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Regulation of alcohol-seeking by orexin (hypocretin) neurons
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Review
Regulation of alcohol-seeking by orexin (hypocretin) neurons Andrew J. Lawrence Howard Florey Institute and Centre for Neuroscience, University of Melbourne, Royal Parade, Parkville, Victoria 3010, Australia
A R T I C LE I N FO
AB S T R A C T
Article history:
Orexins (hypocretins) are found primarily within a restricted portion of neurons within the
Accepted 22 July 2009
hypothalamus, but provide innervation across the neuraxis. Orexin A (hypocretin 1) has
Available online 29 July 2009
been implicated in drug and food reward. Not surprisingly therefore, interest has come to bear on whether orexins are implicated in aspects of alcohol consumption and/or seeking.
Keywords:
This mini-review provides a concise, but timely, discussion on this issue. The evidence to
Orexin
date would suggest a role for orexins in alcohol use, and integration of orexin-containing
Alcohol
neurons in reward-seeking circuitry. There are however still many unanswered questions,
Relapse
some of which are canvassed herein.
Lateral hypothalamus
© 2009 Elsevier B.V. All rights reserved.
Contents
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
In 2007 over 14.2 million Australians aged >14 years old consumed alcohol in the previous 12 months (NDSHS, 2007). Alcohol-related health issues are the second most preventable cause of death and hospitalisation in Australia following those from tobacco use (Loxley et al., 2005). Notwithstanding these somewhat sobering statistics, the above figures do not take into account the social cost of alcohol-related harm, in Australia this has recently been estimated as ∼ $15.3 billion (Collins and Lapsley, 2008). Add to these the emotional costs of alcoholism upon the afflicted and their families, and we see a problem of dramatic proportions, one that is difficult to overestimate and that overshadows the problems caused by illicit drugs. How can we make inroads into this issue that faces many developed countries? Clearly, strategies of public education in relation to safe levels of consumption, resisting peer pressure
and other similar issues have a place. Nevertheless, despite the most robust policies, there will be a proportion of people who experience alcohol use disorders of some form. Accordingly, there is an ongoing need to develop safe, effective and reliable medications as part of a battery of approaches to curb excessive/harmful alcohol consumption and assist in relapseprevention. The latter issue is pertinent to all addictions and highlights the nature of the disorder, plus the fact that even the best therapeutic options currently available are far from ideal. Indeed, addiction has been described as a chronic, relapsing disorder accompanied by cravings, a psychological state of desire for the drug which may cause individuals to return to using the drug many times throughout their lives (Grimm et al., 2001). The most informed way to develop new pharmacotherapeutics is from a detailed understanding of the circuitry, and its underlying chemistry, responsible for the
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aberrant behaviour patterns. This will then facilitate a study of potential neural adaptation following chronic drug use and/or during protracted withdrawal that may relate to persistent relapse propensity. Early animal studies of self-stimulation in different brain regions implicated the lateral hypothalamus as an area where rodents would willingly perform an instrumental task to receive a positively reinforcing electrical stimulus (Olds, 1956; Olds and Milner, 1954). Indeed, subsequent studies indicated that following an ibotenic acid lesion of the middle part of the lateral hypothalamus (LH), rats showed diminished electrical self-stimulation within the anterior medial forebrain bundle, with a variable effect in more posterior placements (Lestang et al., 1985). The authors concluded that self-stimulation of the anterior aspect of the medial forebrain bundle was influenced by projections from the mid-LH. Another study showed that mice would reliably self-administer morphine directly into the lateral hypothalamus (Cazala et al., 1987), an effect that was sensitive to systemic naloxone indicating an opioid receptor-mediated behaviour. Consequently, a place for the lateral hypothalamus in drug reward-related circuitry was suggested. This assertion was extended following collision test experiments, where rats could self-stimulate in the LH, ventral tegmental area (VTA) or both, which indicated that the fibres implicated in supporting selfstimulation behaviour directly linked the LH with the VTA (Shizgal, 1989). Accordingly, self-stimulation of the lateral hypothalamus (LH) increased dopamine and glutamate levels in the VTA of freely-moving rats (You et al., 2001). Moreover, reversible (bilateral) inactivation of the LH indicates a critical role for the LH in context-induced reinstatement of rewardseeking (Marchant et al., 2009). Therefore, while over the past 50 years the LH has become cemented within the continually evolving circuitry of reward, the chemical content of those LH neurons remained uncertain. Moreover, given the expression of multiple transmitters in individual neurons, the identity of reward-related neurochemicals has been a source of much research focus. Orexin (hypocretin)-containing neurons appear to be largely confined to this area of the hypothalamus. Thus, orexin-containing neurons can be found in the LH, perifornical region and dorsomedial hypothalamus; however, these