Involvement of the endogenous opioid system in the psychopharmacological actions of ethanol: the role of acetaldehyde
- Area de Psicobiología, Universitat Jaume I, Castellón, Spain
Significant evidence implicates the endogenous opioid system (EOS) (opioid peptides and receptors) in the mechanisms underlying the psychopharmacological effects of ethanol. Ethanol modulates opioidergic signaling and function at different levels, including biosynthesis, release, and degradation of opioid peptides, as well as binding of endogenous ligands to opioid receptors. The role of β-endorphin and µ-opioid receptors (OR) have been suggested to be of particular importance in mediating some of the behavioral effects of ethanol, including psychomotor stimulation and sensitization, consumption and conditioned place preference (CPP). Ethanol increases the release of β-endorphin from the hypothalamic arcuate nucleus (NArc), which can modulate activity of other neurotransmitter systems such as mesolimbic dopamine (DA). The precise mechanism by which ethanol induces a release of β-endorphin, thereby inducing behavioral responses, remains to be elucidated. The present review summarizes accumulative data suggesting that the first metabolite of ethanol, the psychoactive compound acetaldehyde, could participate in such mechanism. Two lines of research involving acetaldehyde are reviewed: (1) implications of the formation of acetaldehyde in brain areas such as the NArc, with high expression of ethanol metabolizing enzymes and presence of cell bodies of endorphinic neurons and (2) the formation of condensation products between DA and acetaldehyde such as salsolinol, which exerts its actions via OR.
Ethanol and the Opioid System
Evidence indicates that ethanol modulates the activity of different components of the endogenous opioid system (EOS), with a large body of data supporting the implication of opioid ligands and receptors in the mediation of some of the psychopharmacological effects of ethanol.
The Endogenous Opioid System at a Glance
The opioid peptide precursors proopiomelanocortin (POMC), proenkephalin (PENK) or prodynorphin (PDYN) (Kieffer and Gavériaux-Ruff, 2002) are the source for the respective peptides β-endorphin, enkephalin, and dynorphin (Nylander and Roman, 2012). These endogenous ligands activate G-protein-coupled µ-, ∂-, and κ-opioid receptors (OR) (µ-OR, ∂-OR and κ-OR), which differ in their affinities and response profiles (Evans et al., 1992; Knapp et al., 1995; Kieffer and Evans, 2009). β-endorphin presents higher affinity for µ- than ∂-, and reduced affinity for κ-OR (Roth-Deri et al., 2008; Trigo et al., 2010). Enkephalin binding to ∂-OR is greater than that for µ-OR (Khachaturian et al., 1985; Raynor et al., 1994; Akil et al., 1998) and dynorphin shows specific affinity for κ-OR (Chavkin et al., 1982; Simon, 1991; Roth-Deri et al., 2008; Trigo et al., 2010). Ethanol can modulate opioidergic transmission at different levels, including synthesis, release, and degradation of opioid peptides, and binding of endogenous ligands to OR (for a review see, Méndez and Morales-Mulia, 2008). Since β-endorphin signaling has been specially implicated in the behavioral effects of ethanol, the present review will focus on the effects of ethanol on this component of the EOS. In this regard, although OR and ligands are widely distributed through the brain, there are important neuroanatomical determinants related to β-endorphin distribution that are worth highlighting. β-endorphin-synthesizing cell bodies are primarily located in the hypothalamic arcuate nucleus (NArc) (Chronwall, 1985). Important brain regions for drug-induced effects such as the nucleus accumbens (NAcb) are under tonic control of β-endorphinic innervations from the NArc (Chronwall, 1985; Khachaturian et al., 1985; Spanagel et al., 1992; Gianoulakis, 2001). These NArc β-endorphin projections exert this control through the direct activation of OR located at the NAcb and by an indirect pathway via OR in the ventral tegmental area (VTA), which in turn modulate NAcb activity via VTA-NAcb dopamine (DA) neurons (Mansour et al., 1988; Di Chiara and North, 1992; Spanagel et al., 1992).
Ethanol-Induced Modulation of β-Endorphinic Neurotransmission
Acute administration of ethanol induces the release of β-endorphin; an effect found in hypothalamic cell cultures and tissue preparations (Gianoulakis, 1990; Boyadjieva and Sarkar, 1994; de Waele et al., 1994; Reddy et al., 1995; De et al., 2002). Ethanol also produces in vivo increases in β-endorphin content at the level of the hypothalamus (Schulz et al., 1980; Patel and Pohorecky, 1989), NAcb (Anwer and Soliman, 1995; Olive et al., 2001; Marinelli et al., 2003a), midbrain including the VTA (Rasmussen et al., 1998; Jarjour et al., 2009) and the central amygdala (CeA) (Lam et al., 2008). Some studies, however, have found inconsistent results, probably related to procedural and methodological differences (Seizinger et al., 1983; Popp and Erickson, 1998; Rasmussen et al., 1998; Leriche and Méndez, 2010). Increased levels of enkephalin in the hypothalamus (Schulz et al., 1980; Seizinger et al., 1983; Milton et al., 1991) and NAcb (Marinelli et al., 2003b) have also been found after acute ethanol.
Long-term exposure to ethanol primarily induces a decrease in POMC expression (Boyadjieva and Sarkar, 1997; Rasmussen et al., 2002; Oswald and Wand, 2004) and in hypothalamic β-endorphin release and levels (Boyadjieva and Sarkar, 1994; Oswald and Wand, 2004). A limited number of studies reported an increase in biosynthesis of POMC and POMC mRNA expression (Seizinger et al., 1984; Gianoulakis et al., 1988) as well as an initial increase followed by a gradual return to normal levels (Wand, 1990). Also, some authors found an increase or no effect on β-endorphin release (Boyadjieva and Sarkar, 1994; Oswald and Wand, 2004). Discrepancies might be attributable to the method of ethanol administration, ethanol dose, time course of drug exposure, administration route and differences in the development of tolerance. Also, it has been observed that alcohol-induced changes depend on the brain region investigated as well as the species and strain of animals used (Gianoulakis, 2001; Méndez and Morales-Mulia, 2008).
Evidence of Behavioral Effects of Ethanol Mediated by the Endogenous Opioid System
Given that β-endorphin, and also enkephalin, activate μ-OR, extensive research has investigated the role of μ-OR in the behavioral effects of ethanol (Gianoulakis, 1993; Herz, 1997; Sanchis-Segura et al., 2000; Thorsell, 2013). Here we will focus on the involvement of these components of the EOS in several behavioral effects of ethanol, including psychomotor stimulation and sensitization, consumption, and associative learning (with a special focus on conditioned place preference (CPP)).
Psychomotor stimulation and sensitization
Increased psychomotor stimulation induced by ethanol in mice can be blocked with non-selective opioid receptor antagonists such as naloxone or naltrexone (Kiianmaa et al., 1983; Camarini et al., 2000; Sanchis-Segura et al., 2004; Pastor et al., 2005; Pastor and Aragon, 2006). Some pharmacological strategies have suggested the existence of three so-called subtypes of µ-OR; µ1, µ2, and, µ3 (Pasternak, 2001a,b; Cadet et al., 2003) and several studies have shown that μ- and specifically the µ1/2 - and µ3-OR subtypes, but not δ- or κ-OR, are involved in the motor stimulant effects of ethanol in adult mice (Pastor et al., 2005), and also in rats during early development (Arias et al., 2010; Pautassi et al., 2012). Other studies conducted in mice have suggested that this involvement of μ-OR in ethanol stimulation is debatable (Cunningham et al., 1998; Gevaerd et al., 1999; Holstein et al., 2005). Consistent with the EOS involvement, however, a lesion of the NArc produces a decrease in ethanol-induced stimulation in mice (Sanchis-Segura et al., 2000), and knockout mice deficient in β-endorphin showed attenuated ethanol-induced stimulation (Dempsey and Grisel, 2012). Also, in rats, naltrexone prevents activation produced by ethanol when locally administered in the NArc (Pastor and Aragon, 2008) and intra-VTA blockade of the μ-OR using either naltrexone or the irreversible and selective μ-OR antagonist β-funaltrexamine reduces ethanol-induced locomotor stimulation (Sánchez-Catalán et al., 2009). Additionally, chronic naltrexone, which upregulates μ-OR (Unterwald et al., 1998; Lesscher et al., 2003), enhances the stimulant effects of ethanol in mice (Sanchis-Segura et al., 2004).
