inhibitory effect on neuronal transmission by inhibiting presynaptic voltage-gated Na+ and Ca2+ channels. As a result, gabapentin inhibits the release of various neurotransmitters, including glutamate. Gabapentin may be efficacious in alleviating the somatic symptoms of alcohol withdrawal. Gabapentin (600–1500 mg/day) reduces alcohol and cocaine craving. It does not appear to reduce methamphetamine use.
Lamotrigine (see Figure 9.2) has a similar mechanism of action to gabapentin. Lamotrigine inhibits the somatic signs of alcohol withdrawal and craving for alcohol. Likewise, it may possess some efficacy for reducing cocaine use and craving but not the subjective effects of cocaine. Topiramate (see Figure 9.2), while similar to gabapentin and lamotrigine, is also an antagonist at AMPA receptors containing the GluR5 subunit. In addition to the attenuation of alcohol withdrawal symptoms, it may also attenuate alcohol’s subjective effects, alcohol craving, and heavy consumption in alcoholic patients. It may even be superior to naltrexone in preventing alcohol relapse. It has been shown to reduce cocaine use and craving in cocaine-dependent individuals. Typical effective doses range from 75 to 350 mg/day.
Modafinil (see Figure 9.2), while an inhibitor of the dopamine transporter, has also been shown to elevate extracellular levels of glutamate in numerous brain regions, including the dorsal striatum. The potential efficacy of modafinil in substance addiction has already been addressed with respect to dopamine. Clinically effective doses of modafinil are typically in the range of 200–400 mg/day.
Finally, memantine (see Figure 9.2) is a non-competitive NMDA receptor antagonist. It is also an antagonist at the serotonin 3 receptor (5-HT3) and at nicotinic acetylcholine receptors. Memantine has shown some efficacy in reducing withdrawal symptoms in detoxifying alcoholics and opiate addicts and is superior to placebo in attenuating ongoing drinking and/or craving for alcohol in alcoholics. It has been suggested that the attenuation of craving for alcohol may be a result of the alcohol-like subjective effects of memantine. Typical doses are 30–60 mg/day range.
Substance abuse induces neuroplasticity within midbrain, striatal, and PFC circuitry. Heightened neural activity in the PFC-NAcc pathway appears to accompany this neuroplasticity. Neuroplasticity is highly dependent upon the excitatory neurotransmitter glutamate at NMDA receptors. The neuroplasticity within this circuitry is sustained during substance abstinence and may provide a neural substrate for a vulnerability to relapse in substance addiction.
Medications that possess the efficacy to reduce glutamate tone in the PFC-NAcc pathway may reduce craving and, ultimately, relapse in substance dependence. At this time, however, there is still a scarcity of preclinical and clinical data in humans demonstrating the unequivocal efficacy of these medications. Further research is required to show how the modulation of glutamate transmission in the brain confers clinical benefits in substance addiction.
References and Further Reading
Amen SL, Piacentine LB, Ahmad ME, et al. (2011). Repeated N-acetyl cysteine reduces cocaine seeking in rodents and craving in cocaine-dependent humans. Neuropsychopharmacology, 36, 871–78.Find this resource:
Baker DA, McFarland K, Lake RW, et al. (2003). Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse. Nature Neuroscience, 6, 743–49.Find this resource:
Glue P and Nutt D (1990). Overexcitement and disinhibition. Dynamic neurotransmitter interactions in alcohol withdrawal. British Journal of Psychiatry, 157, 491–9.Find this resource:
Krystal JH, Petrakis IL, Limoncelli D, et al. (2011). Characterization of the interactive effects of glycine and D-cycloserine in men: further evidence for enhanced NMDA receptor function associated with human alcohol dependence. Neuropsychopharmacology, 36, 701–10.Find this resource:
LaRowe SD, Mardikian P, Malcolm R, et al. (2006). Safety and tolerability of N-acetylcysteine in cocaine-dependent individuals. American Journal on Addictions, 15, 105–10.Find this resource:
Mardikian PN, LaRowe SD, Hedden S, et al. (2007). An open-label trial of N-acetylcysteine for the treatment of cocaine dependence: a pilot study. Progress in Neuropsychopharmacology & Biological Psychiatry, 31, 389–94.Find this resource:
Olive MF, Cleva RM, Kalivas PW, et al. (2012). Glutamatergic medications for the treatment of drug and behavioral addictions. Pharmacology, Biochemistry and Behavior, 100, 801–10.Find this resource:
Schmaal L, Veltman DJ, Nederveen A, et al. (2012). N-acetylcysteine normalizes glutamate levels in cocaine-dependent patients: a randomized crossover magnetic resonance spectroscopy study. Neuropsychopharmacology, 37, 2143–52.Find this resource:
Umhau JC, Momenan R, Schwandt ML, et al. (2010). Effect of acamprosate on magnetic resonance spectroscopy measures of central glutamate in detoxified alcohol-dependent individuals: a randomized controlled experimental medicine study. Archives of General Psychiatry, 67, 1069–77.Find this resource:
Watson BJ, Wilson S, Griffin L, et al. (2011). A pilot study of the effectiveness of D-cycloserine during cue-exposure therapy in abstinent alcohol-dependent subjects. Psychopharmacology (Berl), 216, 121–9.Find this resource: