It is now clear that glutamate plays a pivotal role in drug addiction, and the NMDA receptor serves as a molecular target for several drugs of abuse. In this review, we will summarize known direct interactions of various drugs of abuse with the NMDA receptor, as well as changes in NMDA receptor subunit expression produced by chronic drug exposure. We will also review the mechanism of action, clinical efficacy, and adverse side effects of NMDA receptor ligands that are currently used in the treatment of drug addiction. Such compounds include the NMDA receptor modulators acamprosate, lamotrigine, topiramate, memantine, as well as the partial NMDA agonist D-cycloserine. Data collected to date suggest that direct NMDA receptor modulators have relatively limited efficacy in the treatment of drug addiction, and clinical examination of newer subunit selective NMDA receptor ligands is needed to determine if the NMDA receptor remains a viable therapeutic target for addictive disorders.
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Substance abuse and drug dependency are cardinal issues of public health that do not discriminate between race, ethnicity, gender, or socioeconomic status of users. Recent estimates of substance abuse and illicit recreational use of drugs revealed that a concerning number of individuals are directly affected by this problem, with more than tens of millions of people reported to have trouble with substance abuse worldwide (World Drug Report, 2009). According to a survey conducted by National Survey on Drug Use and Health (NSDUH) more than 20 million Americans over the age of 12 are affected by substance use disorders (2010). Some of the most commonly abused substances include alcohol, nicotine, marijuana, methamphetamine, cocaine, heroin, and prescription medications. Both legal and illicit drugs may be used for a variety of reasons, including altering mental state, experience of rewarding effects, performance enhancement, and self-medication. Repeated consumption of drugs can result in drug dependency that manifests as an overpowering desire for the drug and impairment in controlling drug-seeking behavior (Kalivas 2011). Although there have been some advances in the fields of behavioral and pharmacological research on the treatment of substance abuse and drug dependency, these disorders continue to maintain their propensity even today, thus illustrating the necessity for further research on the underlying neuropathological properties that precipitate disorders of abuse and addiction.
Despite the notion that substance abuse can quite often lead to drug dependency, substance abuse and drug dependency are in fact disparate disorders with distinct criteria characteristics as defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) by the American Psychiatric Association. Substance or drug abuse is most commonly described as intentional misuse of a substance, which can include recurring maladaptive patterns of substance use despite having persistent or recurrent problems caused by or exacerbated by the effects of the substance that result in physical, psychological, interpersonal, or legal problems. Drug dependency incorporates the aforementioned characteristics of misuse but also comprises of marked tolerance to a substance, withdrawal symptoms following cessation, increased quantity and/or frequency of use, as well as recurring but unsuccessful desire to stop using (American Psychiatric Association 2000). Occasional or limited use of a drug with high potential for abuse is clinically distinct from drug dependency due to the behavioral and psychological characteristics of dependency, including escalated use of drug, inability to control limiting drug intake, and the development of chronic compulsive drug-seeking behavior. The distinction between drug use, abuse, and dependence can also be seen in data showing that approximately 15.6% (29 million) of the US adult population will participate in nonmedical or illicit drug use at some point in their lives, however only about 2.9% of the population will progress from use/abuse to substance dependence (Koob and Volkow, 2010; Grant and Dawson, 1998; Grant et al, 2004). Drug dependency, or addiction, occurs through physiological changes that take place in the brain over the course of chronic drug abuse resulting in physical cellular changes which lead to maladaptive behavioral patterns (Nestler, 2001). This distinct clarification between these two disorders is fundamental for providing appropriate treatment due to the differences in acute as well as permanent neurological changes that each disorder engenders [for thorough review of neurocircuitry of addiction refer to Koob and Volkow, 2010].
In recent years clinical and laboratory research has shown that there is considerable overlap between the neural substrates that normally serve reward-related learning underlying addiction to drugs and non-drug "behavioral" addictions, including pathological gambling and kleptomania (Olive et al, 2011; Grant et al, 2010). A recent review addresses addiction as a "runaway phenomenon" that has directly affected almost half of the US population and includes "process" addiction such as eating, shopping, sex, and exercise (Lee, 2012; Sussman and Griffiths, 2011). From a historical standpoint, addiction was initially viewed as pertaining to pharmacological substances. Over the last decades, however, substantial research investigating addictive behaviors has pointed to the idea that addiction might be better viewed as its own disorder in the DSM-IV, for which there is no diagnostic category (Lee 2012).