A critical role of the EOS in the motor sensitizing effects of ethanol has also been proposed (Camarini et al., 2000; Miquel et al., 2003; Pastor and Aragon, 2006). Unspecific OR antagonism prevents development (Camarini et al., 2000) but not expression (Abrahao et al., 2008) of ethanol-induced locomotor sensitization. μ-OR are particularly involved in ethanol sensitization (Camarini et al., 2000), without a clear role of any of the µ-OR subtypes in mediating this process; µ1/2 -OR antagonism slowed down, but did not block development of sensitization (Pastor and Aragon, 2006). Facilitation of ethanol-induced sensitization found after a period of voluntary alcohol consumption in mice was also seen to be absent in μ-OR deficient CXBK mice (Tarragón et al., 2012). The involvement of μ-OR in ethanol sensitization might be related to ethanol-induced increases in β-endorphin release as a recent study demonstrated that β-endorphin-deficient mice do not show locomotor sensitization to ethanol (Dempsey and Grisel, 2012). Also, animals with selective lesions of the NArc show prevented sensitization to ethanol (Miquel et al., 2003; Pastor et al., 2011). Altogether these data suggest that opioids and specifically β-endorphins, via μ-OR, might be critical mediators of ethanol-induced neuroplasticity underlying psychomotor sensitization.
Numerous studies conducted during the last few decades showed that systemic, as well as local administration of opioid antagonists decrease ethanol consumption under a variety of schedules in different animal species (for reviews see Herz, 1997; Gianoulakis, 2001; Oswald and Wand, 2004; Modesto-Lowe and Fritz, 2005). These conclusions have also been supported by the use of OR knockout mouse models (Roberts et al., 2000; Méndez and Morales-Mulia, 2008). This strong pre-clinical basis has lead to the use of opioid antagonists in alcoholism pharmacotherapy (O’Malley et al., 1992). In rodents, the use of non-selective, as well as selective μ-OR antagonists proved to be effective at reducing ethanol consumption (Méndez and Morales-Mulia, 2008). However, the effects of these manipulations have been seen to be, in some cases, non-specific; fat, saccharin, sucrose and water intake were also reduced by these manipulations (Krishnan-Sarin et al., 1995; Nielsen et al., 2008; Rao et al., 2008; Simms et al., 2008; Corwin and Wojnicki, 2009; Wong et al., 2009). These data are compatible with the interpretation that OR, and especially μ-OR might be a key mediator of the processing of positive reinforcement, both at emotional and motivational levels (Herz, 1997; Peciña and Berridge, 2005).
In general, data obtained with κ-OR or δ-OR manipulations are less conclusive. A recent review of the literature indicates that κ-OR stimulation generally antagonizes the reinforcing effects of alcohol whereas κ-OR blockade has no consistent effect (Wee and Koob, 2010). Dynorphin/κ-OR system appears to be involved in the negative reinforcing effects of ethanol by producing an aversive effect rather than by directly modulating the rewarding mechanism of ethanol (Wee and Koob, 2010; Walker et al., 2012). However, under an alcohol dependent-state, antagonism of κ-OR results effective in decreasing ethanol voluntary consumption (Wee and Koob, 2010; Walker et al., 2012). It has been reported that blockade of δ-OR either attenuates (Lê et al., 1993; Froehlich, 1995; Krishnan-Sarin et al., 1995; June et al., 1999; Hyytiä and Kiianmaa, 2001; Ciccocioppo et al., 2002), increases (Margolis et al., 2008) or has no effect on ethanol intake (Ingman et al., 2003). These discrepancies may be related to dynamic changes in δ-OR efficacy during ethanol exposure (Margolis et al., 2008). All these data support the participation of the POMC and PENK systems in maintaining alcohol consumption (Froehlich et al., 1991; Vengeliene et al., 2008).
Associative learning and conditioned place preference
It has been suggested that the EOS participates in the underlying mechanisms mediating conditioned effects induced by abused drugs, including ethanol. This implication is supported by two groups of experiments. On one hand, evidence indicates that OR antagonists attenuate cue-induced reinstatement of previously extinguished responding for ethanol self-administration (Lê et al., 1999; Ciccocioppo et al., 2002, 2003; Liu and Weiss, 2002; Burattini et al., 2006; Dayas et al., 2007; Marinelli et al., 2009), which suggests a role of EOS in cue-induced incentive motivational effects influencing ethanol-seeking behavior. This interpretation is consistent with clinical data showing that opioid antagonists increase abstinence duration periods in alcohol abusers (O’Malley et al., 1992), probably by reducing cue-induced seeking behavior. On the other hand, pretreatment with opioid receptor antagonism, while not influencing the acquisition of ethanol-induced CPP, reduces the expression and facilitates the extinction of this drug-free conditioned response (Bormann and Cunningham, 1997; Middaugh and Bandy, 2000; Kuzmin et al., 2003; Pastor et al., 2011). Mice lacking μ-OR also showed attenuated ethanol CPP (Hall et al., 2001). Further studies have suggested that expression of ethanol-induced CPP depends on OR located in the VTA, CeA, as well as anterior cingulated cortex (Bechtholt and Cunningham, 2005; Bie et al., 2009; Gremel et al., 2011). Additionally, a neurotoxic lesion of the β-endorphin neurons of the NArc, showed a facilitated extinction of ethanol-induced CPP (Pastor et al., 2011). β-endorphin and μ-OR appear to be therefore critically involved in the mechanisms underlying ethanol CPP. As Cunningham and collaborators have suggested, it is possible that altered opioid signaling might in turn alter conditioned motivation that normally maintains cue-induced seeking behavior during CPP testing (Cunningham et al., 1998). It is interesting to mention that pharmacological blockade of δ-OR with naltrindole in the CeA reduces expression of CPP induced by ethanol in rats (Bie et al., 2009). Activation of κ-OR has been shown to blunt acquisition of ethanol CPP (Logrip et al., 2009). Supporting these results, κ-OR knockout mice also showed enhanced ethanol CPP (Femenía and Manzanares, 2012).
Acetaldehyde: A Psychoactive Metabolite
The specific mechanism by which ethanol modulates the activity of the EOS remains to be understood. Evidence indicates that one possible mechanism might involve the role of acetaldehyde, the first metabolite of ethanol (Miquel et al., 2003; Sanchis-Segura et al., 2005b; Pastor and Aragon, 2008). Acetaldehyde is a psychoactive compound that produces behavioral and neurochemical effects suggested to mediate at least some of the effects of ethanol. Acetaldehyde is self-administered orally (Peana et al., 2010, 2012; Cacace et al., 2012) and directly into the brain (Brown et al., 1979; McBride et al., 2002; Rodd-Henricks et al., 2002; Peana et al., 2011). Its administration induces CPP (Smith et al., 1984; Quertemont and De Witte, 2001; Peana et al., 2009; Spina et al., 2010) as well as behavioral stimulation and sensitization when centrally administered (Arizzi et al., 2003; Correa et al., 2003a,b, 2009; Rodd et al., 2005; Arizzi-LaFrance et al., 2006; Sánchez-Catalán et al., 2009). The oxidation of ethanol to acetaldehyde in the brain is essentially mediated by the catalase-H2O2 system (Aragon et al., 1992a; Gill et al., 1992). Reduced brain catalase activity, which have been seen to decrease ethanol-derived central acetaldehyde formation in brain tissue preparations (Hamby-Mason et al., 1997) and in the brain of free-moving rats (Jamal et al., 2007), decreases ethanol consumption (Aragon and Amit, 1992; Koechling and Amit, 1994; Correa et al., 2004; Karahanian et al., 2011), ethanol-induced locomotor stimulation (Aragon et al., 1992b; Correa et al., 1999b, 2004; Sanchis-Segura et al., 1999a,b,c; Pastor et al., 2002; Pastor and Aragon, 2008), the anxiolityc effects of alcohol (Correa et al., 2008) and modulates ethanol-induced CPP (Font et al., 2008). Strategies aimed at increasing the production of brain acetaldehyde via an enhancement in activity of the enzymatic catalase system have also been used. These manipulations produced an increase in the motor stimulant properties of ethanol in mice (Correa et al., 1999a, 2000; Pastor et al., 2002). Other ethanol-induced effects such as taste aversion (Aragon et al., 1985) and social memory recognition have also been seen to be modulated by changes in brain catalase (Manrique et al., 2005).
Apart from brain catalase manipulation, the direct inactivation of acetaldehyde has also been shown to reduce ethanol effects, including drinking (Font et al., 2006a) and alcohol-induced relapse drinking (Orrico et al., 2013), CPP (Font et al., 2006b; Peana et al., 2008) and motor stimulation (Font et al., 2005; Martí-Prats et al., 2010; Pautassi et al., 2011).