cells provide a widespread innervation of the neuraxis with orexinergic fibres (De Lecea et al., 1998; Peyron et al., 1998). Cloning studies have indicated the presence of two main orexin peptides, namely orexins A and B (hypocretins 1 and 2), plus two main orexin receptors, namely orexin1 and orexin2 receptors (Sakurai et al., 1998). Of interest, orexin A (hypocretin 1) has to date only been demonstrated to occur within neuronal cell bodies of the hypothalamus; however, orexin B (hypocretin 2) has also been identified within cells in extrahypothalamic structures including the central amygdala and sub-regions of the bed nucleus of the stria terminalis (Ciriello et al., 2003; Siegel, 2004). Given the widespread projections of hypothalamic orexin-containing neurons, orexin1 and orexin2 receptor mRNA and protein are distributed throughout the nervous system (Hervieu et al., 2001; Cluderay et al., 2002). Importantly, in the context of the early studies discussed above, a direct innervation of VTA cells by orexin A-containing neurons of the LH and medial perifornical area has been demonstrated (Fadel
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and Deutch, 2002). More recent experiments have confirmed and extended these observations, with LH orexin neurons implicated in cocaine-induced plasticity at excitatory synapses onto VTA dopaminergic cells (Borgland et al., 2006). While initially implicated in the regulation of feeding (Sakurai et al., 1998), orexins also appear critically involved in vigilance, arousal and regulation of sleep–wake cycles (Chemelli et al., 1999; Hara et al., 2001; Lin et al., 1999; Adamantidis et al., 2007). The notion that orexin-containing neurons of the LH may have relevance for drug-seeking was first suggested based upon the observations that these neurons innervated structures implicated in responses to drugs of abuse and states of arousal (DiLeone et al., 2003; Winsky-Sommerer et al., 2003; Georgescu et al., 2003), indicating that these neurons may represent those identified through self-stimulation experiments. Indeed, orexins were (along with other hypothalamic peptides) implicated in the activation of reward pathways and concomitant dampening of satiety signals thought to contribute towards over-eating induced obesity (Erlanson-Albertsson, 2005). In support of this, infusions of orexin A into the anterior LH enhanced selfadministration of palatable food (Thorpe et al., 2005). In this regard, polymorphisms in the MTMR9 gene are associated with obesity, and MTMR9 (myotublarin related protein 9) colocalises to orexinergic cells of the LH where its expression is regulated by diet (Yanagiya et al., 2007). It is now becoming clear that addiction and obesity may share some commonality of neurocircuitry (Volkow et al., 2008). Two landmark studies provided the vital findings that clearly implicated orexins in reward, drug-seeking and relapse. The first study showed that orexin-containing neurons in the LH (but not perifornical or dorsomedial hypothalamus) were strongly activated in rats that exhibited a place preference following conditioning with either morphine, food or cocaine (Harris et al., 2005). In addition, activation of LH orexin cells was sufficient to reinstate an extinguished place preference for opiates that could be prevented by pre-treatment with the orexin1 receptor antagonist SB-334867. Similarly, microinjection of orexin A into the VTA also elicited a reinstatement of opiate-seeking using the place preference paradigm. The second study showed that intracerebroventricular (icv) infusions of orexin A (hypocretin 1) reinstated cocaine-seeking and food-seeking under operant conditions (Boutrel et al., 2005). In addition, icv infusions of orexin A elevated reward thresholds, while orexin A-induced reinstatement of cocaine-seeking was attenuated by clonidine (an α2-adrenoceptor agonist) and a non-selective CRF receptor antagonist, suggesting a link between the orexin system and brain stress pathways in relation to drug-seeking. Consistent with this, footshock-induced reinstatement of cocaine-seeking was prevented with SB-334867. Thus, taken together, these studies provided evidence for a role of orexin-containing neurons in drug reward-related behaviour, consistent with their activation during foraging for natural rewards (Mileykovskiy et al., 2005). In addition, they also indicated the potential for overlap between orexinergic neurons and stress systems, a subject that will be revisited below. Interestingly, the study by Harris et al. (2005) presented evidence for the possibility of functional heterogeneity within orexinergic neurons, since within their Pavlovian conditioning
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paradigm, only the LH orexin-containing cells were activated. Such heterogeneity was also proposed in the first publication relating orexin systems with alcohol use. Thus, the expression of the mRNA encoding prepro-orexin was not different between alcohol-preferring and non-preferring rats, suggesting that, in the absence of any alteration to post-translational processing, the basal orexin systems are similar between these rat strains and seemingly therefore likely not implicated in contributing to the alcohol-preferring nature of iP rats. Chronic consumption of ethanol for 10 weeks also had no significant impact upon the density of prepro-orexin mRNA expression in the hypothalamus of preferring rats; however, the area of mRNA expression was increased compared to NP and alcohol naïve iP rats. Notably, this effect was only apparent in the LH and not in medial orexinergic regions. These data therefore suggest