Servicio de Psiquiatría y Centro de Investigación, Hospital Universitario 12 de Octubre, Avda. Córdoba s/n, 28041 Madrid, Spain
* Author to whom correspondence should be addressed: Edificio Materno-Infantil, Planta 6, 613-A, Hospital Universitario 12 de Octubre, Avda. Cordoba s/n, 28041 Madrid, Spain. Tel.: 34 91 390 8252; Fax: 34 91 390 8538; E-mail: jmanzanares6{at}terra.es
(Received 16 September 2004; first review notified 2 September 2004; in revised form 14 September 2004; accepted 16 September 2004)
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ABSTRACT |
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INTRODUCTION |
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A summary of facts relating alcohol intake, development of alcohol dependence and genetic vulnerability to alcohol with endogenous opioid and cannabinoid receptor systems are depicted in Fig. 1. As shown, excessive alcohol consumption is a complex, multifactorial problem that includes not only the alteration of neurochemical elements in the brain but also a number of psychosocial conditions that may possibly favour the development of problems related to alcohol intake, which has been observed in dependent subjects. From these conditions (left part of Fig. 1), several personality traits such as high impulsivity, low self-esteem and sensation-seeking behaviour may contribute greatly to enhance vulnerability to alcohol dependence. In addition, a number of psychiatric disorders (phobias, attention-deficit hyperactive disorder or affective disorders) may also modify the effects of alcohol, enhancing its reinforcing properties and leading towards the progression to alcohol dependence. Although psychological traits and psychiatric conditions play a major role in the development, treatment and relapse of alcoholism, the findings of neurochemical alterations reported in a number of preclinical studies have allowed the identification of potential targets involved in the development, treatment and reinstatement of alcohol seeking behaviour.
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In recent years, several reports have suggested a close interaction between the endogenous cannabinoid system and alcohol consumption. It has been suggested that ethanol, using neuronal cells, increases the release of the endogenous cannabinoid ligands arachidonylethanolamide (AEA) and 2-arachidonylglycerol (2-AG) (Basavarajappa and Hungund, 1999a; Basavarajappa et al., 2000
, 2003
). The increase in ligand release may continuously activate the receptor, potentially down-regulating the cannabinoid CB1 receptor, after chronic ethanol administration, as shown recently (Basavarajappa et al., 1998
; Basavarajappa and Hungund, 1999b
; Ortiz et al., 2004a
). On the other hand, although it remains to be clarified, the administration of low doses of cannabinoid agonists enhances ethanol intake and this effect appears to be dependent upon the conditions of the experimental paradigm (Gallate and McGregor, 1999
; Colombo et al., 2002
). Conversely, several authors suggest that the administration of cannabinoid receptor antagonists reduces ethanol intake in rodents (Arnone et al., 1997
; Colombo et al., 1998
). Several mechanisms may participate in reducing ethanol intake in rats treated with the cannabinoid antagonist. First, as shown in Fig. 1, the blockade of cannabinoid CB1 receptors may impede the increase in opioid release induced by ethanol. Second, cannabinoid receptor antagonists may reduce the ethanol-induced increase in mesencephalic dopamine neurons or block the disinhibition of GABAergic neurons (for review see Piomelli, 2003
) that, in turn, results in the activation of dopamine neurons. This represents hypothetically distinct mechanisms by which the use of cannabinoid antagonists may be effective in reducing ethanol intake.
Taking into account that the administration of cannabinoid receptor agonists enhances endogenous opioid activity (Corchero et al., 1997a,b
; Manzanares et al., 1999
), differences in endogenous cannabinoid and opioid function may suggest a distinct vulnerability to ethanol consumption and/or dependence. Therefore, it is tempting to speculate that animals with low opioid expression and more vulnerability to ethanol may have impaired cannabinoid receptor function in key regions of the brain related to motivation and reward.
In the present review, we examined some of the effects of ethanol on opioid and cannabinoid receptors systems in the brain in relation to chronic consumption, genetic vulnerability towards high preference for ethanol and the pharmacological response to opioid and cannabinoid receptor antagonists in relation to ethanol consumption.
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ROLE OF OPIOID SYSTEM ON ETHANOL INTAKE, VULNERABILITY AND DEPENDENCE |
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Opioid peptides
It is well established that ethanol induces the release of opioid peptides, which interact with brain nuclei closely involved in reward and positive reinforcement systems (Jamensky and Gianoulakis, 1997; Koob et al., 1998
). Acute ethanol administration increases endorphin and enkephalin gene expression in discrete regions of the brain and increases the release of these peptides in the brain and pituitary of rodents (Schulz et al., 1980
; Gianoulakis and Barcomb, 1987
; Patel and Pohorecky, 1989
; Anwer and Soliman, 1995
; Li et al., 1998
; Rasmussen et al., 1998
; Oliva et al., 2002a
, 2003a
) (Table 2).