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Although there have been a number of medications approved for other medical conditions that have been investigated as possible treatment aids of addictive disorders, in the US there are only a few medications approved for treating specific addictions to substances such as nicotine, opiates, and alcohol. To date, there are no approved medications used in the treatment of addiction to cocaine, methamphetamine, or marijuana nor are there any approved to treat behavioral addictions. Currently, many of the medications developed for the treatment of addictive disorders have shown very modest efficacy, possibly due to poor medication compliance and negative side effects (Olive et al, 2011).
While in the past much attention was given to the neurobiological substrates that underlie the rewarding and reinforcing effects of drugs of abuse focusing on the mesolimbic dopamine reward circuitry, the last several decades have produced a tremendous amount of research demonstrating that glutamatergic transmission plays a pivotal role in addiction and thus may be a key target for possible pharmacological treatment of addiction (Gass & Olive, 2008; Nemirovsky & Olive 2012). Glutamate, or glutamic acid, is the main excitatory neurotransmitter in the central nervous system (CNS) and can bind three different classes of ionotropic glutamate receptors (iGluR) and three different groups of classes of metabotropic glutamate receptors (mGluR), each of which induces a particular series of cascading neurotransmission. Glutamate synthesis, metabolism, receptor regulation, primary pathways, and its ability to excite nearly all CNS neurons are crucial components for normal brain functioning (Stahl 2011). With regard to the mesolimbic dopamine reward circuitry, glutamate projects to the nucleus accumbens (NAcc), amygdaloid complex (Amyg) and frontal cortex (FC) (For a thorough review of glutamatergic substrates of addiction and alcoholism refer to Gass and Olive, 2008). The N-methyl-D-aspartate (NMDA) receptor is one of three types of ionotropic glutamate receptors. Its activation requires that both agonist binding and membrane depolarization occur in order to allow passages of sodium ions, calcium, and potassium ions, which contribute to further membrane depolarization and activation of intracellular signaling pathways. NMDA receptors are involved in synaptic plasticity, learning, and memory (Myers & Carlezon, 2012; Seeburg et all, 1995; Nicoll & Maleka, 1999; Tang et al, 1999).
The following sections of the article will address NMDA receptor structure, expressions patterns and pharmacology, as well as its potential to be a primary molecular target for the treatment of substance abuse and addictive disorders. In this review, we will describe known direct interactions of various drugs of abuse with the NMDA receptor, as well as changes in NMDA receptor subunit expression produced by chronic drug exposure. This review will also provide an overview of the mechanism of action, clinical efficacy, and adverse side effects of NMDA receptor ligands that are currently used in the treatment of drug addiction. Such compounds include the NMDA receptor modulators acamprosate, lamotrigine, topiramate, memantine, as well as the partial NMDA agonist D-cycloserine.
- NMDA Receptor Structure, Expression Patterns, and Pharmacology
The N-methyl-d-aspartate (NMDA) receptor has long been known to influence synaptic plasticity and long-term potentiation, both of which alter physical elements within the synapse to increase the functioning and efficiency of neurotransmission. Synaptic plasticity and LTP are critical for shaping the development of learning and memory (Alford & Brodin, 1994; Garthwaite, 1994; Lau & Zukin, 2007). Abnormal functioning of the NMDA receptor is theorized to be associated with several diseases, such as schizophrenia, epilepsy, Alzheimer's disease, chronic motor disorders and drug addiction. Abnormal functioning of the receptor can include hyper or hypo-activation. Hyper-activation of the NMDA receptor results in an influx of ca2+, which causes excitotoxicity of the cell (Albensi, 2007; Hardingham & Bading, 2003) and ultimately leads to cell death and possible disease progression. Hypo-activation of the NMDA receptor may produce hallucinations, coma, and developmental abnormalities that can lead to disease symptoms and if untreated the perseveration or worsening of those symptoms (Albensi, 2007; Haberny et al., 2002; Smith, 2003). Because of the sensitivity of the NMDA receptor, therapeutic manipulation must be affective through an indirect mechanism.