that chronic voluntary consumption of alcohol by preferring rats apparently increases the number of neurons that densely express orexin mRNA within the LH. It would therefore appear that while chronic ethanol consumption does not apparently activate cells that already express high basal levels of orexin, those that under basal conditions express undetectable levels of orexin seem to be recruited to produce increased amounts of orexin (Lawrence et al., 2006). The potential for heterogeneity within the orexin neurons was further highlighted using the ABA renewal paradigm of context-driven relapse to reward-seeking. This paradigm differs from the standard extinction-reinstatement model in that reward-seeking is extinguished in a different context/ environment compared to that for self-administration. Thus, self-administration sessions occur in context “A”; extinction training in context “B”: drug-seeking can then be examined in either context “A” (ABA) or context “B” (ABB) (eg Crombag and Shaham, 2002). The LH, along with the basolateral amygdala and ventral shell of the accumbens, are suggested as common substrates for the context-induced renewal of extinguished responding for drug and non-drug rewards (Hamlin et al., 2006, 2007). Notably however, while there was no activation of orexin-containing cells following renewal of sucrose-seeking (Hamlin et al., 2006), activation of orexinergic cells occurred upon renewal of alcohol-seeking (Hamlin et al., 2007). Both ABA and ABB test conditions resulted in activation of orexin neurons in the lateral and perifornical sub-regions, but not in the dorsomedial hypothalamus (DMH) (Hamlin et al., 2007). Importantly, responding on the active lever was no different to extinction under the ABB condition, whereas under ABA there was a robust context-driven increase (renewal) in alcoholseeking. While on the surface this may question a role of hypothalamic orexin neuron activation in contextual relapse, the study pointed out a significant positive correlation between the activation of orexin neurons and relapse responding on the active lever. This latter factor suggests that both orexin-positive and orexin-negative neurons of this region of the hypothalamus are implicated in contextual alcohol-seeking. Moreover, using a similar approach to examine contextual relapse to cocaine-seeking, these workers found no renewal-related activation of orexin-containing neurons. Animals in both ABA and ABB test conditions did show some activation of perifornical orexinergic neurons, suggesting a possible role for activity/exploratory behaviour
rather than cocaine-seeking per se (Hamlin et al., 2008). Collectively therefore, these data would suggest that (i) orexin-containing neurons are implicated in alcohol-related behaviours, (ii) orexinergic neurons are functionally heterogeneous and (iii) sub-populations of orexinergic neurons may differentiate between natural and drug rewards. Indeed, further evidence for heterogeneity in the response of orexincontaining neurons to drug challenges was provided when it was shown that in rats sensitized to amphetamine, activation of orexin-containing neurons was more pronounced in the DMH and perifornical region compared to the LH (McPherson et al., 2007). Indeed, differential responsivity of hypothalamic orexin-containing neurons to psychotropic drug challenge had previously been established (Fadel et al., 2002). These findings contribute towards the notion of a dichotomy in orexin neurons between reward processing and stress-arousal pathways (Harris and Aston-Jones, 2006). Given the different approaches employed, how this heterogeneity translates in a functional sense remains to be clarified. The first direct evidence that orexins may play a role in alcohol-seeking was established with the demonstration that a selective antagonist of orexin1 receptors (SB-334867) reduced operant alcohol self-administration and could prevent a cueinduced reinstatement of alcohol-seeking in preferring (iP) rats (Lawrence et al., 2006). Subsequent studies corroborated these findings showing SB-334867 treatment reduced alcohol (but not sucrose) self-administration in Long–Evans rats, plus blocked a yohimbine-induced reinstatement of alcohol-seeking (Richards et al., 2008). Fos protein expression studies confirmed these pharmacological approaches when cueinduced alcohol-seeking was found to activate orexin-containing neurons in the hypothalamus (Dayas et al., 2008). A logical conclusion to be drawn from these concurring studies is that integration of the cues previously associated with alcohol availability is sufficient and adequate to evoke the release of endogenous orexin to drive alcohol-seeking. In addition, stress pathways may also interact with the orexin system to regulate drug-seeking (Boutrel et al., 2005; Richards et al., 2008; Boutrel, 2008; Boutrel and de Lecea, 2008), although it is noteworthy that the mechanism behind yohimbineinduced reinstatement is somewhat unclear, as a direct effect of yohimbine on 5-HT1A receptors has recently been established (Le et al., 2009). Nevertheless, it would appear reasonable to conclude that there is involvement of orexin neurons in a hypothalamic–thalamic–striatal network implicated in the regulation of behavioural state, feeding and reward (Kelley et al., 2005). A role for orexin in alcohol consumption (Lawrence et al., 2006; Richards et al., 2008) is supported by the demonstration that microinjection of orexin A into the LH or paraventricular nucleus of the hypothalamus (PVN) increased alcohol intake in rats (Schneider et al., 2007). These latter data suggest the possibility that endogenous hypothalamic peptides may in fact act in a positive feedback manner that could contribute to excessive alcohol consumption and/or eating (see Leibowitz (2007) for a review of this subject). Consonant with this hypothesis are observations of the effect of alcohol consumption on orexin and orexin receptor gene expression (Lawrence et al., 2006; Pickering et al., 2007). Therefore, while there is little doubt that orexin-containing neurons can regulate
