Abstract
Here we discuss treatment strategies that are based on pharmacological interventions to reduce craving and relapse in alcohol-dependent patients. We will first provide a historical overview about relapse prevention strategies. We will then review the development of disulfiram, naltrexone, acamprosate, and nalmefene and discuss their neurobiological modes of action. Then the concept of convergent genomic analysis will be introduced for the discovery of new molecular treatment targets. Finally, we will provide convincing evidence for the use of N-methyl-D-aspartate (NMDA) receptor channel blockers as substitution drugs. Important conclusions of this review are: (i) learning from other addictive substances is very helpful—e.g., substitution therapies as applied to opiate addiction for decades could also be translated to alcoholics, (ii) the glutamate theory of alcohol addiction provides a convincing framework for the use of NMDA receptor antagonists as substitution drugs for alcohol-dependent patients, (iii) a combination of behavioral and pharmacological therapies may be the optimal approach for future treatment strategies—one promising example concerns the pharmacological disruption of reconsolidation processes of alcohol cue memories, (iv) given that many neurotransmitter systems are affected by chronic alcohol consumption, numerous druggable targets have been identified; consequently, a “cocktail” of different compounds will further improve the treatment situation, (v) in silico psychopharmacology, such as drug repurposing will yield new medications, and finally, (vi) the whole organism has to be taken into consideration to provide the best therapy for our patients. In summary, there is no other field in psychiatric research that has, in recent years, yielded so many novel, druggable targets and innovative treatment strategies than for alcohol addiction. However, it will still be several years before the majority of the “treatment-seeking population” will benefit from those developments.
Keywords
1 Introductory Remarks
This review focuses on treatment strategies that are based on pharmacological interventions to reduce craving and relapse in alcohol-dependent patients, although other non-pharmacological interventions may also be effective. For example, deep brain stimulation may become a treatment alternative especially for heavily dependent alcoholics. The first clinical studies employing bilateral deep brain stimulation in the nucleus accumbens in patients with severe and treatment-resistant alcohol abuse show that alcohol craving is greatly reduced and that the patients are able to abstain from drinking for extended periods of time (Kuhn et al. 2007, 2011; Müller et al. 2009; for more information see also "Deep brain stimulation as a therapy for alcohal addiction" from Thomas F. Münte). However, only a hand full of patients have so far undergone this treatment and much more research is needed, not only to see the effectiveness of this treatment, but also to understand its underlying mechanisms, identify its limitations, study its long-term consequences and side-effects, and most importantly, define its ethical implications. Psychotherapeutic-based interventions such as cue extinction training are promising as well, and it should be emphasized that each effective psychotherapeutic approach has a neurobiological underpinning. Hence, a recent randomized controlled trial (RCT) in abstinent alcohol-dependent patients using functional magnetic resonance imaging (fMRI) showed that extinction training impacts brain areas relevant for memory formation and attentional focus to alcohol-associated cues and affects the mesocorticolimbic reinforcement system (Vollstädt-Klein et al. 2011). In particular, extinction training in combination with pharmacological compounds that potentially facilitate the extinction process might become a further future alternative. On the preclinical level we have already shown that the partial N-methyl-D-aspartate (NMDA) receptor and partial agonist D-cycloserine can facilitate extinction of alcohol-seeking in rats (Vengeliene et al. 2008)—a finding that must now be translated to the human level. Another psychotherapeutic-based intervention concerns the disruption of reconsolidation processes. During reconsolidation, a retrieved memory transiently returns into a labile state and may require new protein synthesis to persist further. During this labile state, the memory is amenable to enhancement or disruption. A very recent study by Schiller et al. (2010) implies that long-lasting drug memories can possibly be updated with non-drug-related information provided during the reconsolidation window—an intervention that may also attenuate alcohol cue memories. In laboratory animals, disruption of reconsolidation can be also achieved via application of NMDA receptor antagonists (von der Goltz et al. 2009; Milton et al. 2012), and again a combination of behavioral and pharmacological treatment strategies might be the optimal approach for future studies.
We will first provide a historical overview about relapse prevention strategies. We will then review the development of disulfiram, naltrexone, and acamprosate. Today these are the drugs of choice for clinicians to treat alcohol-dependent patients who have a strong motivation for abstinence.Footnote 1 A large phase III RCT with nalmefene, sponsored by Lundbeck, has just been completed and the preliminary results are very positive. In 2012, the approval of nalmefene is expected by the food and drug administration (FDA) and other regulatory agencies; the opioid receptor antagonist nalmefene will then be introduced to the market as the first harm reduction medication. Serotonin-reuptake inhibitors and several other classes of psychotherapeutics are not only used for the treatment of comorbidities of alcohol dependence, but also with the indirect intention of reducing drinking, craving, and relapse. These “indirect” pharmacological treatment options will not be reviewed here. Instead, we will give an overview of newly developed preclinical compounds (e.g., neramexane) and describe how they can best be translated into the clinical situation.
2 Brief Historical Overview of Relapse Prevention Strategies
Here we will concentrate on historical developments in Europe and America, although prevention strategies have been developed in China and other countries centuries ago. In a recent book entitled “Drugs for Relapse Prevention of Alcoholism” (Spanagel and Mann 2005), Griffith Edwards from London provided a comprehensive overview of the history of the prevention of relapse that is briefly recapitulated here. In the sixteenth century, punishment was the approach to diminish alcohol consumption. For example, during the reign of François I in France, an edict in the year 1536 stipulated:
Anybody who appeared in public in the state of intoxication should on the first occasion be imprisoned on bread and water. On the second occasion chastised with birch and whip, and on the third occasion publically flogged. Should further relapses occur the delinquent was to have an ear cut off and suffer banishment.