Positive allosteric modulators (PAMs) enhance NMDA receptor functioning without ever acting directly on the NMDA receptor (Kew, 2004). PAMs binding site rests within the transmembrane of group 1 mGluRs, which is physically linked to the NMDA receptor through their intracellular anchors, post synaptic density (PSD) proteins 95 and synaptic associated proteins (SAP) 102 (Lau & Zukin, 2007). Therefore, the activation of group 1 mGluRs facilitates NMDA receptor activity through their intracellular PSD link. Negative allosteric modulators (NAMs) have the opposite effect. NAMs have the same binding site as PAMs but their mechanistic actions include non-competitive antagonists and inverse agonists (Kew, 2004).
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NMDA receptors are cation channels. They are heterotetrameric comprised of an NR1 subunit, which is mandatory and three other subunits which can be of any combination of NR2A-D, NR3A or NR3B subunits (Albensi, 2007). The receptor itself has an extracellular N-terminus and can be manipulated by protons or polyamines aside from its orthogonal binding site. Each subunit has 4 transmembrane domains (M1-M4), and a cytoplasmic C-terminal domain is present intracellularly and interacts with downstream receptor signaling proteins (Chen & Lipton, 2006; Lau & Zukin, 2007). This receptor is permeable to both Na+ & Ca2+ (Chen & Lipton, 2006). During the receptors resting state the channel is blocked my Mg2+ (Lau & Zukin, 2007). Endogenous binding sites include glutamate, glycine and D-serine, which share a site, Zn2+, H+, and polyamines (Siegel et al., 2006). Currently there are 8 different splice variants known for the NR1 subunit (Waxman & Lynch, 2005). NR2 subunits are encoded by 4 different, but similar genes (Digledine et al., 1999).
NMDA receptors are mostly found post-synaptically but can also be found extra-synaptically and peri-synaptically, the latter two meaning out of reach of presynaptic glutamate release. These nontraditional receptor sites may exist to theoretically catch glutamate spillover (Hardingham & Bading, 2010). Intense glutamate neurotransmission occurring at the normal synaptic NMDA receptor site triggers downstream genomic processes that protect neurons, making them more resistant to aptosis and oxidative insults (Hardingham & Bading, 2010). Stimulation of the extra and perisynpatic NMDA receptors however causes downstream effects that trigger aberrant mitochondrial and cell death (Hardingham & Bading, 2010).
The NMDA receptor is voltage gated, meaning in order to be stimulated AMPA receptors need to first be activated, thereby depolarizing the cell enough to dislodge the Mg2+ block of the NMDA receptor, and enabling Ca2+ and Na+ to enter the channel (Lau & Zukin, 2007). Activation of several downstream pathways, including but not limited to PKC/PKA, can lead to up-regulation of the NMDA receptor and stimulation of the NMDA receptor can lead to up-regulation of AMPA receptors which would facilitate LTP (Lau & Zukin, 2007; MacDonald et al., 2001).
NMDA receptors have specific expression patterns, in a rat brain NR2A subunits are found in the forebrain and cerebellum. NR2B subunits are mostly within the forebrain region, NR2C subunits are mostly in the cerebellum and NR3A subunits are in the spinal cord and cortex, where as NR3B subunits can be found in motor neurons (Seeburg et al., 1994; Siegel et al., 2006). Although the human brain has been less extensively explored, it is known that the expression is not identical but similar to the rats' brain. NR1 and NR2A and NR2B subunits are the same as the rats' expression patterns but the typical composition involves two NR1's and two NR2's (Law et al, 2003). Also of interest, in human brains the NMDA receptors are found most densely in the hippocampus and cerebral cortex, which are areas necessary for reference memory and higher ordered cognition (Curran & Monaghan, 2001).
Drug addiction occurs through physiological changes that take place in your brain over the course of chronic drug abuse. These cellular changes lead to drug tolerance, sensitization, and dependence (Nestler & Aghajanian, 1997). Cellular changes include up-regulation of cAMP pathways and alteration of opiod and dopamine receptor sensitivity in the locus coeruleus and the nucleus accumbens. These changes are effects from downstream changes in gene expression mediated by transcription factors CREB, Fos and Jun. Other alterations include changes in neurotransmission, dendritic structure, and effective synaptic connections, which are also a result of downstream gene changes. These physical cellular changes lead to the behavioral symptoms associated with drug addiction (Nestler, 2001.)