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alcohol consumption and relapse to alcohol-seeking triggered by cues or yohimbine, the loci of these effects remain to be fully elucidated. A direct action within the hypothalamus is implicated from microinjections of orexin A (Schneider et al., 2007) and also from recent studies showing that intra-LH injections of Neuropeptide S augment a cue-induced reinstatement of alcohol-seeking that is prevented by SB-334867, suggesting mediation via orexinergic neurons (Cannella et al., 2009). Given the widespread innervation of the neuraxis, including reward-related structures, by orexin-containing neurons (De Lecea et al., 1998; Peyron et al., 1998; Fadel and Deutch, 2002), it would seem likely that extra-hypothalamic sites are also implicated, either directly or indirectly, in the ability of orexins to regulate drug-seeking. In this regard, SB-334867 pretreatment attenuates behavioural signs of opiate withdrawal and withdrawal-induced expression of Fos protein in accumbens shell neurons (Sharf et al., 2008). In addition, orexin A increases the AMPA/NMDA receptor current ratio at corticostriatal synapses, by increasing cell surface expression of AMPA receptors in an ERK-dependent manner (Shin et al., 2009). From a cortical perspective, antagonism of orexin1 receptors in the insular cortex regulates nicotine self-administration (Hollander et al., 2008). Evidence also suggests that the dopamine-containing cells of the VTA are a distinct target for the ability of orexin to regulate dopamine release and behavioural responses to opiates (Narita et al., 2006; AstonJones et al., 2009) and cocaine (Borgland et al., 2006). Moreover, the conditioned rewarding effect of ethanol is expressed through a VTA-dependent mechanism (Bechtholt and Cunningham, 2005). Consequently, there are a number of potential nuclei where orexin receptor activation/antagonism may regulate alcohol consumption and/or seeking, not restricted to those canvassed above. Confirmation of such sites awaits future functional mapping approaches. In relation to relapse to drug/alcohol-seeking, it is widely established that cues previously paired with drug availability, drug-priming and stressors are all able to precipitate behaviour in animals consistent with relapse-like seeking out of a reward (Shaham et al., 2003). The brain systems and chemicals involved in these different means of precipitating reinstatement differ, although substantial overlap does exist (Shaham et al., 2003). Given that the orexin system has been implicated in cue-induced reinstatement (Lawrence et al., 2006; Hamlin et al., 2007; Dayas et al., 2008; Cannella et al., 2009) as well as stress-induced reinstatement (Boutrel et al., 2005; Richards et al., 2008), it would appear that orexin neurons may be part of a common substrate driving these forms of relapse. Importantly, recent evidence suggests that the LH per se is critical for contextual cue-driven reinstatement of alcohol-seeking (Marchant et al., 2009). Indeed, LH orexin neurons projecting to the VTA have previously been implicated in the association of environmental cues and drug reward (Harris et al., 2007). Given the apparent heterogeneity within the orexin neurons of the hypothalamus it is clearly possible that subpopulations of orexin-containing neurons are involved in integration of drug cues vs stress in relation to drug-seeking behaviour. The latter hypothesis is supported by a recent study showing that while intra-VTA application of the
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selective orexin1 antagonist (SB-408124) prevented orexinprecipitated reinstatement of cocaine-seeking, it had no impact upon footshock-induced reinstatement (Wang et al., 2009). Moreover, the latter study also demonstrated that while CRF receptors were implicated in the footshock-induced relapse, they appeared to have no role in the orexin-induced relapse (Wang et al., 2009). These findings suggest that while in some circumstances there may well be an interaction between orexin and CRF systems in terms of drug-seeking (Boutrel et al., 2005), this would not appear to always be the case, and as such these two peptides may also work in parallel/independently as well as in series, depending upon the brain nuclei and systems involved. In summary therefore, a role for orexin (hypocretin) in aspects of alcohol use and abuse would seem well established. There are however a number of questions that remain unanswered. For example, where in the brain do these actions occur; under what circumstances is this system activated; are sub-populations of orexin neurons implicated in different aspects of alcohol-seeking; are orexins implicated in motivational properties of alcohol; how and when do orexins interact with other peptide and non-peptide systems to regulate alcohol-seeking; are orexins implicated in neural adaptations following chronic intermittent alcohol use and/or withdrawal? Clearly this list of questions is far from exhaustive, yet it indicates the need for concerted endeavour to improve our understanding of the fundamental neurobiology of the orexin system and how it pertains to alcohol use, abuse, dependence and withdrawal.