Although the concept of punishment might have caused fear in sporadic populations of individuals experiencing drunkenness, it became outdated in the eighteenth century when a first epidemic of gin consumption permeated England. There were no regulations on gin distillation and it could be sold tax-free throughout the country. In the working class in London and other large English cities, extreme Gin inebriation provoked moral outrage and became a major societal health problem. The government was forced to react on these societal excesses and in 1750 The Sale of Spirits Act was enacted to reduce gin consumption by raising taxes and prohibiting gin distillers from selling to unlicensed merchants. At the same time, the English painter William Hogarth (1697–1764) pictured the unpleasant consequences of alcoholism on “gin lane” and proposed that replacing gin with beer (Beer street; Fig. 1) would reduce the harm of alcohol drinking and in an imaginative ideal would even result in a society full of harmony.
Today “beer street” gets celebrated each year at the Oktoberfest in Munich, and though one might have the impression of a societal harmonically event, within the blink of an eye comes the realization of the harmful effects of excessive alcohol consumption, such as aggressive behavior, sexual disinhibition, and the devastating effects the day after. Nevertheless, William Hogarth’s idea to shift from gin to beer drinking was probably the first public effort of an artist to interfere with societal issues and his prints were published in support of the Gin Act. What is really fascinating regarding the proposed shift from gin lane to beer street was the suggestion of a replacement therapy even at that early time. Today most researchers, clinicians, and also politicians are not tolerant of the idea that alcohol could be replaced by another psychoactive compound (e.g., GHB), despite the fact that this is the most successful treatment option in opiate addiction (Dole and Nyswander 1967; for a recent Cochrane Database Systematic Review, see Mattick et al. 2009). Later in this chapter we will return to the introduction of neramexane—a NMDA receptor channel blocker—as a replacement therapy for alcohol-dependent patients.
In the nineteenth century, alcoholism was more and more seen from a medical and psychological perspective. The concept emerged that excessive drinking is a learned habit, an idea that was particularly well-developed by Scottish physician Thomas Trotter (1760–1832) in his famous “Essay on Drunkenness.” This book was among the first attempts to characterize excessive drinking as a disease or medical condition, concluding that drunkenness is a disease that could be cured. This disease concept of alcoholism became the framework for the twentieth century, during which the pharmacological treatments for alcohol dependence emerged. The first modern pharmacological intervention strategy was, as often in pharmacology, discovered by accident in 1947 at the Royal Danish School of Pharmacy in Copenhagen. At that time Danish researchers Eric Jacobsen and Jens Hald were studying compounds for possible use in treating parasitic stomach infections. In a self-experiment—a kind of heroic behavior that has unfortunately disappeared from the landscape of modern work attitudes of chemists and pharmacists—they administered to themselves a small dose of one of their compounds to check for possible side effects. The next day they became very ill after having a drink. Because each of them experienced the same symptoms at the same time, they assumed that the drug and alcohol interaction was responsible for their illness. Antabuse® (disulfiram) (Fig. 2) was born and further human experiments quickly led to the conclusion that Antabuse is a drug that sensitizes the organism to ethanol, a finding published in Lancet one year after the initial observation was made (Hald and Jacobsen 1948). These first clinical observations instigated several clinical trials in different countries and an expert panel, on request by the Canadian Medical Association delivered in the early 1950s the conclusive statement that Antabuse would prove valuable as an adjunct in the treatment of alcoholic patients but should be used only on carefully selected patients, with a full realization of its potential danger. In the last 60 years, thousands of patients have been treated with Antabuse, and the determination is that this medication reveals a mixed outcome pattern—some evidence that drinking frequency is reduced but minimal evidence to support improved continuous abstinence rates (Garbutt et al. 1999). Nevertheless, as initially suggested, in carefully selected patients with a continuous clinical monitoring, Antabuse has its value.
What does disulfiram do to the organism? Under physiological metabolic conditions, ethanol is broken down in the liver by the enzyme alcohol dehydrogenase to acetaldehyde, which is then converted by the enzyme acetaldehyde dehydrogenase to harmless acetic acid. Disulfiram interrupts this reaction at the intermediate stage by inhibiting the enzyme acetaldehyde dehydrogenase. After alcohol intake under the influence of disulfiram, the concentration of acetaldehyde in the blood may be 5–10 times higher than that found during metabolism of the same amount of alcohol alone. As acetaldehyde is one of the major causes of the symptoms of a “hangover,” this produces an immediate and severe negative reaction to alcohol intake, including flushing of the skin, accelerated heart rate, shortness of breath, nausea, vomiting, throbbing headache, visual disturbance, mental confusion, etc. It was found later that disulfiram also blocks dopamine-ß-hydroxylase (Goldstein et al. 1964)—an enzyme that leads to the conversion of dopamine into noradrenaline. Disulfiram-induced inhibition of dopamine-ß-hydroxylase thus leads to an accumulation of dopamine and concurrently to a reduction of noradrenaline in peripheral and central tissues. This bi-directional action of disulfiram on monamines may provide a new rationale for the treatment of cocaine addiction (Sofuoglu and Sewell 2009).
3 Current State of Pharmacological Relapse Prevention
What is the current state in terms of pharmacological relapse prevention? Beside Antabuse®, naltrexone—and a once-monthly extended release injectable naltrexone formulation marketed under the trade name Vivitrol® (Gastfriend 2011)—and acamprosate have been approved by most regulatory bodies and are available in most countries across the globe (Fig. 2).
Cochrane Reviews, which provide the highest standard in evidence-based health care, recently published two systematic reviews in which Rösner et al. (2010a, b) summarized all studies on naltrexone and acamprosate, and concluded that naltrexone significantly reduces the risk of habit drinking with a relative risk (RR) of 0.83, whereas acamprosate significantly reduces the risk of any drinking with a RR of 0.86. A relative risk of 1 means that there is no difference between placebo and treatment, whereas a RR < 1 means that relapse occurs less frequently in the treatment group. The effectiveness of both compounds is comparable.
