Chapter 2 70 Effect of novel nop receptor ligands on ethanol drinking in the alcohol-preferring msP rats Chapter 3 96




НазваниеChapter 2 70 Effect of novel nop receptor ligands on ethanol drinking in the alcohol-preferring msP rats Chapter 3 96
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UNIVERSITY OF CAMERINO


Department of Experimental Medicine and Public Health


________________________________________________________

The NOP receptor as a target

in the treatment of alcohol abuse


by

Daina Economidou


Supervisors: Prof.Maurizio Massi

Prof. Roberto Ciccocioppo

List of Papers


This thesis is based on the papers list below:


  1. Ciccocioppo R, Economidou D, Fedeli A, Massi M. The nociceptin/orphanin FQ/NOP receptor system as a target for treatment of alcohol abuse: a review of recent work in alcohol-preferring rats. Physiol Behav 79:121-128, 2003




  1. Ciccocioppo R, Economidou D, Fedeli A, Angeletti S, Weiss F, Heilig, M, Massi M. Attenuation of Ethanol Self-Administration and of Conditioned Reinstatement of Alcohol-Seeking Behaviour by the Antiopioid Peptide Nociceptin/OrphaninFQ in Alcohol-Preferring Rats. Psycopharmacology 172:170-178, 2004




  1. Ciccocioppo R, Economidou D, Rimondini R, Sommer W, Massi M, Heilig M. Buprenorphine reduces alcohol drinking through activation of the Nociceptin/Orphanin FQ-NOP receptor system. Biol Psychiatry Mar 11, 2006 [Epub ahead of print]




  1. Economidou D, Fedeli A, Massi M, Ciccocioppo R. Effect of novel NOP receptor ligands on ethanol drinking in the alcohol-preferring msP rats. Peptides Manuscript submitted for publication




  1. Economidou D, Hansson A, Fedeli A, Massi M, Heilig M, Ciccocioppo R. The Central Nucleus of the Amygdala is the neuroanatomical site of action for the effects of N/oFQ on alcohol drinking. J Neurosc Manuscript submitted for publication




  1. Economidou D, Ubaldi M, Lourdusamy A, Massi M, Ciccocioppo R. Activation of brain NOP receptors attenuates alcohol withdrawal symptoms in rats. Manuscript

CONTENTS




Chapter 1 General Introduction 4



The nociceptin/orphanin FQ/NOP receptor system as a target for treatment of alcohol abuse: a review of recent work in alcohol-preferring rats


Chapter 2 70



Effect of novel NOP receptor ligands on ethanol drinking in the alcohol-preferring msP rats


Chapter 3 96



Buprenorphine reduces alcohol drinking through activation of the Nociceptin/Orphanin FQ-NOP receptor system.


Chapter 4 116





Attenuation of ethanol self-administration and of conditioned reinstatement of alcohol-seeking behaviour by the antiopioid peptide nociceptin/orphanin FQ in alcohol-preferring rats


Chapter 5 151





The Central Nucleus of the Amygdala is the neuroanatomical site of action for the effects of N/oFQ on alcohol drinking


Chapter 6 182



Activation of brain NOP receptors attenuates alcohol withdrawal symptoms in rats


Chapter 7 207




Summary, conclusions and suggestions for further research

Chapter 8 230


Scientific Publications

Acknowledgements


Chapter 1


General Introduction


General introduction


1. Alcoholism


    1. Epidemiology


Alcohol is the second most commonly abused psychotropic drug after caffeine in the world today (Samson & Harris, 1992), and alcoholism has emerged as a major social and health problem (Royal College of Psychiatrists, 1986). In the United States 19% of men and 8% of women have been diagnosed, at some time in their lives, with alcohol dependence as defined in the American Psychiatric Association’s (1994) Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (Grant et al., 1994). In Australia, in 1977 it was estimated that one in five hospital beds were occupied by those suffering the effects of alcohol (Commonwealth Department of Community Services and Health, 1987).

In addition to causing numerous serious medical disorders (e.g., liver and heart disease), alcohol dependence is associated with costly, adverse social consequences such as disruption of families, crime, traumatic accidents, and lost productivity. As a result, the annual costs related to alcohol dependence in the United States for 1998 have been estimated at $185 billion (Harwood, 1998, 2000).