Acknowledgment The author is grateful to the National Health and Medical Research Council of Australia for ongoing support. REFERENCES
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available at www.sciencedirect.com
www.elsevier.com/locate/brainres
Review
Regulation of alcohol-seeking by orexin (hypocretin) neurons Andrew J. Lawrence Howard Florey Institute and Centre for Neuroscience, University of Melbourne, Royal Parade, Parkville, Victoria 3010, Australia
A R T I C LE I N FO
AB S T R A C T
Article history:
Orexins (hypocretins) are found primarily within a restricted portion of neurons within the
Accepted 22 July 2009
hypothalamus, but provide innervation across the neuraxis. Orexin A (hypocretin 1) has
Available online 29 July 2009
been implicated in drug and food reward. Not surprisingly therefore, interest has come to bear on whether orexins are implicated in aspects of alcohol consumption and/or seeking.
Keywords:
This mini-review provides a concise, but timely, discussion on this issue. The evidence to
Orexin
date would suggest a role for orexins in alcohol use, and integration of orexin-containing
Alcohol
neurons in reward-seeking circuitry. There are however still many unanswered questions,
Relapse
some of which are canvassed herein.
Lateral hypothalamus
© 2009 Elsevier B.V. All rights reserved.
Contents
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
In 2007 over 14.2 million Australians aged >14 years old consumed alcohol in the previous 12 months (NDSHS, 2007). Alcohol-related health issues are the second most preventable cause of death and hospitalisation in Australia following those from tobacco use (Loxley et al., 2005). Notwithstanding these somewhat sobering statistics, the above figures do not take into account the social cost of alcohol-related harm, in Australia this has recently been estimated as ∼ $15.3 billion (Collins and Lapsley, 2008). Add to these the emotional costs of alcoholism upon the afflicted and their families, and we see a problem of dramatic proportions, one that is difficult to overestimate and that overshadows the problems caused by illicit drugs. How can we make inroads into this issue that faces many developed countries? Clearly, strategies of public education in relation to safe levels of consumption, resisting peer pressure
and other similar issues have a place. Nevertheless, despite the most robust policies, there will be a proportion of people who experience alcohol use disorders of some form. Accordingly, there is an ongoing need to develop safe, effective and reliable medications as part of a battery of approaches to curb excessive/harmful alcohol consumption and assist in relapseprevention. The latter issue is pertinent to all addictions and highlights the nature of the disorder, plus the fact that even the best therapeutic options currently available are far from ideal. Indeed, addiction has been described as a chronic, relapsing disorder accompanied by cravings, a psychological state of desire for the drug which may cause individuals to return to using the drug many times throughout their lives (Grimm et al., 2001). The most informed way to develop new pharmacotherapeutics is from a detailed understanding of the circuitry, and its underlying chemistry, responsible for the
E-mail address: [email protected]. 0006-8993/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2009.07.072
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aberrant behaviour patterns. This will then facilitate a study of potential neural adaptation following chronic drug use and/or during protracted withdrawal that may relate to persistent relapse propensity. Early animal studies of self-stimulation in different brain regions implicated the lateral hypothalamus as an area where rodents would willingly perform an instrumental task to receive a positively reinforcing electrical stimulus (Olds, 1956; Olds and Milner, 1954). Indeed, subsequent studies indicated that following an ibotenic acid lesion of the middle part of the lateral hypothalamus (LH), rats showed diminished electrical self-stimulation within the anterior medial forebrain bundle, with a variable effect in more posterior placements (Lestang et al., 1985). The authors concluded that self-stimulation of the anterior aspect of the medial forebrain bundle was influenced by projections from the mid-LH. Another study showed that mice would reliably self-administer morphine directly into the lateral hypothalamus (Cazala et al., 1987), an effect that was sensitive to systemic naloxone indicating an opioid receptor-mediated behaviour. Consequently, a place for the lateral hypothalamus in drug reward-related circuitry was suggested. This assertion was extended following collision test experiments, where rats could self-stimulate in the LH, ventral tegmental area (VTA) or both, which indicated that the fibres implicated in supporting selfstimulation behaviour directly linked the LH with the VTA (Shizgal, 1989). Accordingly, self-stimulation of the lateral hypothalamus (LH) increased dopamine and glutamate levels in the VTA of freely-moving rats (You et al., 2001). Moreover, reversible (bilateral) inactivation of the LH indicates a critical role for the LH in context-induced reinstatement of rewardseeking (Marchant et al., 2009). Therefore, while over the past 50 years the LH has become cemented within the continually evolving circuitry of reward, the chemical content of those LH neurons remained uncertain. Moreover, given the expression of multiple transmitters in individual neurons, the identity