Nalmefene may soon become an interesting treatment alternative. In mid-2011, a large phase III trial was concluded. In previous smaller clinical trials conducted by Barbara Mason and colleagues, nalmefene was shown to be effective in preventing relapse to heavy drinking as compared to placebo (Mason et al. 1994, 1999). Subsequently the so-called “targeted approach” was developed; i.e., subjects were instructed to take nalmefene when they believed that drinking was about to happen. In a first Finish RCT in more than 400 patients, it was shown that this targeted approach was safe and effective in reducing heavy drinking (Karhuvaara et al. 2007). A still unpublished large phase III study has also used the targeted approach with excellent effectiveness (see trial watch: Nat Rev Drug Discov 10:566, 2011 and the study leader Karl Mann, personal communication). Hence, nalmefene might be the first “pill on demand” for treating relapse behavior.
Nalmefene is a μ-opioid receptor antagonist but also exhibits in vivo antagonistic properties at the κ-opioid receptor (KOR) (Fig. 3). Researchers at the Scripps Institute in La Jolla compared the effects of nalmefene and naltrexone in alcohol-dependent rats and demonstrated that nalmefene was significantly more effective in suppressing alcohol intake than naltrexone (Walker and Koob 2008). It was suggested that this additional effect arises from a blockade of KORs, and indeed nor-BNI, a selective antagonist at this specific opioid receptor, also suppressed alcohol intake in dependent animals (Walker et al. 2011). Why would a blockade of KOR be beneficial in reducing heavy drinking? The underlying concept was developed in the laboratory of Albert Herz at the Max-Planck-Institute of Neuropharmacology in Martinsried, Germany. There it was discovered that KOR agonists produce place aversion in rats (Mucha and Herz 1985) and induce a strong dysphoric response in human volunteers (Pfeiffer et al. 1986). In view of the euphorigenic properties of μ-opioid receptor agonists, these results suggest the existence of opposing opioid systems affecting motivational, emotional, and perceptual experiences. Subsequently, it was shown on the neurochemical level that mesolimbic dopamine neurons are modulated by opposing endogenous opioid systems, whereby the dynorphin/KOR system reduces basal dopamine levels in the nucleus accumbens (Spanagel et al. 1992). These results imply that a reduced basal dopamine level in the reinforcement system is the neurochemical substrate of aversive and dysphoric behavior. Interestingly, chronic alcohol intake leads to an up-regulation of the dynorphin/KOR system in the brain of alcohol-dependent rats and humans (Shippenberg et al. 2007; D’Addario et al. 2011; Bazov et al. 2011), and prodynorphin and KOR knockouts show reduced alcohol consumption (Kovacs et al. 2005; Blednov et al. 2006; but see also Femenía and Manzanares 2012). Further evidence that an altered dynorphin/KOR system contributes to alcohol dependence comes from genetic association studies. An association of several single nucleotide polymorphisms (SNPs) in the prodynorphin and KOR gene, respectively, and alcohol dependence has been repeatedly shown (Xuei et al. 2006; Williams et al. 2007; Flory et al. 2011), and there is elevated methylation of prodynorphin CpG-SNPs associated with alcohol dependence (Taqi et al. 2011). We conclude that in the alcohol-dependent brain there is an up-regulation of the dynorphin/KOR system, and therefore a blockade of KOR may suppress the negative drive and compulsive alcohol use (for review of this concept see Wee and Koob 2010). However, the translation into the human condition has been hampered so far by the fact that there are only a few selective KOR antagonists available, all of which possess extremely long-lasting activity that limits their clinical application (Spanagel et al. 1994; for review see Peng and Neumeyer 2007). Therefore, nalmefene provides for the first time a treatment option for targeting the KOR in the human brain as it exhibits in vivo antagonistic properties at this receptor, and this effect might be the reason why nalmefene is superior in the treatment of heavy drinking in comparison to naltrexone.
4 Identification of New Drug Targets
Multiple neurochemical pathways have been identified as being involved in mediating, craving, and relapse to alcohol (Vengeliene et al. 2008, 2009; Spanagel 2009), and such knowledge provides the basis for the classical hypothesis-driven drug target definition and subsequent compound development. Using this approach, many new targets have been identified and several new compounds are currently undergoing clinical testing (for an extensive overview, see Drugs for Relapse Prevention of Alcoholism, edited by Spanagel and Mann 2005; for more recent reviews, see Spanagel and Kiefer 2008; Heilig et al. 2010a, b; Edwards et al. 2011; and see a recent special issue on Pharmacotherapy of Alcoholism in Current Pharmaceutical Design, edited by Leggio and Addolorato 2010). Examples of this hypothesis-driven approach are described below.
Markus Heilig and George Koob postulated that corticotropin-releasing hormone (CRH) signaling via its CRH1 receptor is a key element of the neuroadaptive changes driving alcoholism and is therefore a major target for the treatment of relapse behavior, especially under stress-related conditions (Hansson et al. 2006; Heilig and Koob 2007). The role of the CRH system is further supported by a series of human genetic studies showing that specific variants of the CRHR1 gene interact with exposure to stressful life events to predict the onset of alcoholism (Treutlein et al. 2006; Blomeyer et al. 2008; Barr 2010; Nelson et al. 2010; Schmid et al. 2010). In fact, this CRHR1 gene × stress × alcohol effect seems to be the most consistent finding in the field of psychiatric genetics (with respect to gene × environment interactions). However, the application of specific CRHR1 antagonists in the translatable human situation may face two limitations. First, only a relapse risk that is driven by a high stress load may be efficiently attenuated, and second, actions of CRHR1 antagonists on hypothalamic–pituitary–adrenal (HPA) axis activity might counteract their desired therapeutic effects in alcohol-dependent patients (Sillaber et al. 2002; Molander et al. 2012). Currently a novel CRHR1 antagonist is being tested in a translational study at the (NIAAA) in Bethesda (Heilig 2011).