Acetaldehyde-Induced Changes in the Opioidergic Neurotransmission
The NArc, the main site of β-endorphin synthesis in the brain, is one of areas with the highest levels of catalase expression (Moreno et al., 1995; Zimatkin and Lindros, 1996) and lower levels of the acetaldehyde-degrading enzyme aldehyde dehydrogenase (Zimatkin et al., 1992). Therefore, it has been thus suggested that catalase-dependent formation of acetaldehyde into the NArc might mediate ethanol-induced increases in the release of β-endorphin from the NArc in turn activating OR at the level of the VTA/NAcb to stimulate behavioral and neurophysiological actions (Sanchis-Segura et al., 2005a; Pastor and Aragon, 2008). Supporting this hypothesis, several authors (Reddy and Sarkar, 1993; Pastorcic et al., 1994; Reddy et al., 1995) have demonstrated that ethanol-induced increases in hypothalamic β-endorphin release are, indeed, mediated by acetaldehyde (Reddy and Sarkar, 1993; Pastorcic et al., 1994; Reddy et al., 1995). Hypothalamic cell cultures exposed to ethanol (12.5–100 µM) led to the formation of acetaldehyde (8–24 µM) and similar concentrations of acetaldehyde (12.5–50 µM) were able to stimulate β-endorphin release when tested in the absence of ethanol (Reddy and Sarkar, 1993; Pastorcic et al., 1994). Moreover, pre-treatment of hypothalamic cell cultures with catalase inhibitors caused dose-dependent decreases in ethanol-stimulated β-endorphin secretion (Reddy et al., 1995).
Another line of research linking the EOS and acetaldehyde is the investigation of the actions of salsolinol (for a review see Hipólito et al., 2012), the condensation product of DA and acetaldehyde. Salsolinol has been shown to alter enkephalin-receptor site binding (Lucchi et al., 1982) and other OR an effect that is blocked by naloxone (Fertel et al., 1980). Interestingly, intra-NAcb administration of salsolinol increases DA levels when microinjected in the core and decreases DA levels if the administration is in the NAcb shell (Hipólito et al., 2009) in a similar way to μ- and δ-OR agonists (Hipólito et al., 2008). It has been demonstrated that μ1-OR receptors exert a tonic modulatory control over activity of the DA system (Di Chiara and North, 1992; Devine et al., 1993). Thus, one possible mechanism by which salsolinol exerts its effects on the OR could be disinhibiting DA neurons in the VTA. Upholding this hypothesis, intra-posterior VTA administration of salsolinol induces a μ-OR dependent increase in DA levels in the NAcb shell (Hipólito et al., 2011). Accordingly, it has been recently shown that salsolinol excites DA neurons of the VTA, by activating µ-OR on local GABA interneurons (Xie et al., 2012).
Evidence of Behavioral Effects of Acetaldehyde Mediated by the Endogenous Opioid System
Whereas accumulating evidence indicates that the EOS participates in the behavioral effects of ethanol, only few studies have studied the involvement of this system in acetaldehyde effects. Self-administration of acetaldehyde appears to be mediated by the EOS; high doses of naloxone reduced intravenous acetaldehyde self-administration in rats, and naltrexone reduced the maintenance, the deprivation effect, and operant break points of acetaldehyde voluntary consumption (Myers et al., 1984; Peana et al., 2011). Treatment with naloxonazine, a specific µ1-OR antagonist reduces maintenance of acetaldehyde oral self-administration (Peana et al., 2011). Blockade of μ-OR using either naltrexone or the irreversible and selective μ-OR antagonist β-funaltrexamine suppress the locomotor stimulation effect of acetaldehyde when microinjected into the rat posterior VTA (Sánchez-Catalán et al., 2009). Additionally, Hipólito et al. (2010) have provided data supporting the hypothesis that acetaldehyde may mediate the actions of ethanol through a mechanism dependent on μ-OR activation. These authors showed that intra-posterior VTA injections of salsolinol induced locomotor stimulation and sensitization in rats; stimulation (but not sensitization) was prevented by μ-OR antagonism. Finally, Sanchis-Segura et al. (2005b) demonstrated that administration of a catalase inhibitor directly into the NArc is sufficient to prevent the effects of ethanol on rat locomotion. Conversely, locomotor stimulation induced by ethanol injected directly into the NArc, was prevented by catalase inhibition or naltrexone, indicating a link between the behavioral effects of a reduction in acetaldehyde formation and the antagonism of μ-OR (Pastor and Aragon, 2008). The NArc, therefore, may represent a critical site to link two independent but related hypotheses: (1) the hypothesis proposing that acetaldehyde may mediate some of the psychopharmacological actions attributed to ethanol (Aragon et al., 1992a; Smith et al., 1997; Quertemont et al., 2005; Correa et al., 2012) and (2) the hypothesis that suggests that the β-endorphin/µ-OR system participate in the reinforcing and psychomotor effects of ethanol (Stinus et al., 1980; Herz, 1997; Gianoulakis, 2001; Sanchis-Segura et al., 2005b; Pastor and Aragon, 2008). Early findings also suggested a role of the opioidergic system in mediating CPP induced by salsolinol in rats (Matsuzawa et al., 2000). Antagonism of μ-OR attenuated CPP induced by salsolinol when achieved under fear stress (Matsuzawa et al., 2000). Moreover, intra-posterior VTA administration of salsolinol, that produced CPP in rats, also produced an increase in DA in the NAcb that was suppressed by β-funaltrexamine administration (Hipólito et al., 2011).
Summary and Perspectives
In the present review we have summarized consistent results indicating that the EOS, and particularly β-endorphin and μ-OR, are critically involved in the psychopharmacological effects of ethanol. Additionally, we have reviewed a large body of data that indicates that the first metabolite of ethanol, acetaldehyde, might be responsible for the activation of β-endorphin release and μ-OR signaling after ethanol administration. There are two main lines of research suggesting a link between acetaldehyde and the EOS: (1) formation of acetaldehyde in brain areas such as the NArc, with high expression of ethanol metabolizing enzymes and presence of cell bodies of endorphinic neurons and (2) the formation of condensation products between DA and acetaldehyde such as salsolinol, which exerts its actions via μ-OR. To a certain degree both lines of research show important incompatibility. The fact that the lesions of the NArc are sufficient to block ethanol-induced behaviors challenge the putative role of salsolinol formed in other non-hypothalamic areas. Future studies will need to explore how to reconcile those two sets of data, and to clarify what is sufficient and/or necessary for acetaldehyde to induce behavioral responses mediated by the EOS. Finally, it is interesting to mention that most of the data suggesting a role of the EOS in acetaldehyde-induced behavioral effects have been linked to acetaldehyde-induced changes in the opioid system that are suggested to impact behavior via modulation of the DA system (Peana et al., 2011). Ethanol as well as acetaldehyde activate firing of dopaminergic neurons in the VTA (Foddai et al., 2004; Diana et al., 2008) and stimulate DA transmission in the NAcb (Melis et al., 2007; Enrico et al., 2009; Sirca et al., 2011), effects that are prevented by D-penicillamine, a sequestering agent of acetaldehyde (Enrico et al., 2009). A recent study demonstrates that in rats, ethanol and acetaldehyde induce via DA D1 receptors, ERK phosphorylation in the NAcb and extended amygdala (Vinci et al., 2010). This effect is blocked by D-penicillamine and by naltrexone, suggesting that the opiodergic modulation of the reinforcing properties of acetaldehyde could be mediated by the dopaminergic system (Vinci et al., 2010; Peana et al., 2011). There are other effects such as ethanol-induced CPP, ethanol drinking in some non-operant conditions and even ethanol-induced sensitization that appear to have a less straightforward involvement of DA signaling (Risinger et al., 1992; Broadbent et al., 1995; Spina et al., 2010; Young et al., 2013). Future research will need to investigate DA-dependent and independent mechanisms by which acetaldehyde might induce behavioral responses via its modulation of the EOS.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
This work was supported by grants from Fundación Bancaixa (P1-1A2011-05), Spain.