The NMDA receptor may contribute to the etiology of drug addiction. Pharmacological experiments have verified these receptors involvement in different types of addiction. NMDA antagonists were shown to attenuate the development of analgesic tolerance to opiates when co-administered. Attenuation of locomotor sensitization to psychostimulants and of drug dependence to known addictive drugs was also seen when co-administered with NMDA antagonists (Elliott et al, 1995; Kalivas, 1995; Trujillo & Akil 1995; Wolf, 1998).
- Interactions of drugs of abuse with the NMDA receptor - alcohol, ketamine, PCP
Alcoholism is one of the most common diseases worldwide (Gant et al., 2004). Conflicting results of ethanol exposure and its effects of the NMDA receptor have been reported throughout literature. One study reported increases in the number of NMDA receptors as an adaptive response to prolonged attenuation or inhibition (Fadda & Rossetti, 1998). Intoxicating concentrations of ethanol were shown to inhibit NMDA receptor activity (Woodward, 2000), but other studies, (Chandler et al., 1997) showed increases in NMDA receptor functioning without changes in the number of receptors which infers the workings of complex processes regulating NMDA receptor function. Increases in NMDAR1 receptor subunit expression in the hippocampus were found due to ethanol exposure (Trevisan et al., 1994). An in-depth study designed to clarify conflicting results found that chronic exposure to ethanol induced synaptic but not extra synaptic targeting of NMDA receptors (Carpenter-Hyland et al., 2004). This study used confocal imaging, immunohistochemistry and electrophysiology. Their idea is that through compensatory mechanisms, ethanol inconsistently alters the expression of NMDA receptor trafficking between certain membrane regions (Carpenter-Hyland et al., 2004).
Dissociative anesthetic hallucinogens ketamine and phencyclidine (PCP) are two drugs that also interact with NMDA receptors and both have been abused in the USA for the previous two decades (Maisto et al., 2004). Ketamine and PCP both directly bind to the cation channel of the NMDA recpetors (Largent et al, 1986; Jones et al, 1987 a/b; Wroblewski et al 1988, and Javitt & Xukin, 1991). Both drugs act as non-competitive NMDA receptor antagonists, meaning they inhibit excitatory amino acid circuitry (Anis et al., 1983; Cotman & monaghan, 1987). Ketamine has been shown to disrupt normal functioning of NMDA receptors throughout the brain but has specifically been shown to inhibit LTP in the hippocampus (Harris, Ganong & Cotman, 1984). Because of this, it is not surprising that acute doses impair learning, memory and cognition. A study using positron emission tomography (PET) showed that ketamine stimulates the release of dopamine from the nucleus accumbens, which is an effect common among drugs of abuse (Smith et al., 1998). PCP has a 10 fold greater affinity for the NMDA receptor over ketamine, and is therefore more physiologically damaging due to excitotoxicity (Maisto et al., 2004; Smith et al., 1998).
It is interesting to note that PCP and ketamine as drugs of abuse act as NMDA antagonists, while novel therapeutic targets for drug addiction share this same mechanism of action. This could be explained through different mechanistic properties of addictive drugs occurring in different brain regions and of course compensatory mechanisms that arise throughout drug addiction (Miyamoto et al., 2004). Another explanation could lie in the different subunits that comprise the NMDA receptor, which could yield different actions (Miyamoto et al, 2004).
- NMDA Receptor Targeted Medications
Memantine is an FDA approved medication for treatment of moderate to severe Alzheimer's disease (Zdanys & Rajesh, 2008). Memantine is derived from amantadine and blocks the NMDA receptor channel much like magnesium (Robinson & Keating, 2006). While similar to magnesium in that memantine binds at or near the magnesium binding site, it blocks the NMDA channel with a higher affinity, but less voltage dependency. Due to its dependency upon prior activation of the receptor by glutamate to access its binding site, memantine is classified as an "uncompetitive antagonist" (Robinson & Keating, 2006). In addition to its antagonist actions at NMDA receptors, memantine also blocks the serotonin type 3 receptor as well as nicotinic acetylcholine receptors (Olive, Cleva, Kalivas, & Malcom, 2012). Memantine has been shown to block NMDAR activity in the presence of prolonged elevations of glutamate concentrations, but it is not as active when glutamate levels increase for shorter periods of time, as in synaptic transmission (Kutzig, Luo, & Firestein, 2012) (Chen & Lipton, 2006). Studies have shown that memantine preferentially blocks extrasynaptic NMDAR channels while sparing normal synaptic activity, which may be the reason there appear to be very few side effects found in patients treated with memantine (Kutzig, Luo, & Firestein, 2012). Unlike other NMDA antagonist drugs, like ketamine or dextromethorphan, memantine is one of the few that appears to not have abuse potential (Olive, Cleva, Kalivas, & Malcom, 2012).