Unfortunately, heavy alcohol use and alcohol dependence has been also increasing among younger people (Windle, 1990; Sobeck et al., 2000), indicating that alcohol dependence may become an ever more prominent public health problem. In fact, 31% of 12th graders in the United States reported getting drunk in the past month and 6–10% of teens meet diagnostic criteria for an alcohol use disorder (Rohde et al., 1996; Clark et al., 2002)


Alcoholism, is a chronically relapsing disorder characterized by compulsive alcohol seeking and use (McLellan et al., 1992; O’Brien et al., 1998). More than 80% of addicts relapse to compulsive drug use after a period of withdrawal and abstinence, during what is known as the protracted withdrawal phase. The long-lasting nature of this compulsion and the high rates of recidivism represent a challenge for effective treatment. Two major factors implicated in the resumption of drinking include subjective reactions provoked by stressful events and by environmental stimuli that have become conditioned to the pharmacological actions of alcohol (Marlatt, 1985; Ludwig et al., 1974; Rogers et al., 1979; O'Brien et al., 1992; Childress et al., 1993; Stormark et al., 1995). In addition, recent data suggest that stress and ethanol-related environmental stimuli interact to augment relapse risk as measured in an operant response-reinstatement model of relapse (Liu & Weiss, 2002a).

Because of the chronically relapsing nature of alcohol addiction, relapse prevention has emerged as a central focus of treatment and medication development efforts. However, understanding the neural basis of the relapse phenomenon is still limited, and research in this area will be of critical importance toward progress with the development of effective “anti-relapse” mediations.


1.2. Genetic Vulnerability to Alcohol Abuse


There is, in recent days, clear evidence that people may be genetically predisposed to alcoholism, although this does not negate the role of environmental factors (Gianoulakis & de Waele, 1994; Begleiter et al., 1995; Ferguson & Goldberg, 1997). An estimated 40 to 60% of the individual variation in alcohol preference and vulnerability to alcoholism is genetic in origin, as revealed by adoption studies (Goodwin et al., 1977; Hesselbrock, 1995; Bohman et al., 1981; Cloninger et al., 1981), and by studies on large samples of cross-sectionally ascertained twin pairs (Heath et al., 1997; Kendler et al., 1995, 1997). In fact, sons of alcoholics are approximately 4 to 9 times more likely to become alcoholic that are sons of nonalcoholics (Cotton, 1979; Cloninger et al., 1981; Goodwin, 1985). Moreover, sons of alcoholics who are adopted by non-alcoholic families early in life, are still more than 3 times more likely to become alcoholic than are similarly adopted sons of nonalcoholics (Bohman, 1978; Bohman et al., 1981; Cloninger et al., 1981; McGue, 1997). In addition, twin studies reported a 50-200% greater concordance rates for alcoholism among identical, compared to non identical twins (McGue, 1997)


It is nowadays well consolidated the important role of the mesocorticolimbic dopamine (DA) system in the brain reward pathway (Imperato & Di Chiara, 1986; Wise & Rompre, 1989; Weiss et al., 1993; Doyon et al., 2003), and the DA neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAcc) are considered to play a key role in mediating the rewarding actions of various drugs of abuse, including alcohol (Koob & Bloom, 1988).

The dopamine D2 receptor (DRD2) gene has been proposed to be a primary candidate in drug addiction, because disturbances in dopamine availability and its receptors have been implicated in neural reward mechanisms (Koob & Swerdlow, 1988). In a study conducted by Konishi et al., (2004a) a significant difference of the genotype frequency for the DRD2-141C insertion/deletion (Ins/Del) allele was found between alcoholic and control Mexican-Americans (Konishi et al., 2004a). In accordance to these data, Ishiguro et al., (1998) also reported that the frequency of the DRD2-141C Ins allele was significantly higher in alcoholics (88%) than in control subjects (77%) in a Japanese population (Ishiguro et al., 1998). In addition, Blum et al., (1990) reported a higher prevalence of the TaqI A1 allele of the DRD2 gene in alcoholics compared with control subjects (Blum et al., 1990). However, despite numerous subsequent case-control studies, the role of the A1 allele as a candidate marker in predisposing alcoholism/drug dependence has remained controversial. Some investigators have found significant associations (Comings et al., 1991; Parsian et al., 1991; Amadeo et al., 1993; Arinami et al., 1993), whereas others have not replicated the finding (Gelernter et al., 1991; Goldman et al., 1992; Turner et al., 1992). However, when the results of 15 published studies, with 1015 alcoholics and 898 control subjects, were combined and compared, the TaqI A1 allele was more prevalent in the alcoholic group than in the control group (Noble, 1998).