Abrahao, K. P., Quadros, I. M., and Souza-Formigoni, M. L. (2008). Morphine attenuates the expression of sensitization to ethanol, but opioid antagonists do not. Neuroscience 156, 857–864. doi: 10.1016/j.neuroscience.2008.08.012
Anwer, J., and Soliman, M. R. (1995). Ethanol-induced alterations in beta-endorphin levels in specific rat brain regions: modulation by adenosine agonist and antagonist. Pharmacology 51, 364–369. doi: 10.1159/000139348
Aragon, C. M., and Amit, Z. (1992). The effect of 3-amino-1,2,4-triazole on voluntary ethanol consumption: evidence for brain catalase involvement in the mechanism of action. Neuropharmacology 31, 709–712. doi: 10.1016/0028-3908(92)90150-n
Aragon, C. M., Spivak, K., and Amit, Z. (1985). Blockade of ethanol induced conditioned taste aversion by 3-amino-1,2,4-triazole: evidence for catalase mediated synthesis of acetaldehyde in rat brain. Life Sci. 37, 2077–2084. doi: 10.1016/0024-3205(85)90579-x
Arias, C., Molina, J. C., and Spear, N. E. (2010). Differential role of mu, delta and kappa opioid receptors in ethanol-mediated locomotor activation and ethanol intake in preweanling rats. Physiol. Behav. 99, 348–454. doi: 10.1016/j.physbeh.2009.11.012
Arizzi, M. N., Correa, M., Betz, A. J., Wisniecki, A., and Salamone, J. D. (2003). Behavioral effects of intraventricular injections of low doses of ethanol, acetaldehyde, and acetate in rats: studies with low and high rate operant schedules. Behav. Brain Res. 147, 203–210. doi: 10.1016/s0166-4328(03)00158-x
Arizzi-LaFrance, M. N., Correa, M., Aragon, C. M., and Salamone, J. D. (2006). Motor stimulant effects of ethanol injected into the substantia nigra pars reticulata: importance of catalase-mediated metabolism and the role of acetaldehyde. Neuropsychopharmacology 31, 997–1008. doi: 10.1038/sj.npp.1300849
Bechtholt, A. J., and Cunningham, C. L. (2005). Ethanol-induced conditioned place preference is expressed through a ventral tagmental area dependent mechanism. Behav. Neurosci. 119, 213–223. doi: 10.1037/0735-7044.119.1.213
Bie, B., Zhu, W., and Pan, Z. Z. (2009). Ethanol-induced delta-opioid receptor modulation of glutamate synaptic transmission and conditioned place preference in central amygdala. Neuroscience 160, 348–358. doi: 10.1016/j.neuroscience.2009.02.049
Boyadjieva, N. I., and Sarkar, D. K. (1994). Effects of chronic alcohol on immunoreactive beta-endorphin secretion from hypothalamic neurons in primary cultures: evidence for alcohol tolerance, withdrawal, and sensitization responses. Alcohol. Clin. Exp. Res. 18, 1497–1501. doi: 10.1006/mcne.1994.1071
Boyadjieva, N. I., and Sarkar, D. K. (1997). Effects of ethanol on basal and prostaglandin E1-induced increases in beta-endorphin release and intracellular cAMP levels in hypothalamic cells. Alcohol. Clin. Exp. Res. 21, 1005–1009. doi: 10.1111/j.1530-0277.1997.tb04245.x
Broadbent, J., Grahame, N. J., and Cunningham, C. L. (1995). Haloperidol prevents ethanol-stimulated locomotor activity but fails to block sensitization. Psychopharmacology 120, 475–482. doi: 10.1007/bf02245821
Brown, Z. W., Amit, Z., and Rockman, G. E. (1979). Intraventricular self-administration of acetaldehyde, but not ethanol, in naive laboratory rats. Psychopharmacology 64, 271–276. doi: 10.1007/bf00427509
Burattini, C., Gill, T. M., Aicardi, G., and Janak, P. H. (2006). The ethanol self-administration context as a reinstatement cue: acute effects of naltrexone. Neuroscience 139, 877–887. doi: 10.1016/j.neuroscience.2006.01.009
Cacace, S., Plescia, F., Barberi, I., and Cannizzaro, C. (2012). Acetaldehyde oral self-administration: evidence from the operant-conflict paradigm. Alcohol. Clin. Exp. Res. 36, 1278–1287. doi: 10.1111/j.1530-0277.2011.01725.x
Cadet, P., Mantione, K. J., and Stefano, G. B. (2003). Molecular identification and functional expression of mu 3, a novel alternatively spliced variant of the human mu opiate receptor gene. J. Immunol. 170, 5118–5123.
Camarini, R., Nogueira Pires, M. L., and Calil, H. M. (2000). Involvement of the opioid system in the development and expression of sensitization to the locomotor-activating effect of ethanol. Int. J. Neuropsychopharmacol. 3, 303–309. doi: 10.1017/s146114570000211x
Ciccocioppo, R., Martin-Fardon, R., and Weiss, F. (2002). Effect of selective blockade of mu(1) or delta opioid receptors on reinstatement of alcohol-seeking behavior by drug-associated stimuli in rats. Neuropsychopharmacology 27, 391–399. doi: 10.1016/s0893-133x(02)00302-0
Ciccocioppo, R., Lin, D., Martin-Fardon, R., and Weiss, F. (2003). Reinstatement of ethanol-seeking behavior by drug cues following single versus multiple ethanol intoxication in the rat: effects of naltrexone. Psychopharmacology 168, 208–215. doi: 10.1007/s00213-002-1380-z
Correa, M., Arizzi, M. N., Betz, A., Mingote, S., and Salamone, J. D. (2003a). Open field locomotor effects in rats after intraventricular injections of ethanol and the ethanol metabolites acetaldehyde and acetate. Brain Res. Bull. 62, 197–202. doi: 10.1016/j.brainresbull.2003.09.013
Correa, M., Arizzi, M. N., Betz, A., Mingote, S., and Salamone, J. D. (2003b). Locomotor stimulant effects of intraventricular injections of low doses of ethanol in rats: acute and repeated administration. Psychopharmacology 170, 368–375. doi: 10.1007/s00213-003-1557-0
Correa, M., Arizzi-LaFrance, M. N., and Salamone, J. D. (2009). Infusions of acetaldehyde into the arcuate nucleus of the hypothalamus induce motor activity in rats. Life Sci. 84, 321–327. doi: 10.1016/j.lfs.2008.12.013
Correa, M., Manrique, H. M., Font, L., Escrig, M. A., and Aragon, C. M. (2008). Reduction in the anxiolytic effects of ethanol by centrally formed acetaldehyde: the role of catalase inhibitors and acetaldehyde-sequestering agents. Psychopharmacology 200, 455–464. doi: 10.1007/s00213-008-1219-3
Correa, M., Miquel, M., and Aragon, C. M. (2000). Lead acetate potentiates brain catalase activity and enhances ethanol-induced locomotion in mice. Pharmacol. Biochem. Behav. 66, 137–142. doi: 10.1016/s0091-3057(00)00204-5
Correa, M., Miquel, M., Sanchis-Segura, C., and Aragon, C. M. (1999a). Acute lead acetate administration potentiates ethanol-induced locomotor activity in mice: the role of brain catalase. Alcohol. Clin. Exp. Res. 23, 799–805.