Another example is the dopamine D3 receptor (D3R). D3Rs exhibit the highest density in the nucleus accumbens and amygdala—brain areas that are thought to be crucial for the integration and response to the presentation of alcohol-associated cues. Furthermore, the number of these receptors is increased in addicted patients and alcohol-dependent animals. And finally, selective DA D3 antagonists show a very promising preclinical profile with no orlittle side effects (Heidbreder et al. 2005; Vengeliene et al. 2006). Moreover, these compounds have also been tested in a variety of animal models related to nicotine, cocaine, and morphine addiction with very consistent and reliable results (Heidbreder et al. 2005). In light of these findings, clinical trials have now been initiated to test the clinical significance of D3 antagonists.
From our perspective, one of the most promising candidate targets derives from the hypothesis that manipulation of the extracellular glycine pool can possibly affect relapse behavior. The glycine system has been defined as an access point for alcohol to the reinforcement system (Molander and Söderpalm 2005; Adermark et al. 2011) and thus selective glycine transporter (GlyT) blockade may affect excessive alcohol consumption via both glycine receptors and NMDARs, which also contain a glycine binding site. In fact, Org25935, a selective GlyT1 antagonist, reduced compulsive relapse-like drinking without the development of tolerance in an animal model of alcohol addiction (Vengeliene et al. 2010; for a description of the model, see Spanagel and Hölter 1999). Importantly, these anti-relapse properties were maintained for at least 6 weeks in a treatment-free period. This persistent effect was paralleled by the reversal of altered expression levels of a set of glycinergic and glutamatergic signaling-related genes in the striatum to levels found in alcohol-naϊve control rats (Vengeliene et al. 2010). In our laboratory, this is the first drug that has produced long-lasting anti-relapse effects in our animal model of alcohol addiction. Due to this finding, in combination with previous results obtained in selected high alcohol-drinking rats that demonstrated reduced alcohol intake and preference following Org25935 treatment (Molander et al. 2007), a RCT investigating the efficacy and safety of Org25935 in relapse prevention in subjects with alcohol dependence has been initiated (ClinicalTrials.gov Identifier: NCT00764660). Following the gigantic merger of Organon (who developed Org25935) with Schering–Plough in 2008, and a year later the full takeover by Merck & Co., the new enterprise implemented several strategic decisions unsupportive of CNS-related programs; consequently, the trial on Org25935 was discontinued. This is an example par excellence of how nonscientific decisions, based more on the shareholder value of a company than progress in medicine, are undermining the development promising medications.
Finally, many more targets have been identified and several promising candidates developed. The list includes, for example, non-peptide agonists of the nociceptin receptor as potential anti-relapse medications (Ciccocioppo et al. 2004; Kuzmin et al. 2007), neurokinin 1 receptor antagonism as a possible therapy for alcoholism (George et al. 2008), and ghrelin receptor blockade (Jerlhag et al. 2009; Landgren et al. 2011), mediated via glutamatergic control of ghrelin action at the level of the reinforcement system (Jerlhag et al. 2011). Another example is agonists at GABAB receptors, such as baclofen (Colombo et al. 2004; Addolorato et al. 2007)—a drug described by French cardiologist Olivier Ameisen in the best-selling book “The End of my Addiction” as the magic bullet. Unfortunately, only future RCT will reveal whether these and other pharmacotherapies will benefit alcohol-dependent patients. We again refer the reader to a series of excellent reviews describing these pharmacological alternatives (Spanagel and Kiefer 2008; Heilig et al. 2010a, b; Edwards et al. 2011; and see a recent special issue on Pharmacotherapy of Alcoholism in Current Pharmaceutical Design, edited by Leggio and Addolorato 2010) and would like to reemphasize that there is no other field in psychiatric research that has yielded as many promising approaches in target definition and drug development than that for alcohol addiction.
Alternatively, the variety of putative targets also demonstrates that alcohol affects many neurotransmitter systems (Vengeliene et al. 2008; Spanagel 2009), and it is unlikely that specifically targeting one access point of alcohol to the brain reinforcement system will benefit a large proportion of alcohol-dependent patients. Therefore, an additional benefit might arise from the combination of different compounds. In fact, two clinical studies have demonstrated that a combination of naltrexone and acamprosate may be more effective than either drug alone (Kiefer et al. 2003; Feeney et al. 2006). However, these findings were not replicated in the COMBINE study, which included 1,383 alcohol-dependent patients treated with a combination of both compounds as well as behavioral interventions (Anton et al. 2006). The reason for this negative finding is most likely due to a recruitment bias of subjects with moderate severity and early stages of alcoholism, which defines a group of patients that is more responsive to naltrexone than acamprosate treatment (Karl Mann, personal communication). In conclusion, we suggest that a “cocktail” of different compounds will further improve the treatment situation. However, the question remains whether the pharmaceutical industry will invest the money for further cost-intensive phase II–III studies. Given their hesitant efforts in the past and their economically motivated lack of interest in testing drug cocktails, joint efforts of academia, and the pharmaceutical industry will be required in the near future.
