1 Division of Analytical Psychopharmacology, New York State Psychiatric Institute, New York, NY, USA 2 Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA and 3 Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA
* Author to whom correspondence should be addressed at: Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA. Tel: +1 845 398 5452/5454; Fax: +1 845 398 5451; E-mail: hungund{at}nki.rfmh.org or basavaraj{at}nki.rfmh.org
(Received 21 July 2004; first review notified 30 July 2004; in revised form 18 September 2004; accepted 1 October 2004)
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ABSTRACT |
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INTRODUCTION |
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The endocannabinoid system comprises cannabinoid receptors, endogenous cannabinoids and the molecules involved in the inactivation of endocannabinoids (uptake and degradation enzyme known as fatty acid amide hydrolase, FAAH). Cannabinoid receptors belong to the large family of seven transmembrane-spanning (7TM) G-protein-coupled receptors (GPCRs). As a class, GPCRs are of fundamental physiological importance, mediating the actions of most known neurotransmitters and hormones. Cannabinoid receptors are intriguing members of this receptor family. There are two types of cannabinoid receptors, CB1 and CB2, defined by their unique localization. The CB1 receptor is widely distributed in several regions of the brain (Herkenham et al., 1990), with a high density in the cortex, hippocampus, basal ganglia and cerebellum. Both CB1 and CB2 receptors have been characterized and cloned (Howlett et al., 2002
). The functional response of the CB1 and CB2 receptors is coupled via Gi/Go proteins, negatively to adenylate cyclase and N- and P/Q-type Ca2+ channels. They are positively coupled to A-type and inwardly rectifying K+ channels and mitogen-activated protein kinases (Basavarajappa and Hungund, 2002
; Howlett et al., 2002
).
In 1992, Devane et al. showed the existence of an endogenous cannabimimetic substance in the mammalian brain, found to bind the CB1 receptor; and it was characterized to be arachidonylethanolamide (anandamide, AEA). Since then, three other endocannabinoids such as 2-arachidonylglycerol (2-AG) (Devane et al., 1992; Mechoulam et al., 1995
; Sugiura et al., 1995
), 2-arachidonylglycerol ether (noladin ether) and virodhamine (Porter et al., 2002
) have been identified.
Unlike classical neurotransmitters and neuropeptides, AEA and 2-AG are not stored in intracellular compartments but are produced on demand by receptor-stimulated cleavage of lipid precursors (Di Marzo et al., 1994; Cadas et al., 1997
; Mechoulam et al., 1998
; Basavarajappa and Hungund, 1999a
; Basavarajappa et al., 2000
, 2003
) and released from neurons immediately afterwards (Di Marzo et al., 1994
; Mechoulam et al., 1998
; Basavarajappa and Hungund, 1999a
; Giuffrida et al., 1999
; Basavarajappa et al., 2000
, 2003
). The AEA precursor is an N-arachidonylphosphatidylethanolamine (N-ArPE), which is believed to originate from the transfer of arachidonic acid (AA) from the sn-1 position of 1,2-sn-di-arachidonylphosphatidylcholine to phosphatidylethanolamine, catalysed by a calcium-dependent transacylase (CDTA). N-ArPE is then cleaved by an N-acylphosphatidylethanolamine (NAPE)-specific phospholiapse D (PLD) (Natarajan et al., 1981
; Schmid et al., 1983
; Di Marzo et al., 1994
), which releases AEA and phosphatidic acid. The biosynthesis of 2-AG has been shown to occur by two possible routes in neurons. Phospholipase C (PLC)-mediated hydrolysis of membrane phospholipids produces diacylglycerol (DAG), which may be converted subsequently to 2-AG by diacylglycerol lipase (DGL) activity. Alternatively, phospholipase A1 (PLA1) may generate a lysophospholipid, which may be hydrolyzed to 2-AG by lyso-PLC activity. AEA and 2-AG are inactivated by the reuptake by a membrane transport molecule, the AEA membrane transporter (AMT) (Beltramo et al., 1997
; Hillard et al., 1997
; Maccarrone et al., 1998
; Beltramo and Piomelli, 2000
; Hillard and Jarrahian, 2000
; Giuffrida et al., 2001
; Basavarajappa et al., 2003
) and by intracellular enzymatic degradation (Di Marzo et al., 1994
; Day et al., 2001
; Deutsch et al., 2001
) through FAAH-mediated hydrolysis (Cravatt et al., 1996
; Beltramo and Piomelli, 2000
; Ueda et al., 2000
; Bisogno et al., 2001
; Deutsch et al., 2001
; Fowler et al., 2001
). The metabolism, pharmacology and physiology of AEA and 2-AG has been covered elsewhere in this issue in detail (Rodríguez de Fonseca et al., 2004
).