The neurotransmitter serotonin (5-HT) is known to play an important role in many physiologic and behavioral functions, such as motor activity, food intake, sleep, and reproductive activity, as well as in mood, cognition, and emotion (LeMarquand et al., 1994; Owens & Nemeroff, 1994). The serotonin transporter (5-HTT) affects serotonergic neurotransmission by reuptake of synaptic serotonin, resulting in termination of serotonergic neurotransmission. Rates of serotonin reuptake vary among individuals, and such variability is partly under genetic control (Meltzer & Arora, 1988). The 5-HTT–linked polymorphic region (5-HTTLPR) has a 44 base pair (bp) insertion/deletion (Ins/Del) functional polymorphism, resulting in short (S) or long (L) alleles. Positive associations were found between the short variant and severely affected alcoholics (Sander et al., 1997), alcohol dependence (Hammoumi et al., 1999; Lichtermann et al., 2000; Thompson et al., 2000), and type II alcoholism (Hallikainen et al., 1999). In addition, Konishi et al., (2004b) demonstrated that the frequency of the 5-HTTLPR (S) allele was significantly higher in alcoholic Mexican-Americans (61.5%) than in nonalcoholic control subjects (52.8%) (Konishi et al., 2004b). In contrast, however, there are some reports showing that the S allele was significantly less frequent in severe alcoholics (Ishiguro et al., 1999) and that the L allele was associated with type II alcoholism (Parsian & Cloninger, 2001). Twitchell et al., (2001) reported that more children with the LL genotype than with the SS/SL genotype had a history of alcohol consumption (Twitchell et al., 2001). However, results of some studies have indicated no relation between the 5-HTTLPR polymorphism and alcohol dependence (Matsushita et al., 2001; Kranzler et al., 2002).


The gamma-aminobutyric acid (GABA) is the most abundant inhibitory neurotransmitter in the brain. It interacts at three classes of receptor sites, designated GABAA, GABAB, and GABAC. Thus, the subunit composition of the GABAA receptor is known to importantly determinate the response to different drugs (Levitan et al., 1988; Ymer et al., 1990). The 3 gene (GABR 3) encodes a major subunit of the GABAA receptor and is clustered with other 5 and 3 subunit genes on human chromosome 15 (Wagstaff et al., 1991). Noble, (1998) reported that variants (G1, 181 bp) of GABR3 contributed to the risk for alcoholism, and, especially when they were combined with DRD2 TaqI A allele, the risk for alcoholism became more robust in Caucasian subjects of European (non-Hispanic) descent (Noble, 1998).


Glutamate, is the major excitatory neurotransmitter in the brain and is known to also play an important role in the pathogenesis of alcohol dependence. The ionotropic glutamatergic N-methyl-D-aspartate receptors (NMDAR) have been implicated as primary target sites for acute and chronic effects of ethanol and, the NR1asplice variant of NMDAR1 subunit and the NMDAR2B subunit were reported the most sensitive to ethanol (Lovinger, 2000). In a study by Wernicke et al., (2003) an association between the A allele of the NMDAR1 gene and alcoholism was showed, whereas, Sander et al., (2000) demonstrated that genetic variation of the astroglial glutamate transporter (EAAT2) gene confers vulnerability to risk-taking behavior in alcoholics (Sander et al., 2000; Wernicke et al., 2003).