5 Convergent Genomic Analysis for New Drug Target Definition
Another potential for drug target definition arises from convergent genomic analysis. A genetic component of vulnerability to alcohol addiction has long been established. The heritability of alcoholism lies at approximately 50–60% (Goldman et al. 2005). Although it is a complex disorder and the contribution of single genes to the clinical phenotype(s) of addictive behavior is rather small, genome wide analysis of variants contributing to increased vulnerability for alcohol addiction may yield new targets. One approach that we took—under the leadership of Gunter Schumann of the Institute of Psychiatry in London—was conducting a genome-wide association study (GWAS) on high alcohol consumption in combination with animal studies (for consilience of alcohol drinking behavior in animals and humans, see Kiefer and Spanagel 2006 and Leeman et al. 2010). Indeed, human genetic data can be further enriched by information from animal studies. A new translational approach for the integration of data sets that derive from forward genetics in animals and genetic association studies, including GWAS in humans, is referred to as convergent functional genomics. We recently obtained new targets by applying this approach (Treutlein et al. 2009; for confirmation, see Frank et al. 2012). The aim of forward genetics in animals and association studies in humans is to identify mutations (e.g., SNPs) that produce a certain phenotype; i.e., from phenotype to genotype. The repertoire of forward genetics in animals includes the generation of random mutations in an organism, either by radiation, or chemical mutagens such as N-ethyl-N-nitrosourea, and then through a series of breeding of subsequent generations, isolating individuals with a phenotype relevant for addictive behavior (Pawlak et al. 2008). Most powerful, however, in terms of forward genetics, is combined quantitative trait loci analysis and differential gene expression profiling in recombinant inbred rodent lines or animals genetically selected for a specific phenotype, such as, for example, high versus low alcohol consumption (Spence et al. 2005; Ehlers et al. 2010). Baysian approaches allow combining such animal genomics data with GWAS information from a similar addiction-relevant human phenotype, thereby enhancing the explanatory power of genetic studies. Within the context of a huge consortium, we performed such a convergent functional genomics analysis. Twelve population-based samples comprising 28,188 individuals screened for their alcohol intake per day in gram intake per kilogram bodyweight, and an almost equally large replication genotyping sample with 21,185 individuals of European ancestry, were used to identify genetic loci associated with high alcohol intake (Schumann et al. 2011). Out of approximately 2.5 million directly genotyped or imputed SNPs, we found a few variants with genome-wide significance. One hit drew our attention, an identified SNP in or near the Ras protein-specific guanine nucleotide releasing factor 2 (RASGRF2) gene that may indeed be of high relevance for excessive and compulsive alcohol consumption, but only in males. The RASGRF2 is a glutamate transmission-related gene that couples NMDA receptors to the activation of the Ras-ERK signaling cascade. The role of NMDA receptors and Ras-ERK signaling in alcohol-induced plasticity is well-established. In recent years, the role of the Ras-ERK pathway and downstream gene expression has extensively been investigated in the striatum, using both pharmacological and genetic approaches. The conclusion of these studies is that an aberrant hyperactivation of Ras-ERK appears to be a key pathogenic factor for addictive behavior (Schroeder et al. 2008; Fasano and Brambilla 2011). In order to study the functional relevance of this gene, we used RASGRF2 knockouts and studied them in free-choice drinking conditions with increasing concentrations of ethanol. The knockouts consumed significantly less alcohol, especially at pharmacologically relevant concentrations. Furthermore, consistent with the aforementioned convergent functional genomics analysis, this phenotype effect occurred only in male mice, as female mutants drank equal amount of acohol as wild-type control animals. These findings have two important implications. First, the Ras-ERK pathway may be a new target for treating compulsive alcohol drinking, and compounds that result in a blockade of this signaling pathway already exist. Second, it is astonishing that a hypothesis-free approach yielded a hit in a gene that is of critical importance for glutamate-NMDA receptor signaling, as one of the major theories in the alcohol addiction research field predicts that blocking a potential hyper-glutamatergic state in the addicted brain may reduce alcohol craving and relapse (Tsai et al. 1995; Krystal et al. 2003; Gass and Olive 2008; Spanagel and Kiefer 2008; Spanagel et al. 2010).
6 Treating a Hyper-Glutamatergic System
In recent years, the glutamate theory of alcoholism and addictive behavior has emerged as a major theory in the addiction research field. In a seminal publication, Lovinger et al. (1989) demonstrated that NMDA receptor function was inhibited by ethanol in a concentration-dependent manner over a range of 5–50 mM, a range that produces intoxication. Further research using site-directed mutagenesis experiments identified putative binding sites for ethanol molecules at the NMDA receptor (for review, see Spanagel 2009). Thus, the first level of interaction of alcohol with brain function concerns the NMDA receptor (among other primary targets of ethanol in the brain; for an overview, see Vengeliene et al. 2008). The NMDA receptor is a ligand-gated ion channel with a heteromeric assembly of NR1, NR2 (A–D), and NR3 subunits. The NR1 subunit is crucial for channel function, the NR2 subunits contain the glutamate binding site, and the NR3 subunits have a modulatory function on channel activity, especially under pathological conditions. Several transmembrane domains of the NR1 and NR2A subunits have putative alcohol binding sites. Beside this direct interaction with the NMDA receptor, alcohol also affects the glutamatergic system at the synaptic and cellular level, and it is further proposed that through various neuroadaptive responses that restore homeostasis, chronic alcohol consumption may lead to an enhanced activity of the glutamatergic system in alcohol-dependent individuals (Tsai and Coyle 1998). This glutamate-induced hyperexcitability within the CNS is uncovered during alcohol withdrawal. Acute alcohol withdrawal responses, which typically occur after discontinuation of prolonged and excessive alcohol ingestion, contribute to disease progression. Some of these neuroadaptations are transient, but the persistent changes remain during protracted abstinence and underlie vulnerability to relapse (Sommer et al. 2008; Heilig et al. 2010a, b). Acute withdrawal is associated with increased central glutamatergic transmission. More than 10 published reports employing brain microdialysis experiments in alcohol-dependent animals have consistently demonstrated augmented extracellular glutamate levels in various brain sites that correlate perfectly with the intensity of the withdrawal response (Rossetti and Carboni 1995; De Witte et al. 2003; Gass and Olive 2008). Furthermore, after repeated cycles of withdrawal, this hyper-glutamatergic response is progressively augmented (Dahchour and De Witte 2003; Gass and Olive 2008; Chefer et al. 2011). Augmented glutamatergic activity also occurs during conditioned withdrawal responses (Cole et al. 2000; Dahchour and De Witte 2003) and may therefore contribute to craving and relapse behavior. In a recent study by Gass et al. (2011), an increase in extracellular glutamate transmission in the nucleus accumbens was found during cue-induced alcohol-seeking behavior. In this study, rats were trained to self-administer either alcohol or food pellets. Each reinforcer was accompanied by the presentation of a light/tone stimulus. Following stabilization of responding for alcohol or food reinforcement, and subsequent extinction training, animals were implanted with glutamate oxidase-coated biosensors and underwent a cue-induced reinstatement testing period. Extracellular levels of glutamate were increased in the nucleus accumbens core during cue-induced reinstatement of alcohol-seeking behavior, an effect that did not occur during conditioned cue-induced food-seeking (Gass et al. 2011). These results indicate that increases in glutamate transmission in the nucleus accumbens core may be a neurochemical substrate of cue-induced alcohol-seeking behavior. In conclusion, these findings suggest that persistent neuroadaptations in glutamatergic functioning may play a key role in the pathophysiology of alcoholism. This provides the rationale for using anti-glutamatergic compounds such as acamprosate for relapse prevention—the suggested mode of action of acamprosate is that it dampens a hyper-glutamatergic state through an as yet unidentified mechanism (Spanagel and Kiefer 2008).