of reward-related neurochemicals has been a source of much research focus. Orexin (hypocretin)-containing neurons appear to be largely confined to this area of the hypothalamus. Thus, orexin-containing neurons can be found in the LH, perifornical region and dorsomedial hypothalamus; however, these cells provide a widespread innervation of the neuraxis with orexinergic fibres (De Lecea et al., 1998; Peyron et al., 1998). Cloning studies have indicated the presence of two main orexin peptides, namely orexins A and B (hypocretins 1 and 2), plus two main orexin receptors, namely orexin1 and orexin2 receptors (Sakurai et al., 1998). Of interest, orexin A (hypocretin 1) has to date only been demonstrated to occur within neuronal cell bodies of the hypothalamus; however, orexin B (hypocretin 2) has also been identified within cells in extrahypothalamic structures including the central amygdala and sub-regions of the bed nucleus of the stria terminalis (Ciriello et al., 2003; Siegel, 2004). Given the widespread projections of hypothalamic orexin-containing neurons, orexin1 and orexin2 receptor mRNA and protein are distributed throughout the nervous system (Hervieu et al., 2001; Cluderay et al., 2002). Importantly, in the context of the early studies discussed above, a direct innervation of VTA cells by orexin A-containing neurons of the LH and medial perifornical area has been demonstrated (Fadel
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and Deutch, 2002). More recent experiments have confirmed and extended these observations, with LH orexin neurons implicated in cocaine-induced plasticity at excitatory synapses onto VTA dopaminergic cells (Borgland et al., 2006). While initially implicated in the regulation of feeding (Sakurai et al., 1998), orexins also appear critically involved in vigilance, arousal and regulation of sleep–wake cycles (Chemelli et al., 1999; Hara et al., 2001; Lin et al., 1999; Adamantidis et al., 2007). The notion that orexin-containing neurons of the LH may have relevance for drug-seeking was first suggested based upon the observations that these neurons innervated structures implicated in responses to drugs of abuse and states of arousal (DiLeone et al., 2003; Winsky-Sommerer et al., 2003; Georgescu et al., 2003), indicating that these neurons may represent those identified through self-stimulation experiments. Indeed, orexins were (along with other hypothalamic peptides) implicated in the activation of reward pathways and concomitant dampening of satiety signals thought to contribute towards over-eating induced obesity (Erlanson-Albertsson, 2005). In support of this, infusions of orexin A into the anterior LH enhanced selfadministration of palatable food (Thorpe et al., 2005). In this regard, polymorphisms in the MTMR9 gene are associated with obesity, and MTMR9 (myotublarin related protein 9) colocalises to orexinergic cells of the LH where its expression is regulated by diet (Yanagiya et al., 2007). It is now becoming clear that addiction and obesity may share some commonality of neurocircuitry (Volkow et al., 2008). Two landmark studies provided the vital findings that clearly implicated orexins in reward, drug-seeking and relapse. The first study showed that orexin-containing neurons in the LH (but not perifornical or dorsomedial hypothalamus) were strongly activated in rats that exhibited a place preference following conditioning with either morphine, food or cocaine (Harris et al., 2005). In addition, activation of LH orexin cells was sufficient to reinstate an extinguished place preference for opiates that could be prevented by pre-treatment with the orexin1 receptor antagonist SB-334867. Similarly, microinjection of orexin A into the VTA also elicited a reinstatement of opiate-seeking using the place preference paradigm. The second study showed that intracerebroventricular (icv) infusions of orexin A (hypocretin 1) reinstated cocaine-seeking and food-seeking under operant conditions (Boutrel et al., 2005). In addition, icv infusions of orexin A elevated reward thresholds, while orexin A-induced reinstatement of cocaine-seeking was attenuated by clonidine (an α2-adrenoceptor agonist) and a non-selective CRF receptor antagonist, suggesting a link between the orexin system and brain stress pathways in relation to drug-seeking. Consistent with this, footshock-induced reinstatement of cocaine-seeking was prevented with SB-334867. Thus, taken together, these studies provided evidence for a role of orexin-containing neurons in drug reward-related behaviour, consistent with their activation during foraging for natural rewards (Mileykovskiy et al., 2005). In addition, they also indicated the potential for overlap between orexinergic neurons and stress systems, a subject that will be revisited below. Interestingly, the study by Harris et al. (2005) presented evidence for the possibility of functional heterogeneity within orexinergic neurons, since within their Pavlovian conditioning