Genetically determined differences in opioid activity have also been found to confer vulnerability for alcoholism. In fact, in a series of studies Gianoulakis et al. showed that individuals with a family history of alcoholism (high risk) have lower basal plasma -endorphin levels, but greater release of -endorphin after exposure to a 0.5-g/kg dose of ethanol than do individuals without this history (low risk) (Gianoulakis et al., 1989; Gianoulakis, 1996, 2001). Further support for the hypothesis that -endorphin response to ethanol may represent a biomarker for increased genetic risk for alcoholism was provided by findings of a recent study of twins confirming that this response has significant heritability (Froehlich et al., 2000).

Into the causes of alcoholism attention has also drawn to the potentially important role of polymorphisms of two major enzymes of alcohol metabolism, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). In fact, in alcoholics functional polymorphisms have been observed at genes encoding these enzyme proteins, inducing a variation in the rate of elimination of ethanol and the rate of formation and elimination of acetaldehyde. For example, among the Atayal the group with alcohol use disorders (alcohol dependence and alcohol abuse) had a significantly lower frequency of the ADH2*2 allele (0.82) than those without alcohol use disorders (0.91) (Chen et al., 1997). In addition, in Asian populations the ADH2*2 allele was found at higher frequencies in controls than in alcoholics (Thomasson et al., 1991; Chen et al., 1997; Shen et al., 1997; Tanaka et al., 1997). Also the ADH3*1 allele is generally found at higher frequencies in controls than in alcoholics (Chen et al., 1997).


Taken together, above data suggest that the predisposition to alcohol misuse and dependence varies greatly between individuals and may be influenced by a number of genes (Radel & Goldman, 2001). In fact, as described above, candidate genes associated with alcoholism risk have been identified.


1.3. Neurobiology of Alcohol Abuse


The reinforcing and rewarding properties of ethanol and ethanol-seeking behaviour, are known to be mediated by several neurochemical systems and in a widespread neuroanatomical sites in the brain (for review see, Koob et al., 1998). In this section, the mechanisms underlying ethanol’s reinforcing properties in the brain and alcohol seeking behaviour will be discussed.


Ethanol Reinforcement


The DAergic mesolimbic system has been proposed to be one of the main neural networks through which the rewarding and reinforcing effects of drugs of abuse, and of alcohols’, are mediated (Self & Nestler, 1995; Wise, 1996, 1998; Koob & Le Moal, 1997; Robbins & Everitt, 1999). The mesolimbic dopaminergic system is comprised of a group of neuronal cell bodies that originates in the VTA in the midbrain. These cells possess axonal processes that terminate in several forebrain regions including the NAcc, prefrontal cortex, amygdala, olfactory tubercle, hippocampus (Fallon & Moore, 1978a, 1978b; Fallon et al., 1978; Swanson, 1982). However, the dopaminergic projection from the VTA to the NAcc consisting mainly by the A10 group of DA neurons (Deutch et al., 1993; Herz, 1997), and the increase of extracellular DA concentrations in the NAcc, are known to be the key function for mediating alcohol-induced reinforcement (Koob, 1992).

The first reports that systemic ethanol administration stimulates DA release in the NAcc, appeared in the literature almost 2 decades ago (Gessa et al., 1985; Imperato & Di Chiara, 1986). Successive studies confirmed and extended this data. In rats, an increased firing of DAergic neurons in the VTA, has been reported both in vivo and in vitro after acute and subchronic exposure to ethanol (Gessa et al., 1985; Brodie et al., 1990; Diana et al., 1992, 1993b). Moreover, ethanol given systemically (Imperato & Di Chiara, 1986; Di Chiara & Imperato, 1988a; Yoshimoto et al., 1991, 1992; Diana et al., 1993b; Heidbreder & De Witte, 1993) or microinjected directly into the VTA (Yoshimoto et al., 1991) induced a dose-dependent release of DA in the NAcc. Microinjections of ethanol into the NAcc (Wozniak et al., 1991; Yim et al., 1998) have also been shown to induce a dose-dependent release of DA in this brain area; however, the high concentrations required suggest that the systemic effect of ethanol on DA release in the NAcc is probably mediated via the VTA (Samson et al., 1997; Yim et al., 1998). In addition, ethanol self-administration both in the nonselected Wistars and ethanol-preferring (P) rats induced a significant increase in DA levels in the NAcc (Weiss et al., 1992, 1993). Conversely, withdrawal from ethanol has been found to induce a significant decrease in DA release in the NAcc (Rossetti et al., 1992; Diana et al., 1993a).