Recently, the glutamate theory has also been tested at the human level. In human alcoholics undergoing acute withdrawal, increased glutamate levels were identified in the anterior cingulate cortex, a brain region known to be critically affected by chronic alcohol intake, using high-resolution magnetic resonance (MR) spectroscopy (Hermann et al. 2011). Furthermore, these increased glutamate levels were significantly higher in treatment-seeking alcoholic patients as compared to healthy control subjects. Importantly, the glutamate signal was also correlated with the severity of the withdrawal reaction. After two weeks of abstinence, glutamate levels returned to levels similar to those detected in controls. By means of ultra high field strength generated by a 9.4 Tesla (T) animal scanner, the authors also observed a similar time course of the glutamate signal in the rat medial prefrontal cortex, a region comparable to the anterior cingulate cortex in humans. There were striking similarities between the human and the rat brain in the baseline measurements and dynamics of the glutamatergic system during the time course of acute and protracted alcohol withdrawal, demonstrating the validity of MR spectroscopy as a translational tool (Hermann et al. 2011). In yet another MR spectroscopy study, the effects of acamprosate in detoxified alcohol-dependent patients on central glutamate levels were assessed (Umhau et al. 2010). Thirty-three patients who met the diagnostic criteria for alcohol dependence and were admitted for medically supervised withdrawal from ongoing alcohol use were included in this study. The design was a 4-week, double-blind, placebo-controlled experimental medicine study, with MR spectroscopy measurements using a 3 T scanner obtained on days 4 and 25. Fifteen patients received acamprosate and 18 received placebo. There was a highly significant suppression of central glutamate levels across time by acamprosate, demonstrating for the first time that this anti-relapse medication may dampen a hyper-glutamatergic state in the brain of alcoholics.
The mode of action of acamprosate, a reduction of a hyper-glutamatergic state, has been thoroughly demonstrated in animal models. Several mutant mouse lines have been identified that exhibit a hyper-glutamatergic state (Spanagel et al. 2005; Lee et al. 2011). One of these mouse models involves the clock gene Period (Per). Interestingly, the mouse Per2 gene modulates, via the glutamate transporter GLAST, extracellular glutamate levels, resulting in hyperexcitability and enhanced consumption of alcohol (Spanagel et al. 2005). If acamprosate acts via a hyper-glutamatergic state to reduce excessive drinking, it can be inferred that mice lacking the Per2 gene should be especially sensitive to acamprosate treatment. Indeed, following repeated acamprosate administration, mutant mice showed decreased alcohol consumption as well as a normalization of extracellular glutamate levels in the nucleus accumbens (Spanagel et al. 2005). In a follow-up study by Brager et al. (2011a), it was confirmed that alcohol intake and preference was much greater in Per2 mutants than in wild-type mice. The authors of this study examined diurnal alcohol drinking activity more closely and found that the suppressive action of acamprosate on alcohol intake was due to a reduction in the amplitude and number of daily drinking bouts and not due to changes in diurnal alcohol drinking patterns. To determine brain sites responsive to acamprosate, a brain mapping study with acamprosate microimplants was conducted (Brager et al. 2011b). Mice were given voluntary access to alcohol followed by a period of abstinence, after which the alcohol deprivation effect (ADE)Footnote 2 was measured. Four days before alcohol was reintroduced, mice received bilateral blank or acamprosate-containing microimplants releasing approximately 50 ng/day into the ventral tegmental area, nucleus accumbens, or suprachiasmatic nucleus. The hippocampus was targeted as a negative control site. Acamprosate in all areas, except the hippocampus, suppressed alcohol intake and preference during the ADE. These data demonstrate that the suppression of alcohol intake and preference by acamprosate during relapse-like drinking is mediated through actions within major reward and circadian sites (Brager et al. 2011b). Another mouse model exhibiting increased glutamate levels in the nucleus accumbens that are paralleled by increased alcohol drinking behavior involves deletion of the type 1 equilibrative nucleoside transporter (Ent1). Similar to the results in Per2 mutant mice, acamprosate significantly reduced alcohol drinking in Ent1 mutant mice while having no effect in wild-type littermates (Lee et al. 2011). Basal and acamprosate-treated accumbal metabolite profiles of Ent1 mutant mice and wild-type mice were further assessed using in vivo 16.4 T MR spectroscopy. Lee et al. (2011) found enhanced basal glutamate levels in the nucleus accumbens in Ent1 mutant mice compared to wild-type mice. They also found that acamprosate treatment significantly reduced glutamate levels in the mutants, while glutamate levels in wild-type mice remained unaltered. In summary, these mouse models (Per2 and Ent1) provide a clear link between a hyper-glutamatergic state and excessive alcohol consumption. They further demonstrate that acamprosate acts only on a hyper-glutamatergic state. Future research should address whether human Per2 gene variants may predict enhanced vulnerability to alcohol dependence and augmented central glutamate levels. If this is the case, screening of human Per2 gene variants could be used to enhance the number of acamprosate responders. In fact, an association study has identified a specific genetic variation of the human Per2 gene that is associated with high alcohol consumption (Spanagel et al. 2005).