Alcohol and endocannabinoids
In the brain, the presence of the endocannabinoid signalling system in the thalamus, hippocampus and cortex or in the striatum, substantia nigra and cerebellum supports a role for the endogenous cannabinoid-signalling system in cognitive and motor responses. The anatomical distribution and actions of endocannabinoids is consistent with the behavioural effects of alcohol, including memory disruption, decrease in motor activity, catalepsy, antinociception and hypothermia (Ryan and Butters, 1980; Brandt et al., 1983
; Gebhardt et al., 1984
; Herkenham et al., 1991b
; Compton et al., 1993
; Fadda and Rossetti, 1998
). Adaptation in several steps of the endocannabinoid system in the brain may play an important role in the development of tolerance to and dependence on alcohol (Basavarajappa et al., 1998a
; Basavarajappa and Hungund, 1999a
,b; Hungund and Basavarajappa, 2000a
,c
).
In the last seven years, several studies, including those from our laboratory, provided evidence for the participation of the endocannabinoid system in the pharmacological actions of alcohol and in alcohol-drinking behaviour. In our earlier studies, we demonstrated that chronic alcohol exposure leads to the activation of Ca2+-dependent and the arachidonic acid-specific phospholipase A2 (PLA2), a key enzyme involved in the formation of endocannabinoids in neuronal cells and the brain (Basavarajappa et al., 1997, 1998b
). Later, we extended these studies to examine the chronic effect of alcohol on the endocannabinoids in an in vitro system. Indeed, it was found that the exposure of SK-N-SH cells or cerebellar granular neurons (CGNs) to chronic alcohol resulted in the increased accumulation of AEA (Basavarajappa and Hungund, 1999a
; Basavarajappa et al., 2003
) and 2-AG (Table 1; Basavarajappa et al., 2000
). In these studies, we demonstrated that the synthesis of AEA and 2-AG increased with increasing duration of alcohol exposure, peaking at 72 h with 100 mM alcohol, the experimental condition known to cause cellular tolerance and dependence to alcohol in neurons. These adaptive changes were further increased by the Ca2+-ionophore or ionomycin and inhibited by pertussis toxin (which selectively inactivates G-protein) and the CB1 receptor antagonist SR 141716A, which is also shown to inhibit alcohol drinking in rodents (Arnone et al., 1997
; Colombo et al., 1998
; Gallate and McGregor, 1999
; Rodríguez de Fonseca et al., 1999
; Freedland et al., 2001
). In a related study, SwissWebster male mice were made alcohol tolerant by inhalation of alcohol vapours for 72 h (Goldstein, 1972
) and the lipids were extracted from the brains of the decapitated mice. The AEA fraction was purified chromatographically. Characterization and quantification were achieved by the gas chromatographic-mass spectral (GC-MS) method using the chemical ionization-single ion monitoring technique (CI-SIM). These results showed that chronic alcohol exposure led to a significant increase in the levels of AEA in the brain and a significant decrease in N-ArPE, an immediate precursor to AEA synthesis, compared with the levels in control brains (Hungund et al., 2002
). A recent study also demonstrated that chronic alcohol exposure in rats caused a decrease in the content of both AEA and 2-AG in the midbrain, whereas AEA content increased in the limbic forebrain, a key area for the reinforcing properties of habit-forming drugs, including alcohol (Gonzalez et al., 2002b
). Although the levels of endocannabinoids are lower in normal tissues, their levels were found to increase significantly during movement disorders, cell injury and tissue degeneration, and during the postmortem period (Schmid et al., 1995
; Felder et al., 1996
; Kempe et al., 1996
). Selective increase in the formation of AEA in the limbic forebrain has also been observed in
9-THC-tolerant rats (Di Marzo et al., 2000b
) and in mouse neuroblastoma cells treated with
9-THC (Hunter and Burstein, 1997
). These observations point to the possible involvement of the endocannabinoids in the alcohol-induced neuroadaptive changes in these cells. These observations suggest the possible involvement of the endocannabinoids in the alcohol-induced neuroadaptive changes in the brain, and that change in endocannabinoid-mediated neurotransmission may be responsible for the activation of the reward system by alcohol.