Out of ten studies (nine randomly controlled studies and one open label study), two showed that patients taking memantine reported decreased craving of alcohol (Bisaga & Evans, 2004) (Krupitsky, et al., 2007), one study showed decreased symptoms of alcohol withdrawal (Krupitsky, et al., 2007), two studies demonstrated decreased quantity of alcohol consumed (Arias, Feinn, Covault, & Kranzler, 2007) (Evans, Levin, Brooks, & Garawi, 2007). However, only one of the experiments directly compared memantine to a placebo, and this study did not report a significant difference between the two groups. (Evans, Levin, Brooks, & Garawi, 2007) (Zdanys & Rajesh, 2008) This study demonstrated that memantine does not reduce on-going drinking behavior in alcohol dependent patients (Olive, Cleva, Kalivas, & Malcom, 2012). Data collected looking at methamphetamine versus placebo discrimination replicated and extended previous research in non-human subjects (Hart, Haney, Foltin, & Fischman, 2002). They found that methamphetamine can serve as a discriminative stimulus in humans; this indicates that NMDA antagonists may not necessarily substitute for amphetamine or cocaine. These results are not congruent with previous preclinical studies that indicate NMDA antagonists can partially or completely substitute for amphetamine and methamphetamine (Hart, Haney, Foltin, & Fischman, 2002).
Negative side effects
Memantine is generally well handled by humans (Areosa, Sherriff, & McShane, 2006). Common side effects include confusion, dizziness, drowsiness, headache, insomnia, and/or hallucinations.
Lamotrigine is an anticonvulsant medication. Neurochemical studies indicate that lamotrigine indirectly decreases release of glutamate by inhibiting presynaptic, voltage-sensitive sodium channels (Margolin, Avants, DePhilippis, & Kosten, 1998) (Olive, Cleva, Kalivas, & Malcom, 2012)
Results from a small, open label study of lamotrigine in a group of HIV-seropositive cocaine-dependent participants showed a significant decrease in the amount of cocaine-positive urine analysis samples (Margolin, Avants, DePhilippis, & Kosten, 1998), however, this study utilized a small sample (n-8) and did not have a control group. Lamotrigine is also reported to exhibit efficacy in reducing cravings for cocaine, alcohol, and abused inhalants (Olive, Cleva, Kalivas, & Malcom, 2012). There is insufficient research to indicate whether lamotrigine would be efficacious in regards to opiates, behavioral addictions, nicotine, or methamphetamine (Olive, Cleva, Kalivas, & Malcom, 2012).
Negative side effects
Lamotrigine carries an uncommon but serious risk of causing a severe skin rash, known as Stevens-Johnson Syndrome. Stevens-Johnson Syndrome has an incidence rate or approximately 2 to 6 cases per million people per year (Wark, Archambault, & Mersfelder, 2010) and can be caused by a number of medications (Rakasha & Marfatia, 2008)
Topiramate is a sulphamate-substituted fructopyranose derivative (Johnson, et al., 2007). Topiramate has two possible mechanisms of action that are relevant to the treatment of substance abuse. Topimarate facilitates gamma-aminobutyric acid (GABA)ergic function through a non-benzodiazepine site on the GABA-A receptor, depressing cortico-mesolimbic dopaminergic activity (Elkashef, et al., 2011). Topiramate also antagonizes glutaminergic activity through an effect at kainite/alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (Elkashef, et al., 2011).