Within the framework of the glutamate theory of alcoholism, it is proposed that NMDA receptors, neuronal glutamate release properties, and other components of the glutamate system are involved in the etiology of alcohol addiction. Given that glutamatergic components are crucial in disease progression, we recently performed a hypothesis-driven gene expression profiling in alcohol drinking rats (Vengeliene et al. 2010) wherein we designed a custom-made microarray containing glutamate transmission-related genes. With this chip we were able to screen for approximately 200 selected genes, including sets of presynaptic genes (vesicles, docking, and exocytosis-associated genes), postsynaptic genes (receptors, anchoring, signal transduction, and transcription associated genes), and perisynaptic genes (glial transporters and other associated genes). This approach of hypothesis-driven gene expression profiling greatly reduces the number of multiple comparisons relative to a whole transcriptome analysis and thereby provides increased statistical power (Gebicke-Haerter 2005). The targeted gene expression profiling was conducted in brain tissue derived from the striatum of an alcohol-naϊve group versus that of a group with excessive alcohol consumption for more than 1 year. Interestingly, of 202 glutamate-transmission-related genes in the striatum, 168 genes showed significant alteration following long-term excessive alcohol consumption. Extensive qRT-PCR analysis validated these findings (Vengeliene et al. 2010). In humans, post-mortem striatal brain tissue from diseased alcoholics demonstrates that various glutamatergic markers are similarly altered, and a systematic analysis of glutamate transmission-related genes in alcohol-dependent patients revealed that NR2A and metabotropic glutamate receptor 5 (mGluR5) have the highest relevance for human alcohol dependence among the genes selected, with odds ratios of 2.35 and 1.69, respectively. In particular, a NR2A variant was associated with positive family history, early onset of alcoholism, and maximum number of drinks in adults as well as harmful drinking patterns in adolescents (Schumann et al. 2008; for replication study, see Domart et al. 2011). To further investigate the association of variation in a set of genes from the NMDA receptor complex and signaling with alcohol dependence, a gene-set analysis was recently conducted (Karpyak et al. 2011). Rather than testing for association with each SNP individually, which typically results in power too low to detect small effects of multiple SNPs, gene-set analysis applies a single statistical test to evaluate whether variation in a set of genes is associated with the phenotype of interest. Almost 1,000 SNPs from 13 genes were examined, and demonstrated a significant association with alcohol dependence for the global effect of variation in the NMDA receptor complex and signaling (Karpyak et al. 2011).
In summary, these findings provide the rationale for using NMDA receptor blockers or other anti-glutamatergic compounds for relapse prevention. A variety of modulators of NMDA receptor activity have recently been considered in the search for pharmacotherapeutic agents that may be useful in the treatment of alcoholism. In particular, neramexane—a noncompetitive NMDA receptor channel blocker—has been proposed as a promising drug for relapse prevention, with many preclinical findings consistent with this proposal. For example, like memantine, neramexane dose-dependently substitutes for the ethanol cue in a discrimination task (Hundt et al. 1998; Hölter et al. 2000), suppresses ethanol withdrawal seizures (Bienkowski et al. 2001; Kotlinska et al. 2004), and reduces responding for ethanol under operant conditions (Bienkowski et al. 1999). Furthermore, neramexane prevents the acquisition and expression of ethanol-induced conditioned place preference (Kotlinska et al. 2004), inhibits the expression of ethanol-induced sensitization (Kotlinska et al. 2006), and most importantly suppresses the ADE when administered chronically either via either osmotic minipumps or repeated injections (Hölter et al. 2000; Vengeliene et al. 2005), consistent with the effects of memantine (Hölter et al. 1996). In concert with its neuroprotective potential on alcohol-induced brain damage, neramexane has a promising profile for the prevention of several consequences of alcohol abuse (Bachteler and Spanagel 2005; Rammes and Schierloch 2006).
Neramexane was tested against placebo in detoxified alcohol-dependent subjects in a multicentre RCT. The study, led by Gerhard Wiesbeck and including 19 centers specialized for the treatment of alcoholism in Austria and Germany, screened 289 patients. Of this pool, 236 were randomized to either the neramexane group (n = 117; 2 × 20 mg per day) or the placebo group (n = 119). After 12 weeks of double-blind treatment, patients treated with neramexane had no benefit in terms of continuous abstinence when compared to the patients treated with placebo (Fig. 4).
A reason for this lack of effect may have been the low doses administered, as relatively high doses of the drug should be administered in the context of its use as a substitution therapy. Alterations in NMDA receptor subunit composition in alcohol-dependent subjects may have also contributed to a lack of effect. NMDA receptors composed of NR1/NR3A subunits exhibit a reduced sensitivity to channel blockers compared with NR1/NR2A receptors (Chatterton et al. 2002). In line with this conclusion, post hoc analysis on the relationship between neramexane plasma levels and the primary parameter of efficacy revealed that patients with high neramexane plasma levels had a higher rate of continuous abstinence after 12 weeks of treatment than matched placebo patients.