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paradigm, only the LH orexin-containing cells were activated. Such heterogeneity was also proposed in the first publication relating orexin systems with alcohol use. Thus, the expression of the mRNA encoding prepro-orexin was not different between alcohol-preferring and non-preferring rats, suggesting that, in the absence of any alteration to post-translational processing, the basal orexin systems are similar between these rat strains and seemingly therefore likely not implicated in contributing to the alcohol-preferring nature of iP rats. Chronic consumption of ethanol for 10 weeks also had no significant impact upon the density of prepro-orexin mRNA expression in the hypothalamus of preferring rats; however, the area of mRNA expression was increased compared to NP and alcohol naïve iP rats. Notably, this effect was only apparent in the LH and not in medial orexinergic regions. These data therefore suggest that chronic voluntary consumption of alcohol by preferring rats apparently increases the number of neurons that densely express orexin mRNA within the LH. It would therefore appear that while chronic ethanol consumption does not apparently activate cells that already express high basal levels of orexin, those that under basal conditions express undetectable levels of orexin seem to be recruited to produce increased amounts of orexin (Lawrence et al., 2006). The potential for heterogeneity within the orexin neurons was further highlighted using the ABA renewal paradigm of context-driven relapse to reward-seeking. This paradigm differs from the standard extinction-reinstatement model in that reward-seeking is extinguished in a different context/ environment compared to that for self-administration. Thus, self-administration sessions occur in context “A”; extinction training in context “B”: drug-seeking can then be examined in either context “A” (ABA) or context “B” (ABB) (eg Crombag and Shaham, 2002). The LH, along with the basolateral amygdala and ventral shell of the accumbens, are suggested as common substrates for the context-induced renewal of extinguished responding for drug and non-drug rewards (Hamlin et al., 2006, 2007). Notably however, while there was no activation of orexin-containing cells following renewal of sucrose-seeking (Hamlin et al., 2006), activation of orexinergic cells occurred upon renewal of alcohol-seeking (Hamlin et al., 2007). Both ABA and ABB test conditions resulted in activation of orexin neurons in the lateral and perifornical sub-regions, but not in the dorsomedial hypothalamus (DMH) (Hamlin et al., 2007). Importantly, responding on the active lever was no different to extinction under the ABB condition, whereas under ABA there was a robust context-driven increase (renewal) in alcoholseeking. While on the surface this may question a role of hypothalamic orexin neuron activation in contextual relapse, the study pointed out a significant positive correlation between the activation of orexin neurons and relapse responding on the active lever. This latter factor suggests that both orexin-positive and orexin-negative neurons of this region of the hypothalamus are implicated in contextual alcohol-seeking. Moreover, using a similar approach to examine contextual relapse to cocaine-seeking, these workers found no renewal-related activation of orexin-containing neurons. Animals in both ABA and ABB test conditions did show some activation of perifornical orexinergic neurons, suggesting a possible role for activity/exploratory behaviour
rather than cocaine-seeking per se (Hamlin et al., 2008). Collectively therefore, these data would suggest that (i) orexin-containing neurons are implicated in alcohol-related behaviours, (ii) orexinergic neurons are functionally heterogeneous and (iii) sub-populations of orexinergic neurons may differentiate between natural and drug rewards. Indeed, further evidence for heterogeneity in the response of orexincontaining neurons to drug challenges was provided when it was shown that in rats sensitized to amphetamine, activation of orexin-containing neurons was more pronounced in the DMH and perifornical region compared to the LH (McPherson et al., 2007). Indeed, differential responsivity of hypothalamic orexin-containing neurons to psychotropic drug challenge had previously been established (Fadel et al., 2002). These findings contribute towards the notion of a dichotomy in orexin neurons between reward processing and stress-arousal pathways (Harris and Aston-Jones, 2006). Given the different approaches employed, how this heterogeneity translates in a functional sense remains to be clarified. The first direct evidence that orexins may play a role in alcohol-seeking was established with the demonstration that a selective antagonist of orexin1 receptors (SB-334867) reduced operant alcohol self-administration and could prevent a cueinduced reinstatement of alcohol-seeking in preferring (iP) rats (Lawrence et al., 2006). Subsequent studies corroborated these findings showing SB-334867 treatment reduced alcohol (but not sucrose) self-administration in Long–Evans rats, plus blocked a yohimbine-induced reinstatement of alcohol-seeking (Richards et al., 2008). Fos protein expression studies confirmed these pharmacological approaches when cueinduced alcohol-seeking was found to activate orexin-containing neurons in the hypothalamus (Dayas et al., 2008). A logical conclusion to be drawn from these concurring studies is that integration of the cues previously associated with alcohol availability is sufficient and adequate to evoke the release of endogenous orexin to drive alcohol-seeking. In addition, stress pathways may also interact with the orexin system to regulate drug-seeking (Boutrel et al., 2005; Richards et al., 2008; Boutrel, 2008; Boutrel and de Lecea, 2008), although it is noteworthy that the mechanism behind yohimbineinduced reinstatement is somewhat unclear, as a direct effect of yohimbine on 5-HT1A receptors has recently been established (Le et al., 2009). Nevertheless, it would appear reasonable to conclude that there is involvement of orexin