Correa, M., Miquel, M., Sanchis-Segura, C., and Aragon, C. M. (1999b). Effects of chronic lead administration on ethanol-induced locomotor and brain catalase activity. Alcohol 19, 43–49. doi: 10.1016/s0741-8329(99)00023-3
Correa, M., Salamone, J. D., Segovia, K. N., Pardo, M., Longoni, R., Spina, L., et al. (2012). Piecing together the puzzle of acetaldehyde as a neuroactive agent. Neurosci. Biobehav. Rev. 36, 404–430. doi: 10.1016/j.neubiorev.2011.07.009
Correa, M., Sanchis-Segura, C., Pastor, R., and Aragon, C. M. (2004). Ethanol intake and motor sensitization: the role of brain catalase activity in mice with different genotypes. Physiol. Behav. 82, 231–40. doi: 10.1016/j.physbeh.2004.03.033
Corwin, R. L., and Wojnicki, F. H. (2009). Baclofen, raclopride, and naltrexone differentially affect intake of fat and sucrose under limited access conditions. Behav. Pharmacol. 20, 537–548. doi: 10.1097/fbp.0b013e3283313168
Cunningham, C. L., Henderson, C. M., and Bormann, N. M. (1998). Extinction of ethanol-induced conditioned place preference and conditioned place aversion: effects of naloxone. Psychopharmacology 139, 62–70. doi: 10.1007/s002130050690
Dayas, C. V., Liu, X., Simms, J. A., and Weiss, F. (2007). Distinct patterns of neural activation associated with ethanol seeking: effects of naltrexone. Biol. Psychiatry 61, 979–989. doi: 10.1016/j.biopsych.2006.07.034
De, A., Boyadjieva, N., and Sarkar, D. K. (2002). Role of protein kinase C in control of ethanol-modulated beta-endorphin release from hypothalamic neurons in primary cultures. J. Pharmacol. Exp. Ther. 301, 119–128. doi: 10.1124/jpet.301.1.119
de Waele, J. P., Kiianmaa, K., and Gianoulakis, C. (1994). Spontaneous and ethanol-stimulated in vitro release of beta-endorphin by the hypothalamus of AA and ANA rats. Alcohol. Clin. Exp. Res. 18, 1468–1473. doi: 10.1111/j.1530-0277.1994.tb01452.x
Devine, D. P., Leone, P., and Wise, R. A. (1993). Mesolimbic dopamine neurotransmission is increased by administration of mu-opioid receptor antagonists. Eur. J. Pharmacol. 243, 55–64. doi: 10.1016/0014-2999(93)90167-g
Diana, M., Peana, A. T., Sirca, D., Lintas, A., Melis, M., and Enrico, P. (2008). Crucial role of acetaldehyde in alcohol activation of the mesolimbic dopamine system. Ann. NY Acad. Sci. 1139, 307–317. doi: 10.1196/annals.1432.009
Enrico, P., Sirca, D., Mereu, M., Peana, A. T., Lintas, A., Golosio, A., et al. (2009). Acetaldehyde sequestering prevents ethanol-induced stimulation of mesolimbic dopamine transmission. Drug Alcohol Depend. 100, 265–271. doi: 10.1016/j.drugalcdep.2008.10.010
Evans, C. J., Keith, D. E. Jr., Morrison, H., Magendzo, K., and Edwards, R. H. (1992). Cloning of a delta opioid receptor by functional expression. Science 258, 1952–1955. doi: 10.1126/science.1335167
Femenía, T., and Manzanares, J. (2012). Increased ethanol intake in prodynorphin knockout mice is associated to changes in opioid receptor function and dopamine transmission. Addict. Biol. 17, 322–337. doi: 10.1111/j.1369-1600.2011.00378.x
Fertel, R. H., Greenwald, J. E., Schwarz, R., Wong, L., and Bianchine, J. (1980). Opiate receptor binding and analgesic effects of the tetrahydroisoquinolines salsolinol and tetrahydropapaveroline. Res. Commun. Chem. Pathol. Pharmacol. 27, 3–16.
Font, L., Aragon, C. M., and Miquel, M. (2006a). Voluntary ethanol consumption decreases after the inactivation of central acetaldehyde by D-penicillamine. Behav. Brain Res. 171, 78–86. doi: 10.1016/j.bbr.2006.03.020
Font, L., Miquel, M., and Aragon, C. (2005). Prevention of ethanol induced behavioral stimulation by D-penicillamine: a sequestration agent for acetaldehyde. Alcohol. Clin. Exp. Res. 29, 1156–1164. doi: 10.1097/01.alc.0000171945.30494.af
Font, L., Miquel, M., and Aragon, C. (2006b). Ethanol-induced conditioned place preference, but not aversion, is blocked by treatment with D-penicillamine, an inactivation agent for acetaldehyde. Psychopharmacology 184, 56–64. doi: 10.1007/s00213-005-0224-z
Font, L., Miquel, M., and Aragon, C. M. (2008). Involvement of brain catalase activity in the acquisition of ethanol-induced conditioned place preference. Physiol. Behav. 93, 733–741. doi: 10.1016/j.physbeh.2007.11.026
Froehlich, J. C., Zweifel, M., Harts, J., Lumeng, L., and Li, T. K. (1991). Importance of delta opioid receptors in maintaining high alcohol drinking. Psychopharmacology 103, 467–472. doi: 10.1007/bf02244246
Gevaerd, M. S., Sultowski, E. T., and Takahashi, R. N. (1999). Combined effects of diethylpropion and alcohol on locomotor activity of mice: participation of the dopaminergic and opioid systems. Braz. J. Med. Biol. Res. 32, 1545–1550. doi: 10.1590/S0100-879X1999001200015
Gianoulakis, C. (1990). Characterization of the effects of acute ethanol administration on the release of beta-endorphin peptides by the rat hypothalamus. Eur. J. Pharmacol. 180, 21–29. doi: 10.1016/0014-2999(90)90588-w
Gianoulakis, C., Hutchison, W. D., and Kalant, H. (1988). Effects of ethanol treatment and withdrawal on biosynthesis and processing of proopiomelanocortin by the rat neurointermediate lobe. Endocrinology 122, 817–825. doi: 10.1210/endo-122-3-817
Gill, K., Menez, J. F., Lucas, D., and Deitrich, R. A. (1992). Enzymatic production of acetaldehyde from ethanol in rat brain tissue. Alcohol. Clin. Exp. Res. 16, 910–915. doi: 10.1111/j.1530-0277.1992.tb01892.x
Gremel, C. M., Young, E. A., and Cunningham, C. L. (2011). Blockade of opioid receptors in anterior cingulate cortex disrupts ethanol-seeking behavior in mice. Behav. Brain Res. 219, 358–362. doi: 10.1016/j.bbr.2010.12.033
Hamby-Mason, R., Chen, J. J., Schenker, S., Perez, A., and Henderson, G. I. (1997). Catalase mediates acetaldehyde formation from ethanol in fetal and neonatal rat brain. Alcohol. Clin. Exp. Res. 21, 1063–72. doi: 10.1111/j.1530-0277.1997.tb04255.x
Hipólito, L., Martí-Prats, L., Sánchez-Catalán, M. J., Polache, A., and Granero, L. (2011). Induction of conditioned place preference and dopamine release by salsolinol in posterior VTA of rats: involvement of μ-opioid receptors. Neurochem. Int. 59, 559–562. doi: 10.1016/j.neuint.2011.04.014
Hipólito, L., Sánchez-Catalán, M. J., Granero, L., and Polache, A. (2009). Local salsolinol modulates dopamine extracellular levels from rat nucleus accumbens: shell/core differences. Neurochem. Int. 55, 187–192. doi: 10.1016/j.neuint.2009.02.014
Hipólito, L., Sánchez-Catalán, M. J., Martí-Prats, L., Granero, L., and Polache, A. (2012). Revisiting the controversial role of salsolinol in the neurobiological effects of ethanol: old and new vistas. Neurosci. Biobehav. Rev. 36, 362–378. doi: 10.1016/j.neubiorev.2011.07.007
Hipólito, L., Sánchez-Catalán, M. J., Zanolini, I., Polache, A., and Granero, L. (2008). Shell/core differences in mu- and delta-opioid receptor modulation of dopamine efflux in nucleus accumbens. Neuropharmacology 55, 183–189. doi: 10.1016/j.neuropharm.2008.05.012