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AEA signalling at the cannabinoid CB1 receptors is terminated by an uptake mechanism that transports AEA into the cell, where it subsequently undergoes rapid degradation by FAAH (Cravatt et al., 1996; Beltramo et al., 1997
; Hillard et al., 1997
; Piomelli et al., 1999
). Based on the available data, it is suggested that AEA uptake is a carrier-mediated process that is time- and temperature-dependent and saturable, and is inhibited by unique pharmacologic agents (Di Marzo et al., 1994
; Beltramo et al., 1997
; Hillard et al., 1997
; Hillard and Jarrahian, 2000
; Rakhshan et al., 2000
). Co-localization of both FAAH and CB1 receptors in the brain may point to a possible role of FAAH in AEA signalling and uptake (Egertova et al., 1998
). Thus, chronic alcohol-induced increases in extracellular AEA could result in a decrease in AEA influx, an increase in AEA efflux from the cell, and/or altered intracellular metabolism (Basavarajappa et al., 2003
). In our recent study, we investigated the chronic and acute effects of alcohol on AEA transport in CGNs (Basavarajappa et al., 2003
). We found that chronic exposure to alcohol leads to an increase in extracellular AEA by inhibiting the uptake of AEA. This effect was independent of the CB1 receptor since CB1 receptor knockout mice have normal uptake activity (Basavarajappa et al., 2003
). After prolonged exposure to alcohol, cells become tolerant to the effects such that AEA uptake is no longer inhibited by acute alcohol (Fig. 1; Basavarajappa et al., 2003
). Chronic exposure to alcohol did not show any direct inhibition of FAAH activity in these neurons. These data suggest that alcohol-induced inhibition of AEA uptake may, in part, be responsible for the alcohol-induced increase in extracellular AEA.
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Chronic drug treatment has been shown to change the levels of G-protein and G-protein activity for various G-protein-coupled receptor systems (Suzdak et al., 1986; Werling et al., 1988
; Wand et al., 1993
; Williams et al., 1993
; Tabakoff et al., 1995
; Traynor and Nahorski, 1995
). Various in vitro and in vivo studies have suggested that chronic alcohol treatment leads to reduced sensitivity of adenylate cyclase (Gordon et al., 1986
; Charness et al., 1988
). A variety of agonists acting at various receptors coupled through Gs to adenylate cyclase have been shown to be reduced by alcohol (Rabin, 1990
). Such a modification was suggested to alter the ability of the enzymes to interact with G-proteins and G-protein-coupled receptors (Tabakoff et al., 1995
). Regulation of either the G-protein or the G-protein mRNA level by chronic alcohol is also a possibility. Decrease in adenylate cyclase activity (Deitrich et al., 1989
; Tabakoff et al., 1995
) and a several fold increase in the Gi levels, but no changes in Gs
, have been reported in brains of mice treated with chronic alcohol (Wand et al., 1993
). Further studies downstream of the CB1 receptor will be of greater significance in understanding the mechanism involved in the development of tolerance to alcohol.