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The role of opioid peptide release and opioid gene expression has also been investigated in relation to increased vulnerability to ethanol dependence. Several studies have shown that basal opioid activity differs between ethanol-preferring and non-preferring strains of rodents. Selectively bred AA (ethanol-preferring) rats present a higher hypothalamic basal pro-opiomelanocortin gene expression compared with ANA (ethanol-avoiding) rats (Marinelli et al., 2000) and more sensitivity to ethanol consumption in selectively bred, ethanol-preferring P rats compared with ethanol-avoiding NP rats (Krishnan-Sarin et al., 1998
) as well as in ethanol-preferring C57BL/6 mice compared with ethanol non-preferring DBA/2 mice (Jamensky and Gianoulakis, 1999
).
Met-enkephalin and Leu-enkephalin peptide levels were lower in the nucleus accumbens of AA compared with ANA rats (Nylander et al., 1994), whereas a more intense proenkephalin expression was reported in the prefrontal cortex of AA compared with ANA rats (Marinelli et al., 2000
). Despite a number of studies that examined the basal functional activity of opioid receptors in selectively bred rats with a high preference for ethanol consumption, the results remain inconclusive. It has been shown that the density of opioid receptors in various regions of the brain is lower, higher or similar in ethanol-preferring compared with non-preferring rats (McBride et al., 1998
; Marinelli et al., 2000
).
Our laboratory has determined opioid functional activity in naïve ethanol-preferring Fawn-Hooded rats and ethanol non-preferring Wistar rats. The Fawn-Hooded strain of rat shows a high preference for ethanol intake (10% v/v) in a two-bottle free-choice situation (Rezvani et al., 1990; Ortiz et al., 2004b
) that may be related, at least in part, to decreased brain opioid function (Cowen et al., 1998
; Rezvani et al., 2002
). Indeed, as depicted in Fig. 2, we have observed lower mu-opioid receptor-stimulated [35S]GTP
S-binding autoradiography in the caudate-putamen and cingulate cortex, lower proenkephalin gene expression in the caudate-putamen and nucleus accumbens, and lower pro-opiomelanocortin gene expression in the arcuate nucleus of Fawn-Hooded compared with Wistar rats. Therefore, the results of this study, in agreement with previous reports, strongly support the hypothesis that the basal functional activity of the opioid system plays a critical role in the vulnerability to ethanol intake.
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ROLE OF THE CANNABINOID SYSTEM ON ETHANOL INTAKE, VULNERABILITY AND ADDICTION |
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Taking into account the idea that lower cannabinoid CB1 receptor function may be associated with increased vulnerability to high ethanol preference and consumption, we recently compared the activity of cannabinoid CB1 receptor (WIN-55,212-stimulated [35S]GTPS-binding autoradiography, and gene expression) in ethanol-preferring Fawn-Hooded and ethanol non-preferring Wistar rats under naïve conditions (Ortiz et al., 2004b
). The results of this study confirmed the presence of lower cannabinoid CB1 receptor-stimulated [35S]GTP
S binding in cingulate cortex, caudate-putamen, nucleus accumbens, ventromedial hypothalamic nucleus, amygdaloid area, and certain fields of the hippocampus in Fawn-Hooded compared with Wistar rats (Fig. 4). The notion is further supported by the fact that the cannabinoid CB1 receptor gene expression was also lower in the cingulate cortex, caudate-putamen, ventromedial hypothalamic nucleus and CA3 area of hippocampus in Fawn-Hooded compared with Wistar rats (Ortiz et al., 2004b
).