However, ethanol-induced increased DA release has been seen in some other brain areas as well, suggesting an important role of these in the reinforcing effects of ethanol. For instance, in a study by Yoshimoto et al., (2000) intraperitoneal injection of 2 g/kg of ethanol significantly increased by 270% over baseline the extracellular levels of DA in the central nucleus of the amygdala (CeA) (Yoshimoto et al., 2000). Moreover, systemic injection of ethanol also increased DA release in the ventral pallidum (VP) of Wistar rats (Melendez et al., 2003).


The importance of the mesolimbic DAergic transmission in the brain in inducing alcohol reinforcement, is also supported by pharmacological studies. Systemic treatment with bromocriptine, a D1 and D2 receptor agonist, and GBR 12909, a dopamine reuptake inhibitor, decreased ethanol intake in the P rats (McBride et al., 1990). In addition, Silvestre et al., (1996) reported that the D1-selective agonist, SKF 38393, decreased the intake of a sweetened ethanol solution in a 23-hr, 2-bottle-choice procedure using food-deprived rats, whereas, the selective D2/D3 agonist, 7-OH-DPAT increased the consumption. In contrast, the D2-selective antagonist, raclopride, did not affect sweetened ethanol consumption in these studies (Silvestre et al., 1996). On the other hand, Samson and Hodge (1993), reported that local microinjections of the D2 receptor antagonist, raclopride, to the NAcc dose-dependently decreased ethanol self administration, which was most likely due to post-synaptic blockade (Samson & Hodge, 1993). However, the D2/D3 receptor agonist quinpirole, when locally injected into the VTA, also dose-dependently decreased ethanol self-administration, probably due to inhibition of the dopaminergic neurons in this area (Samson & Hodge, 1993). In addition, El-Ghundi et al., (1998) demonstrated the importance of the D1 receptor in alcohol reinforcement, as D1 receptor deficient (D1-/-; ‘knockout’) mice showed markedly decreased ethanol consumption and preference respect to wild-type (D1+/+) controls (El-Ghundi et al., 1998). Treatment with the D2 receptor antagonist decreased residual drinking in the knockout mice and caused a small decrease in ethanol consumption in the wild type mice, thus, the authors suggested that the D1 receptor was more important in mediating “alcohol-seeking behaviour” than the D2 receptor (El-Ghundi et al., 1998). Lastly, treatment with the selective D3 receptor antagonist, SB-277011-A, induced a significant attenuation in ethanol preference, intake and lick responses in the P rats suggesting an important role of this receptor in alcohol reinforcement (Thanos et al., 2005).


In recent days, is also well consolidated the importance of the brain opioidergic system in controlling and mediating the reinforcing and rewarding properties of ethanol, both in humans and in rodents (Reid et al., 1991; Gianoulakis, 1996; Herz, 1997; Oswald & Wand, 2004). It has been proposed, in fact, that alcohol may stimulate the release of endogenous opioid peptides in the brain, which in turn could interact with areas associated with reward and positive reinforcement (Jamensky & Gianoulakis, 1997; Koob et al., 1998). Moreover, it has been suggested that increased activity of brain enkephalin or -endorphin opioid peptide systems, in response to ethanol exposure may be important for initiating and maintaining high alcohol consumption (Gianoulakis et al., 1989; Rasmussen et al., 1998). Likewise, increased density of  or  (or both) opioid receptors in brain regions involved in the reinforcing effects of drugs of abuse, may also be important in initiating and maintaining high alcohol consumption (DeWaele & Gianoulakis, 1997; Marinelli et al., 2000). Conversely, increased dynorphin activity or increased  binding site density may inhibit high ethanol consumption (McLearn & Rodgers, 1959; Herz, 1997).