Research has showed that topiramate is effective at improving the drinking outcomes of alcohol dependent individuals (Johnson, et al., 2003). Many studies have been published in the last ten years demonstrating the ability of toprimate to reduce alcohol cravings, subjective effects, and heavy consumption in alcohol patients (Olive, Cleva, Kalivas, & Malcom, 2012) (Anderson & Oliver, 2003) (Johnson, Ait-Daoud, & Ma, Oral topiramate reduces the consequences of drinking and imporves the quality of life of alcohol-dependent individuals: A randomised controlled trial, 2004)
Negative Side Effects
Topiramate does not express a high rate of side effects. In one study, the adverse events that were reported were also reported in nearly equal percentages in the placebo condition, they included: headache, fatigue, paresthesia, nausea, dizziness, and dysgeusia. Of all the negative side effects reported, only paresthesia and dysgeusia were statistically significantly different between groups (Elkashef, et al., 2011). Other topiramate addiction studies, looking at both cocaine (Nuijten, Blanken, van den Brink, & Hendricks, 2011) and methamphetamines use (Johnson, et al., 2007) reported that participants did not experience adverse side effects from Topiramate, but the small number of reports of increased heart rates were from the administration of the stimulant.
Acamprosate is a synthetic compound derived from acetylhomotaurinate (Mason & Heyser, 2010). It is very similar to many amino acids like glycine, taurine, aspartate, glutamate, and gamma-aminobutyric acid (GABA) (Chabenat, Chretien, Daoust, & al., 1988) (Kiefer & Mann, 2010). The molecule is formulated as calcium salt to aid in its absorption from the gastrointestinal tract, and is N-acetylated to help it cross the blood brain barrier (Olive, Cleva, Kalivas, & Malcom, 2012) (Mason & Heyser, 2010). Radioligand binding studies report that acamprosate had weak partial agonist effects on NMDA receptors by way of indirect actions on a polyamine site on the NMDAR complex (Kiefer & Mann, 2010). Neuronal network data showed that acamprosate may have differential effects on NMDA receptors at low concentrations, and on GABA(A) receptors at higher concentrations (Kiefer & Mann, 2010).
The clinical efficacy of acamprosate has been studied throughout the world (Mason & Heyser, 2010), however the results have been conflicting. Studies looking at overall alcohol consumption, subjective measures of alcohol craving, and promoting abstinence demonstrate effect sizes ranging from small to moderate (Kiefer & Mann, 2010) (Mason & Heyser, 2010) (Olive, Cleva, Kalivas, & Malcom, 2012). However, there are also studies reporting that acamprosate is no more effective than the placebo in reducing alcohol related cravings or overall abstinence (Donovan, Anton, Miller, Longabaough, & Youngblood, 2008) (Richardson, et al., 2008) (Olive, Cleva, Kalivas, & Malcom, 2012) (Gass & Olive, 2008). These discrepancies are still being investigated and debated (Olive, Cleva, Kalivas, & Malcom, 2012). Acamprosate has been shown to be ineffective in studies looking to see whether or not acamprosate develops a conditioned place preference in mice to morphine (Mcgeehan & Olive, 2006). Acamprosate is also shown to be ineffective in self-administration and relapse of heroin use in rats (Spanagel, Sillaber, Zieglgansberger, Corrigall, Steward, & Shaham, 1998). Effects of acamprosate on cocaine addiction appear to be more promising. Studies so far report that acamprosate diminishes cocaine and cue induced reinstatement of cocaine seeking behavior in rats without affecting basal levels of cocaine IVSA (Gass & Olive, 2008).
Negative Side Effects
There are very few, and mostly mild side effects. The most commonly reported side effect is diarrhea; with it being reported 16% versus 10% in placebo-treated groups (Mason & Heyser, 2010). Other side effects include dizziness and nausea, but not reported at rates higher than that of the placebo group (Mason & Heyser, 2010)
- D-cycloserine (DCS)
Mechanism of action
D-cycloserine (D-4-amino-3-isoxazolidone), a derivative of the naturally occurring amino acid serine, is an NMDA receptor partial agonist. It acts as co-agonist at the strychnine-insensitive glycine binding site on the NR1 subunit of the NMDA receptor. DCS increases the activation probability of the NMDA receptor, however it requires the presence of glutamate binding to the receptor in order to exert its effects (Myers & Carlezon, 2012; Lanthorn, 1994). DCS activation enhances NMDA functioning by increasing calcium influx through these receptors without causing neurotoxicity (Sheinin et al., 2001; Olive et al., 2011). However, DCS is less efficient than the endogenous ligands glycine and D-serine because its effects on modulating NMDA receptor function can be dose-dependent. High doses of DCS displace the more efficacious endogenous ligands, however moderate doses of DCS have shown to facilitate NMDA receptor-dependent forms of synaptic plasticity and learning (Myers & Carlezon, 2012).