Hipólito, L., Sánchez-Catalán, M. J., Zornoza, T., Polache, A., and Granero, L. (2010). Locomotor stimulant effects of acute and repeated intrategmental injections of salsolinol in rats : role of μ-opioid receptors. Psychopharmacology 209, 1–11. doi: 10.1007/s00213-009-1751-9
Holstein, S. E., Pastor, R., Meyer, P. J., and Phillips, T. J. (2005). Naloxone does not attenuate the locomotor effects of ethanol in FAST, SLOW, or two heterogeneous stocks of mice. Psychopharmacology 182, 277–289. doi: 10.1007/s00213-005-0066-8
Hyytiä, P., and Kiianmaa, K. (2001). Suppression of ethanol responding by centrally administered CTOP and naltrindole in AA and Wistar rats. Alcohol. Clin. Exp. Res. 25, 25–33. doi: 10.1111/j.1530-0277.2001.tb02123.x
Ingman, K., Salvadori, S., Lazarus, L., Korpi, E. R., and Honkanen, A. (2003). Selective delta-opioid receptor antagonist N,N(CH3)2-Dmt-Tic-OH does not reduce ethanol intake in alcohol-preferring AA rats. Addict. Biol. 8, 173–179. doi: 10.1080/1355621031000117400
Jamal, M., Ameno, K., Uekita, I., Kumihashi, M., Wang, W., and Ijiri, I. (2007). Catalase mediates acetaldehyde formation in the striatum of free-moving rats. Neurotoxicology 28, 1245–1248. doi: 10.1016/j.neuro.2007.05.002
Jarjour, S., Bai, L., and Gianoulakis, C. (2009). Effect of acute ethanol administration on the release of opioid peptides from the midbrain including the ventral tegmental area. Alcohol. Clin. Exp. Res. 33, 1033–1043. doi: 10.1111/j.1530-0277.2009.00924.x
June, H. L., Grey, C., Warren-Reese, C., Durr, L. F., Ricks-Cord, A., Johnson, A., et al. (1999). The opioid receptor antagonist nalmefene reduces responding maintained by ethanol presentation: preclinical studies in ethanol-preferring and outbred wistar rats. Alcohol. Clin. Exp. Res. 22, 2174–2185. doi: 10.1111/j.1530-0277.1998.tb05931.x
Karahanian, E., Quintanilla, M. E., Tampier, L., Rivera-Meza, M., Bustamante, D., Gonzalez-Lira, V., et al. (2011). Ethanol as a prodrug: brain metabolism of ethanol mediates its reinforcing effects. Alcohol. Clin. Exp. Res. 35, 606–612. doi: 10.1111/j.1530-0277.2011.01439.x
Khachaturian, H., Lewis, M. E., Alessi, N. E., and Watson, S. J. (1985). Time of origin of opioid peptide-containing neurons in the rat hypothalamus. J. Comp. Neurol. 236, 538–546. doi: 10.1002/cne.902360409
Kiianmaa, K., Hoffman, P., and Tabakoff, B. (1983). Antagonism of the behavioral effects of ethanol by naltrexone in BALB/c, C57BL/6, and DBA/2 mice. Psychopharmacology 79, 291–294. doi: 10.1007/bf00433403
Krishnan-Sarin, S., Portoghese, P. S., Li, T. K., and Froehlich, J. C. (1995). The delta 2-opioid receptor antagonist naltriben selectively attenuates alcohol intake in rats bred for alcohol preference. Pharmacol. Biochem. Behav. 52, 153–159. doi: 10.1016/0091-3057(95)00080-g
Kuzmin, A., Sandin, J., Terenius, L., and Ogren, S. O. (2003). Acquisition, expression, and reinstatement of ethanol-induced conditioned place preference in mice: effects of opioid receptor-like 1 receptor agonists and naloxone. J. Pharmacol. Exp. Ther. 304, 310–318. doi: 10.1124/jpet.102.041350
Lam, M. P., Marinelli, P. W., Bai, L., and Gianoulakis, C. (2008). Effects of acute ethanol on opioid peptide release in the central amygdala: an in vivo microdialysis study. Psychopharmacology 201, 261–271. doi: 10.1007/s00213-008-1267-8
Lê, A. D., Poulos, C. X., Harding, S., Watchus, J., Juzytsch, W., and Shaham, Y. (1999). Effects of naltrexone and fluoxetine on alcohol self-administration and reinstatement of alcohol seeking induced by priming injections of alcohol and exposure to stress. Neuropsychopharmacology 21, 435–444. doi: 10.1016/s0893-133x(99)00024-x
Lê, A. D., Poulos, C. X., Quan, B., and Chow, S. (1993). The effects of selective blockade of delta and mu opiate receptors on ethanol consumption by C57BL/6 mice in a restricted access paradigm. Brain Res. 630, 330–332. doi: 10.1016/0006-8993(93)90672-a
Leriche, M., and Méndez, M. (2010). Ethanol exposure selectively alters beta-endorphin content but not [3H]-DAMGO binding in discrete regions of the rat brain. Neuropeptides 44, 9–16. doi: 10.1016/j.npep.2009.11.009
Lesscher, H. M., Bailey, A., Burbach, J. P., Van Ree, J. M., Kitchen, I., and Gerrits, M. A. (2003). Receptor-selective changes in mu-, delta- and kappa-opioid receptors after chronic naltrexone treatment in mice. Eur. J. Neurosci. 17, 1006–1012.
Liu, X., and Weiss, F. (2002). Additive effect of stress and drug cues on reinstatement of ethanol seeking: exacerbation by history of dependence and role of concurrent activation of corticotropin-releasing factor and opioid mechanisms. J. Neurosci. 22, 7856–7861.
Manrique, H. M., Miquel, M., and Aragon, C. M. (2005). Brain catalase mediates potentiation of social recognition memory produced by ethanol in mice. Drug Alcohol Depend. 79, 343–350. doi: 10.1016/j.drugalcdep.2005.02.007
Margolis, E. B., Fields, H. L., Hjelmstad, G. O., and Mitchell, J. M. (2008). Delta-opioid receptor expression in the ventral tegmental area protects against elevated alcohol consumption. J. Neurosci. 28, 12672–12681. doi: 10.1523/jneurosci.4569-08.2008
Marinelli, P. W., Funk, D., Harding, S., Li, Z., Juzytsch, W., and Lê, A. D. (2009). Roles of opioid receptor subtypes in mediating alcohol seeking induced by discrete cues and context. Eur. J. Neurosci. 30, 671–678. doi: 10.1111/j.1460-9568.2009.06851.x
Marinelli, P. W., Quirion, R., and Gianoulakis, C. (2003a). Estradiol valerate and alcohol intake: a comparison between Wistar and Lewis rats and the putative role of endorphins. Behav. Brain Res. 139, 59–67. doi: 10.1016/s0166-4328(02)00057-8
Marinelli, P. W., Quirion, R., and Gianoulakis, C. (2003b). A microdialysis profile of beta-endorphin and catecholamines in the rat nucleus accumbens following alcohol administration. Psychopharmacology 169, 60–67. doi: 10.1007/s00213-003-1490-2
Martí-Prats, L., Sánchez-Catalán, M. J., Hipólito, L., Orrico, A., Zornoza, T., Polache, A., et al. (2010). Systemic administration of D-penicillamine prevents the locomotor activation after intra-VTA ethanol administration in rats. Neurosci. Lett. 483, 143–147. doi: 10.1016/j.neulet.2010.07.081
Matsuzawa, S., Suzuki, T., and Misawa, M. (2000). Involvement of mu-opioid receptor in the salsolinol-associated place preference in rats exposed to conditioned fear stress. Alcohol. Clin. Exp. Res. 24, 366–372. doi: 10.1111/j.1530-0277.2000.tb04624.x
Melis, M., Enrico, P., Peana, A. T., and Diana, M. (2007). Acetaldehyde mediates alcohol activation of the mesolimbic dopamine system. Eur. J. Neurosci. 26, 2824–33. doi: 10.1111/j.1460-9568.2007.05887.x
Middaugh, L. D., and Bandy, A. L. (2000). Naltrexone effects on ethanol consumption and response to ethanol conditioned cues in C57BL/6 mice. Psychopharmacology 151, 321–327. doi: 10.1007/s002130000479