We conclude that high-dose treatment with neramexane results in an effective anti-relapse treatment. Two hundred and fifty years ago, William Hogarth suggested the idea of replacement therapy for gin drinkers via the use of “the less harmful beer consumption.” We now have for the first time the availability of a drug that may be successful as a replacement therapy. However, neramexane may only act as a substitution therapy in alcohol-dependent patients when sufficient doses of the drug are administered.
7 Concluding Remarks and Future Perspective
Major conclusions and some future perspectives of this review are:
-
(i)
Learning from other addictive substances is very helpful—e.g., substitution therapies as applied to opiate addiction for decades could also be translated to alcoholics. In this respect, the merger of the NIAAA and the NIDA (Kaiser 2010) will produce synergistic knowledge.
-
(ii)
The glutamate theory of alcohol addiction provides a convincing framework for the use of NMDA receptor antagonists as substitution drugs for alcohol-dependent patients, especially the channel blocker neramexane or memantine. Both compounds have a fast on/off kinetic at the NMDA receptor channel and thereby produce less side effects than other compounds, and are promising substitution drugs provided very high doses are applied.
-
(iii)
A combination of behavioral and pharmacological therapies might be the optimal approach for future treatment strategies—one promising example is pharmacological disruption of reconsolidation processes of alcohol cue memories. In the process of reconsolidation, a retrieved memory transiently returns into a labile state and requires new protein synthesis to persist further. During this labile state, the memory is amenable to enhancement or disruption. It has been shown that pharmacological disruption of the reconsolidation of alcohol-associated memories can be achieved by use of protein synthesis inhibitors and NMDA receptor antagonists, and thus may provide a potential new therapeutic strategy for the prevention of relapse in alcohol addiction. Two NMDA receptor antagonists are currently being studied to this effect: memantine and the noble gas xenon. Both substances are already approved in several countries for different indications with a limited side effect profile.
-
(iv)
Given that many neurotransmitter systems are affected by chronic alcohol consumption, numerous druggable targets have been identified; consequently, a “cocktail” of different compounds will likely further improve the treatment situation. For example, combining naltrexone and acamprosate produces a better outcome in relapse prevention than either drug on its own (Kiefer et al. 2003).
-
(v)
In silico psychopharmacology, such as drug repurposing (Andronis et al. 2011), will yield new medications.
-
(vi)
One size does not fit all. We have not discussed new pharmacogenetic findings that will eventually assist in individualized pharmacotherapy. Pharmacological treatment response is indeed influenced by genetic polymorphisms in drug target genes. For example, it has recently been demonstrated that a functional SNP in the µ-opioid receptor gene predicts naltrexone efficacy as measured by relapse behavior (Oslin et al. 2003; for a first meta-analysis, see Chamorro et al. 2011). Preliminary results indicate that genetic variations in GATA4 might influence relapse and treatment response to acamprosate in alcohol-dependent patients via modulation of atrial natriuretic peptide plasma levels (Kiefer et al. 2011). These results may help identify alcohol-dependent patients with an increased risk of relapse and who may better respond to acamprosate treatment. For those who are interested on the topic of pharmacogenetic approaches to the treatment of alcohol addiction, we refer the reader to an excellent recent review provided by Heilig et al. (2011; see also Sturgess et al. 2011).
-
(vii)
Finally, the whole organism has to be taken into consideration to provide the best therapy for our patients.
Notes
- 1.
In a few countries (e.g., Italy), γ-Hydroxybutyric acid (GHB) is a treatment option officially approved by the respective regulatory agencies and a large European trial has been initiated to further test the effectiveness of this drug. However, it should be emphasized that GBH is a street drug categorized as illegal in many countries. Clearly, GBH bears a strong potential to be abused and even in the context of being used as a substitution drug may produce multiple side effects, including the impairment of the immunological status of an abuser (Pichini et al. 2010).
- 2.
Relapse-like behavior in animals is characterized by the ADE. Following a period of alcohol abstinence, animals considerably but temporally increase voluntary alcohol intake as compared to basal consumption levels. Following repeated deprivation phases, the ADE is characterized by an increased and compulsive demand for alcohol that clearly dissociates from normal drinking behavior (Spanagel and Hölter 1999; Vengeliene et al. 2009).
Abbreviations
- ADE:
-
Alcohol deprivation effect
- CRH:
-
Corticotropin-releasing hormone
- D3R:
-
Dopamine D3 receptor
- FDA:
-
Food and Drug Administration
- fMRI:
-
Functional magnetic resonance imaging
- GHB:
-
γ-Hydroxybutyric acid
- GWAS:
-
Genome-wide association study
- GlyT:
-
Glycine transporter
- HPA:
-
Hypothalamic–pituitary–adrenal
- KOR:
-
κ-Opioid receptor
- MR:
-
Magnetic resonance
- MOR:
-
μ-Opioid receptor
- NMDA:
-
N-metlyl-D-aspartat
- Per:
-
Period
- RCT:
-
Randomized controlled trial
- RR:
-
Relative risk
- SNP:
-
Single nucleotide polymorphisms
- Ent1:
-
Type 1 equilibrative nucleoside transporter
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Acknowledgments
This work was supported by the Bundesministerium für Bildung und Forschung (NGFN Plus; FKZ: 01GS08152, FKZ: 01GS08155 see under www.ngfn-alkohol.de and Spanagel et al. 2010; FKZ: 01GS08151) and the Deutsche Forschungsgemeinschaft (DFG): SFB636/Project B1 and D7, Reinhart-Koselleck Award SP 383/5-1, and The Deep Brain Stimulation project SP383/6-1.
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Spanagel, R., Vengeliene, V. (2012). New Pharmacological Treatment Strategies for Relapse Prevention. In: Sommer, W., Spanagel, R. (eds) Behavioral Neurobiology of Alcohol Addiction. Current Topics in Behavioral Neurosciences, vol 13. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-28720-6_205
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