The administration of nonspecific opioid receptor antagonists, such as naltrexone, as well as of  and  selective opioid receptor antagonists has been shown to decrease alcohol consumption in a dose-dependent manner in a number of animal species and in a number of experimental paradigms (Altshuler et al., 1980; Myers et al., 1986; Froehlich et al., 1990, 1991; Weiss et al., 1990; Kornet et al., 1991; Hubbell et al., 1993; Hyytia, 1993; Krishnan-Sarin et al., 1995a, 1995b; Honkanen et al., 1996; Davidson & Amit, 1996; Franck et al., 1998; Heyser et al., 1999). Different studies also demonstrated that -opioid receptor agonists may also attenuate alcohol consumption (DiChiara & Imperato, 1988b; Sandi et al., 1988; Spanagel et al., 1990, 1992). Naltrexone has been reported to be an effective treatment for individuals with alcohol dependence (Volpicelli et al., 1992; O’Malley, 1996). Combined with behavioural therapy, naltrexone, has been shown to reduce craving and alcohol intake in alcoholic patients (O’Malley, 1996).


Important neurochemical targets for the acute effects of alcohol are also the facilitation of inhibitory GABAergic (widely accepted to underlie the acute sedative effects of alcohol), and inhibition of excitatory glutamatergic neurotransmission. Long-term adaptive changes in these two neurotransmitter systems to the sedative effects of alcohol are thought to underlie the development of alcohol dependence. In response to chronic exposure to alcohol, there is a compensatory up-regulation of the glutamatergic system and a down-regulation of the GABAergic system resulting in an increased tolerance for alcohol (Grobin et al., 1998). However, when alcohol is abruptly withdrawn, a state of hyper-excitability emerges, perceived by the subject as a disagreeable state of arousal, anxiety and sleeplessness. This is the core of the negative affective state from which the alcoholic patient will drink to relieve. These plastic changes in the brain, brought about by changes in protein synthesis, are only slowly reversible. This may explain the persistence of negative craving during alcohol withdrawal, and why stable abstinence after acute detoxification is so difficult to achieve.

Pharmacological studies also support the important role of the GABAergic and glutamatergic neurotransmission in the reinforcing properties of alcohol. Treatment with GABAA antagonists, for instance, decreased operant alcohol self-administration. Using an operant model of ethanol self-administration, pretreatment with RO 15-4513, a benzodiazepine inverse agonist, at low doses selectively decreased responding for ethanol but not for water (Samson et al., 1987). Isopropylbicyclophosphate, a picrotoxinin site ligand, selectively decreased responding for ethanol at very low doses in alcohol-preferring, alcohol nonpreferring, and Wistar rats (Rassnick et al., 1993). Above data, suggest that acute blockade of GABAA receptor function can block the motivation for responding for ethanol, supporting the hypothesis that activation of GABA is an important component in the acute reinforcing effects of ethanol. On the other hand, treatment with a selective GABAB agonist, decreased ethanol self-administration in nondependent animals (Janak & Gill, 2003) and the alcohol deprivation effect in alcohol preferring rats (Colombo et al., 2003a, 2003b). Several clinical studies also have shown a potential efficacy of baclofen in reducing alcohol craving and ethanol withdrawal (Addolorato et al., 2002a, 2002b). These studies and evidence that GABAB receptor agonists may modulate mesolimbic dopamine neurons have provided a rationale for the hypothesis that activation of GABAB receptors may decrease the reinforcing actions of ethanol (Cousins et al., 2002). In addition, a very potent GABAA antagonist, SR 95531, when microinjected into the basal forebrain, significantly decreased ethanol consumption (Hyytia & Koob, 1995). SR 95531, was injected bilaterally into the NAacc, bed nucleus of the stria terminalis (BNST) and CeA in rats trained to self-administer alcohol in a limited access procedure. The most sensitive site of the effect of this drug was, however, the CeA (Hyytia & Koob, 1995). The GABAergic neurotransmission into the CeA has been reported to be an important target in alcohols’ reinforcing properties also by other researchers (Koob, 2003, 2004; Koob & Le Moal, 2001). Acute intraperitoneal injection of ethanol increased c-fos immunoreactivity in the CeA and over 70% of these cells were GABAergic neurons (Morales et al., 1998). In addition, electrophysiological studies showed an increased GABA release in the CeA after ethanol superfusion, an effect blocked by treatment with a GABAA receptor antagonist (Roberto et al., 2003). Moreover, in a study conducted by June et al., (2003), it was reported that microinjections of a GABAA receptor antagonist into the VP produced marked reductions in alcohol-reinforced behaviors in two selectively bred rodent models of chronic alcohol drinking, the high alcohol drinking (HAD) and alcohol-preferring (P) rats (June et al., 2003).