Milton, G. W., Verhaert, P. D., and Downer, R. G. (1991). Immunofluorescent localization of dopamine-like and leucine-enkephalin-like neurons in the supraoesophageal ganglia of the american cockroach, periplaneta americana. Tissue Cell 23, 331–340. doi: 10.1016/0040-8166(91)90051-t
Miquel, M., Font, L., Sanchis-Segura, C., and Aragon, C. M. (2003). Neonatal administration of monosodium glutamate prevents the development of ethanol-but not psychostimulant-induced sensitization: a putative role of the arcuate nucleus. Eur. J. Neurosci. 17, 2163–2170. doi: 10.1046/j.1460-9568.2003.02646.x
Moreno, S., Mugnaini, E., and Cerù, M. P. (1995). Immunocytochemical localization of catalase in the central nervous system of the rat. J. Histochem. Cytochem. 43, 1253–1267. doi: 10.1177/43.12.8537642
Nielsen, C. K., Simms, J. A., Pierson, H. B., Li, R., Saini, S. K., Ananthan, S., et al. (2008). A novel delta opioid receptor antagonist, SoRI-9409, produces a selective and long-lasting decrease in ethanol consumption in heavy-drinking rats. Biol. Psychiatry 64, 974–981. doi: 10.1016/j.biopsych.2008.07.018
O’Malley, S. S., Jaffe, A. J., Chang, G., Schottenfeld, R. S., Meyer, R. E., and Rounsaville, B. (1992). Naltrexone and coping skills therapy for alcohol dependence. A controlled study. Arch. Gen. Psychiatry 49, 881–887. doi: 10.1001/archpsyc.1992.01820110045007
Orrico, A., Hipólito, L., Sánchez-Catalán, M. J., Martí-Prats, L., Zornoza, T., Granero, L., et al. (2013). Efficacy of D-penicillamine, a sequestering acetaldehyde agent, in the prevention of alcohol relapse-like drinking in rats. Psychopharmacology doi: 10.1007/s00213-013-3065-1. [Epub ahead of print]
Pastor, R., and Aragon, C. M. (2006). The role of opioid receptor subtypes in the development of behavioral sensitization to ethanol. Neuropsychopharmacology 31, 1489–1499. doi: 10.1038/sj.npp.1300928
Pastor, R., and Aragon, C. M. (2008). Ethanol injected into the hypothalamic arcuate nucleus induces behavioral stimulation in rats: an effect prevented by catalase inhibition and naltrexone. Behav. Pharmacol. 19, 698–705. doi: 10.1097/fbp.0b013e328315ecd7
Pastor, R., Font, L., Miquel, M., Phillips, T. J., and Aragon, C. M. (2011). Involvement of the beta-endorphin neurons of the hypothalamic arcuate nucleus in ethanol-induced place preference conditioning in mice. Alcohol. Clin. Exp. Res. 35, 2019–2029. doi: 10.1111/j.1530-0277.2011.01553.x
Pastor, R., Sanchis-Segura, C., and Aragon, C. M. (2002). Ethanol-stimulated behaviour in mice is modulated by brain catalase activity and H2O2 rate of production. Psychopharmacology 165, 51–59. doi: 10.1007/s00213-002-1241-9
Pastor, R., Sanchis-Segura, C., and Aragon, C. (2005). Effect of selective antagonism of mu(1)-, mu(1/2)-, mu(3)-, and delta-opioid receptors on the locomotor-stimulating actions of ethanol. Drug Alcohol Depend. 78, 289–295. doi: 10.1016/j.drugalcdep.2004.11.007
Pastorcic, M., Boyadjieva, N., and Sarkar, D. K. (1994). Comparison of the effects of alcohol and acetaldehyde on proopiomelanocortin mRNA levels and beta-endorphin secretion from hypothalamic neurons in primary cultures. Mol. Cell. Neurosci. 5, 580–586. doi: 10.1006/mcne.1994.1071
Pautassi, R. M., Nizhnikov, M. E., Acevedo, M. B., and Spear, N. E. (2012). Early role of the κ opioid receptor in ethanol-induced reinforcement. Physiol. Behav. 105, 1231–1241. doi: 10.1016/j.physbeh.2012.01.003
Pautassi, R. M., Nizhnikov, M. E., Fabio, M. C., and Spear, N. E. (2011). An acetaldehyde-sequestering agent inhibits appetitive reinforcement and behavioral stimulation induced by ethanol in preweanling rats. Pharmacol. Biochem. Behav. 97, 462–469. doi: 10.1016/j.pbb.2010.10.005
Peana, A. T., Assaretti, A. R., Muggironi, G., Enrico, P., and Diana, M. (2009). Reduction of ethanol-derived acetaldehyde induced motivational properties by L-cysteine. Alcohol. Clin. Exp. Res. 33, 43–48. doi: 10.1111/j.1530-0277.2008.00809.x
Peana, A. T., Enrico, P., Assaretti, A. R., Pulighe, E., Muggironi, G., Nieddu, M., et al. (2008). Key role of ethanol-derived acetaldehyde in the motivational properties induced by intragastric ethanol: a conditioned place preference study in the rat. Alcohol. Clin. Exp. Res. 32, 249–258. doi: 10.1111/j.1530-0277.2007.00574.x
Peana, A. T., Muriggironi, G., Fois, G. R., Zinellu, M., Sirca, D., and Diana, M. (2012). Effect of (L)-cysteine on acetaldehyde self-administration. Alcohol 46, 489–497. doi: 10.1016/j.alcohol.2011.10.004
Peana, A. T., Muggironi, G., Fois, G. R., Zinellu, M., Vinci, S., and Acquas, E. (2011). Effect of opioid receptor blockade on acetaldehyde self-administration and ERK phosphorylation in the rat nucleus accumbens. Alcohol 45, 773–783. doi: 10.1016/j.alcohol.2011.06.003
Peciña, S., and Berridge, K. C. (2005). Hedonic hot spot in nucleus accumbens shell: where do mu-opioids cause increased hedonic impact of sweetness?. J. Neurosci. 25, 11777–11786. doi: 10.1523/jneurosci.2329-05.2005
Quertemont, E., Tambour, S., and Tirelli, E. (2005). The role of acetaldehyde in the neurobehavioral effects of ethanol: a comprehensive review of animal studies. Prog. Neurobiol. 75, 247–274. doi: 10.1016/j.pneurobio.2005.03.003
Rao, R. E., Wojnicki, F. H., Coupland, J., Ghosh, S., and Corwin, R. L. (2008). Baclofen, raclopride, and naltrexone differentially reduce solid fat emulsion intake under limited access conditions. Pharmacol. Biochem. Behav. 89, 581–590. doi: 10.1016/j.pbb.2008.02.013
Rasmussen, D. D., Boldt, B. M., Wilkinson, C. W., and Mitton, D. R. (2002). Chronic daily ethanol and withdrawal: 3. Forebrain pro-opiomelanocortin gene expression and implications for dependence, relapse, and deprivation effect. Alcohol. Clin. Exp. Res. 26, 535–546. doi: 10.1111/j.1530-0277.2002.tb02572.x
Rasmussen, D. D., Bryant, C. A., Boldt, B. M., Colasurdo, E. A., Levin, N., and Wilkinson, C. W. (1998). Acute alcohol effects on opiomelanocortinergic regulation. Alcohol. Clin. Exp. Res. 22, 789–801. doi: 10.1111/j.1530-0277.1998.tb03870.x
Reddy, B. V., and Sarkar, D. K. (1993). Effect of alcohol, acetaldehyde, and salsolinol on beta-endorphin secretion from the hypothalamic neurons in primary cultures. Alcohol. Clin. Exp. Res. 17, 1261–1267. doi: 10.1111/j.1530-0277.1993.tb05239.x
Reddy, B. V., Boyadjieva, N., and Sarkar, D. K. (1995). Effect of ethanol, propanol, butanol, and catalase enzyme blockers on beta-endorphin secretion from primary cultures of hypothalamic neurons: evidence for a mediatory role of acetaldehyde in ethanol stimulation of beta-endorphin release. Alcohol. Clin. Exp. Res. 19, 339–344. doi: 10.1111/j.1530-0277.1995.tb01512.x
Risinger, F. O., Dickinson, S. D., and Cunningham, C. L. (1992) Haloperidol reduces ethanol-induced motor activity stimulation but not conditioned place preference. Psychopharmacology 107, 453–456. doi: 10.1007/bf02245175
Roberts, A. J., McDonald, J. S., Heyser, C. J., Kieffer, B. L., Matthes, H. W., Koob, G. F., et al. (2000). Mu-Opioid receptor knockout mice do not self-administer alcohol. J. Pharmacol. Exp. Ther. 293, 1002–1008.