Dopamine, the CB1 receptor antagonist and voluntary alcohol consumption
There is strong evidence that the dopaminergic system that projects from the ventral tegmental area (VTA) of the midbrain to the nucleus accumbens (NAc) and to other forebrain sites including the dorsal striatum, is the major substrate of reward and reinforcement produced by most drugs of abuse including alcohol (Wise and Bozarth, 1987; Di Chiara and Imperato, 1988
; Robbins and Everitt, 1996
; Wise, 1996
; Koob et al., 1998
; Koob and Roberts, 1999
; Koob and Le Moal, 2001
). It is well established that cannabinoids activate dopaminergic neurons in the VTA (Wise and Bozarth, 1987
; Di Chiara and Imperato, 1988
; Robbins and Everitt, 1996
; Wise, 1996
; Tanda et al., 1997
; Gessa et al., 1998
), resulting in the release of dopamine in the NAc (Szabo et al., 1999
). Activation of D2 receptors evokes AEA release in the striatum (Giuffrida and Piomelli, 2000
). The regulation of dopamine function by cannabinoids is further supported by several biochemical and behavioural studies. In vivo experiments suggest that chronic treatment with D2-receptor antagonists upregulates the CB1 receptor expression in the rat striatum (Mailleux and Vanderhaeghen, 1993
). Furthermore, a D2 receptor antagonist has been shown to attenuate the alcohol-induced formation of 2-AG in CGNs (Basavarajappa et al., 2000
). In addition, the hyperactivity associated with the postsynaptic D2 receptor activation is accompanied by a dramatic increase in AEA output within the striatum and this effect is potentiated by the CB1 receptor antagonist SR 141716A (Giuffrida et al., 1999
). Our recent results provide unequivocal evidence that the acute alcohol-induced dopamine release in NAc is mediated by CB1 receptors (Hungund et al., 2003
). The acute alcohol-induced increase in dopamine in NAc dialysates in C57BL/6 mice was completely inhibited by pretreatment with the SR 141716A or deletion of the CB1 receptors in mice (CB1 receptor knockout) (Fig. 2; Hungund et al., 2003
). Further, SR 141716A blocked alcohol-evoked dopamine release in the shell of the NAc following alcohol administration (Cohen et al., 2002
). It should be noted that CB1 receptors are not localized in dopamine cell bodies or in their nerve terminals (Herkenham et al., 1991a
; Mailleux and Vanderhaeghen, 1992
). It is therefore unlikely that the observed block of alcohol-induced dopamine release by SR 141716A may involve afferent pathways to the VTA. This action may also explain the reducing effects of SR 141716A on alcohol self-administration by indirectly blocking the activation of the mesolimbic dopaminergic transmission (Cohen et al., 2002
).
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The adaptive changes noted in the endocannabinoid system after chronic alcohol treatment may be important for the development of alcohol-seeking behaviour and further research is required to establish this phenomenon. The available evidence for the participation of the cannabinoidergic system in alcohol drinking behaviour is derived from the observed differences in CB1 receptor function in two genetic strains of alcohol-preferring C57BL/6 and alcohol-avoiding DBA/2 mice. In this study, we found that C57BL/6 mice have a significantly lower level of CB1 receptor binding sites and higher affinity for [3H]CP-55,940 than DBA/2 mice (Hungund and Basavarajappa, 2000b). Interestingly, the significantly higher levels of CB1 receptors found in DBA/2 mice are less coupled to G-proteins as shown by GTP
S binding assay compared with C57BL/6 mouse strains (Table 3; Basavarajappa and Hungund, 2001
), suggesting the participation of these receptors in controlling voluntary alcohol consumption. Thus, genetically determined differences in the activities of distinct components of the endogenous cannabinoidergic system under basal conditions or in response to alcohol exposure may exist between alcohol-preferring and alcohol-avoiding animals and may be partially responsible for the differences in their voluntary alcohol intake. This hypothesis was further examined using genetically modified CB1 receptor knockout mice. Genetics and CB1 receptor aspects of alcoholism are covered elsewhere in this special issue (Lallemand and De Witte, 2004
).
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CONCLUSION |
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ACKNOWLEDGEMENTS |
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