The glutamatergic system is also a target for the actions of ethanol. N-methyl-D-aspartate (NMDA) receptor antagonists decreased ethanol intake in rats selectively bred for high ethanol preference (McMillen et al., 2004). Moreover, neramexane and acamprosate, an uncompetitive and a functional, respectively, NMDA receptor antagonists suppressed the rewarding effects of ethanol as measured in conditioned place preference (Kotlinska et al., 2004; McGeehan & Olive 2003). In addition, the mGluR5 antagonist MPEP decreased operant ethanol self-administration in the P and Wistar rats (Backstrom et al., 2004; Schroeder et al., 2005) and in the alcohol-preferring inbred C57BL6/J mice (Hodge et al., 2006).


Cue-Induced Reinstatement of Alcohol Seeking Behavior


Research utilizing reinstatement models of relapse points predominantly to a role for dopamine and opioid systems in the motivating effects of ethanol-associated environmental stimuli. However, there is also growing evidence for a role of glutamatergic (Glu) neurotransmission as well.

In rats, re-exposure to environments associated with ethanol availability increases extracellular DA levels in the NAcc (Katner et al., 1996; Gonzales & Weiss, 1998; Bespalov et al., 1999; Weiss & Porrino, 2002), and ethanol-related visual cues activate the ventral striatum in abstinent alcoholics (Braus et al., 2001), suggesting that mesolimbic DA transmission may have an important function in the incentive-motivational effects of ethanol and, by extension, ethanol craving and relapse. Indeed, appetitively motivated behavior preceding delivery of an ethanol solution is more sensitive to reversal by DA antagonists than behavior maintained by ethanol itself (Czachowski et al., 2001b). A role of DA in relapse associated with exposure to alcohol cues has been confirmed more directly by pharmacological findings, where selective blockade of either D1 or D2 receptors dose-dependently increased latency to initiate responding and reduced the number of responses at a previously active ethanol-paired lever (Ludwig et al., 1974; Liu & Weiss, 2002b).

A role of opioid systems in relapse has also been implicated. In fact, clinical findings suggest that the nonselective opiate antagonist, naltrexone, attenuates craving associated with exposure to ethanol cues (Gerrits et al., 1999; Monti et al., 1999; Rohsenow et al., 2000) and reduces relapse rates in abstinent alcoholics (Krystal et al., 2001; O'Brien et al., 1996). Experimental support for this hypothesis comes from pre-clinical findings that naltrexone as well as - and delta-selective opiate antagonists reverse conditioned reinstatement of ethanol-seeking by ethanol-associated contextual stimuli (Katner et al., 1999; Ciccocioppo et al., 2002).


With respect to glutamate transmission, evidence is accumulating for the role of this excitatory amino acid in processing of drug-associated stimuli. In fact, presentation of alcohol-associated stimuli has been found to increase accumbal glutamate levels in laboratory animals (Hotsenpiller et al., 2001). Treatment with acamprosate, a functional NMDA receptor antagonist reported to act through a partial interplay with the mGlu5 receptors (Harris et al., 2002), dose-dependently reduced reinstatement of ethanol-seeking behaviour (Bachteler et al., 2005), whereas, in the same study, pretreatment with neramexane, a noncompetitive NMDA receptor antagonist, did not significantly modify cue-induced alcohol-seeking, suggesting an involvement of the mGlu5 receptor in this behaviour (Bachteler et al., 2005). In respect to this data, pretreatment with MPEP, a noncompetitive mGlu5 receptor antagonist significantly attenuated in a dose-related manner ethanol-seeking behavior (Backstrom et al., 2004). In another study, treatment with the mGlu2/3 receptor agonist LY379268 and the mGlu8 receptor agonist (S)-3,4-DCPG, also blocked alcohol reinstatement (Backstrom & Hyytia, 2005). Moreover, in a more recent study, a significant reduction of cue-induced alcohol-seeking behaviour was also seen with the AMPA receptor antagonist GYKI 52466 (Sanchis-Segura et al., 2006).