Due to its ability to enhance NMDA facilitation involved in "Pavlovian" learning, in combination with cue-exposure therapy (CET), administration of DCS has provided great evidence in treating anxiety and fear responses in a number of clinical studies (reviewed in Davis et al., 2006; Myers et al., 2011; Myers and Davis, 2007). Addiction, like fear and anxiety, involves conditioned responses to stimuli (cues). Cues that are associated with drug use and acute withdrawal elicit conditioned craving and withdrawal responses that contribute to recurring drug use and relapse (Childress et al, 1986; Wikler, 1948; Siegel & Ramos 2002). Although CET alone has not been effective in reducing drug-related conditioned responses in addicts involving exposure to drug related cues, coupling DCS with therapy could aid in improving its efficacy.
In a 2009 clinical study of nicotine dependent cigarette smokers undergoing CET, Santa Ana et al. found that administration of DCS significantly lessened physiological as well as subjective "urge to smoke" rating responses compared to placebo treatment. Although there were no effects found on general smoking behavior during a follow up assessment, these preliminary findings support the notion that DCS may be beneficial in combination with CET to augment effects of cues and adverse effects during attempts to quit smoking cigarettes (review in Olive et al, 2012 and Myers & Carlezon 2012). On the contrary, a 2011 study by Kamboj et al., which expanded on the Santa Ana et al. (2009) to include two CET sessions with DCS or placebo administration along with follow up assessments of smoking behavior, found no significant effects of DCS on cravings and smoking behavior (reviewed in Myers & Carlezon 2012). With these contradictory findings, it may be of value to continue exploring possible alternative combinations of DCS and CET for nicotine addiction.
Preliminary clinical findings in a 2009 study by Price et al reported very unexpected findings from administration of DCS along with CET in cocaine dependent patients. Unlike preclinical studies that showed DCS reduced reacquisition and enhanced extinction learning in animal models of cocaine addiction (Thanos et al, 2009; Nic Dhonnchadha et al., 2010; Thanos et al., 2011), the clinical study showed an increase in subjective reporting of cocaine craving in the DCS treatment group during the first of two CET sessions and no statistically significant differences between placebo and DCS treatment in the second CET session nor follow up sessions (Price et al, 2009). Due to the contradictory findings between human and animal models, further investigation is necessary.
Literature on clinical studies of DCS treatment for alcohol-dependent subject all concluded that no significant effect was found when compared to placebo (reviewed in Myers & Carlezon, 2012). Although DCS appears to be a promising addition to CET treatment for drug addiction on a conceptual level, clinical evidence suggests that more research should be conducted with variations in treatment plans, dose, and timing of administration of this pharmacotherapy to better explore clinical efficacy of DSC. A recent correspondence regarding clinical relevance of DCS and CET research for addiction treatment suggests that current data may not be statistically significant due to both type I and type II errors (Das & Kamboj, 2012; review in Myers and Carlezon, 2012). There is also debate over the clinically utilized criteria in relapse prevention treatment, specifically regarding the clinical efficacy for treating disorders of addiction when compared to the treatment of anxiety and fear disorders (Das & Kamboj, 2012).
Adverse side effects
Due to the limited amount of clinical data on administration of DCS in the treatment of drug addiction, adverse effects are sparsely mentioned. Some of the most common adverse effects of D-cycloserine, used as an antibiotic for tuberculosis, mainly include CNS manifestations such as headache, irritability, depression, psychosis, and convulsions.
With regards to the five medications reviewed here that possess a glutamatergic mechanism of action (NMDA receptor modulators acamprosate, lamotrigine, topiramate, memantine, as well as the partial NMDA agonist D-cycloserine), we conclude that topiramate, lamotrigine, and memantine have the greatest potential for use in the treatment of drug, alcohol, and behavioral addictions. Although current data suggest the limited efficacy of NMDA receptor modulators in the treatment of addiction, some drugs show promise in helping to treat the long and increasingly difficult battle with drug addiction. Although none of the medications reviewed here will be a universal treatment for all addiction, when used in combination with appropriate behavioral therapy many of pharmacotherapies can provide increased aid in treating specific addictions such as alcohol and nicotine.