Rodd, Z., Bell, R. L., Zhang, Y., Murphy, J. M., Goldstein, A., Zaffaroni, A., et al. (2005). Regional heterogeneity for the intracranial self-administration of ethanol and acetaldehyde within the ventral tegmental area of alcohol-preferring (P) rats: involvement of dopamine and serotonin. Neuropsychopharmacology 30, 330–338. doi: 10.1038/sj.npp.1300561
Rodd-Henricks, Z. A., Melendez, R. I, Zaffaroni, A., Goldstein, A., McBride, W. J., and Lu, T. K. (2002). The reinforcing effects of acetaldehyde in the posterior ventral tegmental area of alcohol-preferring rats. Pharmacol. Biochem. Behav. 72, 55–64. doi: 10.1016/s0091-3057(01)00733-x
Sánchez-Catalán, M. J., Hipólito, L., Zornoza, T., Polache, A., and Granero, L. (2009). Motor stimulant effects of ethanol and acetaldehyde injected into the posterior ventral tegmental area of rats: role of opioid receptors. Psychopharmacology 204, 641–653. doi: 10.1007/s00213-009-1495-6
Sanchis-Segura, C., Correa, M., and Aragon, C. M. (2000). Lession on the hypothalamic arcuate nucleus by estradiol valerate results in a blockade of ethanol-induced locomotion. Behav. Brain Res. 114, 57–63. doi: 10.1016/s0166-4328(00)00183-2
Sanchis-Segura, C., Correa, M., Miquel, M., and Aragon, C. M. (2005b). Catalase inhibition in the arcuate nucleus blocks ethanol effects on the locomotor activity of rats. Neurosci. Lett. 376, 66–70. doi: 10.1016/j.neulet.2004.11.025
Sanchis-Segura, C., Grisel, J. E., Olive, M. F., Ghozland, S., Koob, G. F., Roberts, A. J., et al. (2005a). Role of the endogenous opioid system on the neuropsychopharmacological effects of ethanol: new insights about an old question. Alcohol. Clin. Exp. Res. 29, 1522–1527. doi: 10.1097/01.alc.0000174913.60384.e8
Sanchis-Segura, C., Miquel, M., Correa, M., and Aragon, C. M. (1999a). Daily injections of cyanamide enhance both ethanol-induced locomotion and brain catalase activity. Behav. Pharmacol. 10, 459–465. doi: 10.1097/00008877-199909000-00004
Sanchis-Segura, C., Miquel, M., Correa, M., and Aragon, C. M. (1999b). The catalase inhibitor sodium azide reduces ethanol-induced locomotor activity. Alcohol 19, 37–42. doi: 10.1016/s0741-8329(99)00016-6
Sanchis-Segura, C., Miquel, M., Correa, M., and Aragon, C. M. (1999c). Cyanamide reduces brain catalase and ethanol-induced locomotor activity: is there a functional link? Psychopharmacology 144, 83–89. doi: 10.1007/s002130050980
Sanchis-Segura, C., Pastor, R., and Aragon, C. M. (2004). Opposite effects of acute versus chronic naltrexone administration on ethanol-induced locomotion. Behav. Brain Res. 153, 61–67. doi: 10.1016/j.bbr.2003.11.003
Seizinger, B. R., Bovermann, K., Maysinger, D., Höllt, V., and Herz, A. (1983). Differential effects of acute and chronic ethanol treatment on particular opioid peptide systems in discrete regions of rat brain and pituitary. Pharmacol. Biochem. Behav. 18(Suppl. 1), 361–369. doi: 10.1016/0091-3057(83)90200-9
Seizinger, B. R., Höllt, V., and Herz, A. (1984). Effects of chronic ethanol treatment on the in vitro biosynthesis of pro-opiomelanocortin and its posttranslational processing to beta-endorphin in the intermediate lobe of the rat pituitary. J. Neurochem. 43, 607–613. doi: 10.1111/j.1471-4159.1984.tb12778.x
Simms, J. A., Steensland, P., Medina, B., Abernathy, K. E., Chandler, L. J., Wise, R., et al. (2008). Intermittent access to 20% ethanol induces high ethanol consumption in Long-Evans and Wistar rats. Alcohol. Clin. Exp. Res. 32, 1816–1823. doi: 10.1111/j.1530-0277.2008.00753.x
Sirca, D., Enrico, P., Mereu, M., Peana, A. T., and Diana, M. (2011). L-cysteine prevents ethanol-induced stimulation of mesolimbic dopamine transmission. Alcohol. Clin. Exp. Res. 35, 862–869. doi: 10.1111/j.1530-0277.2010.01416.x
Smith, B. R., Aragon, C. M. G., and Amit, Z. (1997). Catalase and the production of central acetaldehyde: a possible mediator of the psychopharmacological effects of ethanol. Addict. Biol. 2, 277–289. doi: 10.1080/13556219772570
Spanagel, R., Herz, A., and Shippenberg, T. S. (1992). Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway. Proc. Natl. Acad. Sci. U S A 89, 2046–2050. doi: 10.1073/pnas.89.6.2046
Spina, L., Longoni, R., Vinci, S., Ibba, F., Peana, A. T., Muggironi, G., et al. (2010). Role of dopamine D1 receptors and extracellular signal regulated kinase in the motivational properties of acetaldehyde as assessed by place preference conditioning. Alcohol. Clin. Exp. Res. 34, 607–616. doi: 10.1111/j.1530-0277.2009.01129.x
Stinus, L., Koob, G. F., Ling, N., Bloom, F. E., and Le Moal, M. (1980). Locomotor activation induced by infusion of endorphins into the ventral tegmental area: evidence for opiate-dopamine interactions. Proc. Natl. Acad. Sci. U S A 77, 2323–2327. doi: 10.1073/pnas.77.4.2323
Tarragón, E., Baliño, P., Aragon, C. M., and Pastor, R. (2012). Ethanol drinking-in-the-dark facilitates behavioral sensitization to ethanol in C57BL/6J, BALB/cByJ, but not in mu-opioid receptor deficient CXBK mice. Pharmacol. Biochem. Behav. 101, 14–23. doi: 10.1016/j.pbb.2011.11.014
Trigo, J. M., Martin-García, E., Berrendero, F., Robledo, P., and Maldonado, R. (2010). The endogenous opioid system: a common substrate in drug addiction. Drug Alcohol Depend. 108, 183–194. doi: 10.1016/j.drugalcdep.2009.10.011
Unterwald, E. M., Anton, B., To, T., Lam, H., and Evans, C. J. (1998). Quantitative immunolocalization of mu opioid receptors: regulation by naltrexone. Neuroscience 85, 897–905. doi: 10.1016/s0306-4522(97)00659-3
Vinci, S., Ibba, F., Longoni, R., Spina, L., Spiga, S., and Acquas, E. (2010). Acetaldehyde elicits ERK phosphorylation in the rat nucleus accumbens and extended amygdala. Synapse 64, 916–927. doi: 10.1002/syn.20811
Walker, B. M., Valdez, G. R., McLaughlin, J. P., and Bakalkin, G. (2012). Targeting dynorphin/kappa opioid receptor systems to treat alcohol abuse and dependence. Alcohol 46, 359–370. doi: 10.1016/j.alcohol.2011.10.006
Wand, G. S. (1990). Differential regulation of anterior pituitary corticotrope function is observed in vivo but not in vitro in two lines of ethanol-sensitive mice. Alcohol. Clin. Exp. Res. 14, 100–106. doi: 10.1111/j.1530-0277.1990.tb00454.x
Wong, K. J., Wojnicki, F. H., and Corwin, R. L. (2009). Baclofen, raclopride, and naltrexone differentially affect intake of fat/sucrose mixtures under limited access conditions. Pharmacol. Biochem. Behav. 92, 528–536. doi: 10.1016/j.pbb.2009.02.002
Xie, G., Hipólito, L., Zuo, W., Polache, A., Granero, L., Krnjevic, K., et al. (2012). Salsolinol stimulates dopamine neurons in slices of posterior ventral tegmental area indirectly by activating-opioid receptors. J. Pharmacol. Exp. Ther. 341, 43–50. doi: 10.1124/jpet.111.186833
Young, E. A., Dreumont, S. E., and Cunningham, C. L. (2013). Role of nucleus accumbens dopamine receptor subtypes in the learning and expression of alcohol-seeking behavior. Neurobiol. Learn. Mem. doi: 10.1016/j.nlm.2013.05.004. [Epub ahead of print]
Zimatkin, S. M., and Lindros, K. O. (1996). Distribution of catalase in rat brain: aminergic neurons as possible targets for ethanol effects. Alcohol Alcohol. 31, 167–174. doi: 10.1093/oxfordjournals.alcalc.a008128
Zimatkin, S. M., Rout, U. K., Koivusalo, M., Bühler, R., and Lindros, K. O. (1992). Regional distribution of low-Km mitochondrial aldehyde dehydrogenase in the rat central nervous system. Alcohol. Clin. Exp. Res. 16, 1162–1167. doi: 10.1111/j.1530-0277.1992.tb00713.x
Keywords: ethanol, acetaldehyde, endogenous opioid system, salsolinol, behavior, animal
Citation: Font L, Luján MÁ and Pastor R (2013) Involvement of the endogenous opioid system in the psychopharmacological actions of ethanol: the role of acetaldehyde. Front. Behav. Neurosci. 7:93. doi:10.3389/fnbeh.2013.00093
Received: 03 May 2013; Accepted: 10 July 2013;
Published online: 31 July 2013.
Edited by:Merce Correa, University Jaume I, Spain
Reviewed by:Elio Acquas, University of Cagliari, Italy
María J. Sánchez-Catalán, Centre National de Recherche Scientifique (CNRS), Institute of Cellular and Integrative Neurosciences (INCI) UPR3212, France
Copyright © 2013 Font, Luján and Pastor. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Laura Font, Area de Psicobiología, Universitat Jaume I, Avda. Sos Baynat s/n, 12071, Castellón, Spain e-mail: firstname.lastname@example.org