Stress-Induced Reinstatement of Alcohol Seeking Behavior


Another major factor implicated in the resumption of compulsive drinking includes the subjective reactions provoked by stressful events (Brown et al., 1995; Sinha et al., 1999, 2000; Weiss et al., 2001; Breese et al., 2005). The significance of stress as a factor for relapse risk is also well documented in the animal literature where footshock stress and intracranial administration of CRF produces strong reinstatement of ethanol-seeking behavior (Le et al., 1999, 2000, 2002; Martin-Fardon et al., 2000; Liu & Weiss, 2002a; Funk et al., 2003), while administration of CRF antagonists prevents drug-seeking behavior induced by these manipulations (Funk et al., 2003; Le et al., 2000, 2002). Data from the literature, proposes two CRF-rich brain regions that are part of the non-neuroendocrine brain stress system, to be mainly implicated in alcohol-seeking responses induced by footshock stress; the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST). The preponderance of existing evidence suggests that the BNST which receives CRF-containing neurons from the CeA (Sakanaka et al., 1986; Gray, 1993), and, like the CeA, contains a dense network of CRF immunoreactive cells, appears to be the most sensitive site for the response-reinstating effects of CRF and footshock. Direct administration of CRF into the BNST, but not into the CeA, elicits cocaine-seeking behavior (Erb et al., 2001). Consistently, local injection of the CRF receptor antagonist D-Phe-CRF(12-41) into the BNST but not the CeA antagonized foot-shock-induced reinstatement of cocaine-seeking behaviour (Erb & Stewart, 1999; Erb et al., 2001). Thus, activation of CRF receptors in the BNST may be a critical substrate for stress-related unconditioned responses in general, including stress-induced alcohol-seeking behavior. It is, however, important to consider that the BNST receives a CRF-containing projection from the CeA (Gray, 1990; Sakanaka et al., 1986) such that stress-induced activation of the CeA may, via this pathway, be responsible for the effects of stress on drug-seeking behavior. Therefore, both the CeA and BNST may participate in the regulation of stress-induced drug-seeking and other unconditioned responses, although the BNST may perhaps represent a critical output pathway for these effects.


Alcohol Withdrawal


Up to 71% of individuals presenting for alcohol detoxification, manifest significant symptoms of alcohol withdrawal (Myrick & Anton, 1998). Alcohol withdrawal, is a clinical syndrome that affects alcoholic patients who either decrease their alcohol consumption or stop drinking completely. The affective withdrawal symptoms, make alcohol abstinence difficult and increase the risk of relapse in recovering alcoholics (Anton, 1999; Spanagel, 2003).

Alcohol withdrawal syndrome is mediated by a variety of mechanisms. The brain is known to maintain neurochemical balance through inhibitory and excitatory neurotransmitters. The main inhibitory neurotransmitter is GABA which acts through the GABAA receptor, while, one of the major excitatory neurotransmitters is glutamate, which acts through the NMDA receptor. Alcohol enhances the effect of GABA on GABAA receptors, resulting in decreased overall brain excitability. Chronic exposure to alcohol results in a compensatory decrease of GABAA receptor response to GABA, evidenced by increasing tolerance of the effects of alcohol. Alcohol inhibits NMDA receptors, and chronic alcohol exposure results in up-regulation of these receptors. Abrupt cessation of alcohol exposure results in brain hyperexcitability, because receptors previously inhibited by alcohol are no longer inhibited. Brain hyperexcitability manifests clinically as anxiety, irritability, agitation, and tremors. Severe manifestations include alcohol withdrawal seizures and delirium tremens.


Benzodiazepines are the treatment of choice for alcohol withdrawal syndrome in humans (Mayo-Smith, 1997) and they are able to prevent most of the clinical manifestations of this condition. NMDA receptor antagonists have also been reported to markedly reduce ethanol withdrawal signs in rodents (Morriset et al., 1990; Liljequist, 1991; Thomas et al., 1997).

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