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Regulation of ethanol intake by cannabinoid receptor agonists
The fact that the exposure and intake of ethanol may induce alterations in the function and activity of the endocannabinoid system supports the notion that pharmacological manipulations of the cannabinoid CB1 system may affect ethanol consumption. Earlier studies by McMillan and Snodgrass (1991) showed that acute administration of
9-tetrahydrocannabinol (THC) reduced ethanol intake in rats by 5 and 7%. However, these authors also reported that chronic administration of THC initially decreased ethanol intake and, when tolerance occurred, ethanol consumption increased, even during THC withdrawal. The hypothesis, which suggests that the activation of cannabinoid CB1 receptor stimulates ethanol intake, was further confirmed by the studies of Gallate and McGregor (1999)
and Colombo et al. (2002)
. These authors showed that acute administration of the cannabinoid CB1 receptor agonists CP-55,940 or WIN-55,212 promoted voluntary ethanol intake in Sardinian ethanol-preferring (sP) rats (Colombo et al., 2002
) and increased the breakpoints for beer (Gallate and McGregor, 1999
). In both studies, the increase in ethanol intake induced by CP-55,940 or WIN-55,212 was prevented by cannabinoid or opioid receptor antagonists, strongly suggesting the participation of both systems in this process.
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ROLE OF CANNABINOID AND OPIOID ANTAGONISTS IN THE TREATMENT OF ETHANOL DEPENDENCE |
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The mechanisms by which the administration of naltrexone reduces ethanol intake have not been examined precisely. Recent reports suggest that naltrexone would render as normal, the endogenous opioid activity modified previously by prolonged ethanol consumption. In agreement, some researchers have shown that the administration of naltrexone reversed the alterations in opioid gene expression (Cowen and Lawrence, 2001; Oliva et al., 2003b
) and opioid receptor densities (Overstreet et al., 1999
) induced by ethanol intake. Preliminary results from our laboratory using the two-bottle-choice preference model revealed that administration of naltrexone reduced ethanol consumption by
50% and that this decrease was accompanied by a reduction in proenkephalin gene expression (elevated previously by prolonged ethanol consumption) in the caudate-putamen, core and shell parts of the nucleus accumbens, and olfactory tubercle (Oliva et al., 2003b
).
The administration of cannabinoid receptor antagonists also reduces ethanol intake in a wide variety of experimental paradigms. The administration of CB1 receptor-selective antagonists such as SR-141716A, SR-147778 or AM-251 reduced voluntary ethanol consumption under the home-cage two-bottle regimen or self administration procedures in ethanol-consuming rats and mice (Arnone et al., 1997; Colombo et al., 1998
; Freedland et al., 2001
; Lallemand et al., 2001
; Rinaldi-Carmona et al., 2004
), blocked acquisition of ethanol-drinking behaviour in rats (Serra et al., 2001
), decreased the motivation to consume ethanol in rats (Gallate and McGregor, 1999
) and completely abolished the ethanol deprivation effect (Serra et al., 2002
). However, little is known of the neurochemical mechanisms involved in this action. Since the increase of ethanol consumption induced by the cannabinoid receptor agonists CP-55,940 or WIN-55,212 can be blocked by administration of either naltrexone or SR-141716A, and cannabinoid receptor agonists increase the endogenous opioid function (for review, see Manzanares et al., 1999
), it is tempting to speculate that the reduction of ethanol intake produced by administration of cannabinoid receptor antagonists may be related, as suggested previously for opioid receptor antagonists, to the normalization of opioid peptides or opioid receptor functional activity altered by prolonged consumption of ethanol. Recent studies carried out in our laboratory revealed that the reduction of ethanol intake induced by the cannabinoid receptor antagonist AM-251 was associated with a lower decrease of DAMGO-stimulated [35S]GTP
binding in the caudate-putamen and pro-opiomelanocortin gene expression in the anterior lobe of the pituitary gland compared with the reduction produced by vehicle-ethanol treated rats (Ortiz et al., unpublished results). That is, administration of AM-251 tended to normalise mu-opioid receptor binding, altered previously by continuous exposure to ethanol.
The neurochemical mechanisms involved in the reduction of ethanol intake induced by either opioid or cannabinoid receptor antagonists may not be exclusively related to alterations in opioid functional activity, and still remain to be determined. Nevertheless, the fact that both opioid and cannabinoid antagonists tend to normalize opioid function disrupted by ethanol intake suggests a potential synergistic action between both antagonists to reduce the consumption of ethanol. Indeed, Gallate et al. (2004) reported recently that a combined low-dose treatment with opioid and cannabinoid receptor antagonists synergistically reduces the motivation to consume ethanol in rats. The mechanisms responsible for this synergistic action are still unknown and a number of preclinical studies are needed to clarify the precise nature of the interaction induced by blockade of both opioid and cannabinoid CB1 receptors. Nevertheless, although these results should be interpreted with caution, they may have an important impact in the treatment of problems related to ethanol in clinical practice. Further double-blind, placebo-controlled studies should be carried out to evaluate the outcome of combined treatment in ethanol-dependent patients.
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CONCLUSIONS |
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