neurons in a hypothalamic–thalamic–striatal network implicated in the regulation of behavioural state, feeding and reward (Kelley et al., 2005). A role for orexin in alcohol consumption (Lawrence et al., 2006; Richards et al., 2008) is supported by the demonstration that microinjection of orexin A into the LH or paraventricular nucleus of the hypothalamus (PVN) increased alcohol intake in rats (Schneider et al., 2007). These latter data suggest the possibility that endogenous hypothalamic peptides may in fact act in a positive feedback manner that could contribute to excessive alcohol consumption and/or eating (see Leibowitz (2007) for a review of this subject). Consonant with this hypothesis are observations of the effect of alcohol consumption on orexin and orexin receptor gene expression (Lawrence et al., 2006; Pickering et al., 2007). Therefore, while there is little doubt that orexin-containing neurons can regulate
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alcohol consumption and relapse to alcohol-seeking triggered by cues or yohimbine, the loci of these effects remain to be fully elucidated. A direct action within the hypothalamus is implicated from microinjections of orexin A (Schneider et al., 2007) and also from recent studies showing that intra-LH injections of Neuropeptide S augment a cue-induced reinstatement of alcohol-seeking that is prevented by SB-334867, suggesting mediation via orexinergic neurons (Cannella et al., 2009). Given the widespread innervation of the neuraxis, including reward-related structures, by orexin-containing neurons (De Lecea et al., 1998; Peyron et al., 1998; Fadel and Deutch, 2002), it would seem likely that extra-hypothalamic sites are also implicated, either directly or indirectly, in the ability of orexins to regulate drug-seeking. In this regard, SB-334867 pretreatment attenuates behavioural signs of opiate withdrawal and withdrawal-induced expression of Fos protein in accumbens shell neurons (Sharf et al., 2008). In addition, orexin A increases the AMPA/NMDA receptor current ratio at corticostriatal synapses, by increasing cell surface expression of AMPA receptors in an ERK-dependent manner (Shin et al., 2009). From a cortical perspective, antagonism of orexin1 receptors in the insular cortex regulates nicotine self-administration (Hollander et al., 2008). Evidence also suggests that the dopamine-containing cells of the VTA are a distinct target for the ability of orexin to regulate dopamine release and behavioural responses to opiates (Narita et al., 2006; AstonJones et al., 2009) and cocaine (Borgland et al., 2006). Moreover, the conditioned rewarding effect of ethanol is expressed through a VTA-dependent mechanism (Bechtholt and Cunningham, 2005). Consequently, there are a number of potential nuclei where orexin receptor activation/antagonism may regulate alcohol consumption and/or seeking, not restricted to those canvassed above. Confirmation of such sites awaits future functional mapping approaches. In relation to relapse to drug/alcohol-seeking, it is widely established that cues previously paired with drug availability, drug-priming and stressors are all able to precipitate behaviour in animals consistent with relapse-like seeking out of a reward (Shaham et al., 2003). The brain systems and chemicals involved in these different means of precipitating reinstatement differ, although substantial overlap does exist (Shaham et al., 2003). Given that the orexin system has been implicated in cue-induced reinstatement (Lawrence et al., 2006; Hamlin et al., 2007; Dayas et al., 2008; Cannella et al., 2009) as well as stress-induced reinstatement (Boutrel et al., 2005; Richards et al., 2008), it would appear that orexin neurons may be part of a common substrate driving these forms of relapse. Importantly, recent evidence suggests that the LH per se is critical for contextual cue-driven reinstatement of alcohol-seeking (Marchant et al., 2009). Indeed, LH orexin neurons projecting to the VTA have previously been implicated in the association of environmental cues and drug reward (Harris et al., 2007). Given the apparent heterogeneity within the orexin neurons of the hypothalamus it is clearly possible that subpopulations of orexin-containing neurons are involved in integration of drug cues vs stress in relation to drug-seeking behaviour. The latter hypothesis is supported by a recent study showing that while intra-VTA application of the
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selective orexin1 antagonist (SB-408124) prevented orexinprecipitated reinstatement of cocaine-seeking, it had no impact upon footshock-induced reinstatement (Wang et al., 2009). Moreover, the latter study also demonstrated that while CRF receptors were implicated in the footshock-induced relapse, they appeared to have no role in the orexin-induced relapse (Wang et al., 2009). These findings suggest that while in some circumstances there may well be an interaction between orexin and CRF systems in terms of drug-seeking (Boutrel et al., 2005), this would not appear to always be the case, and as such these two peptides may also work in parallel/independently as well as in series, depending upon the brain nuclei and systems involved. In summary therefore, a role for orexin (hypocretin) in aspects of alcohol use and abuse would seem well established. There are however a number of questions that remain unanswered. For example, where in the brain do these actions occur; under what circumstances is this system activated; are sub-populations of orexin neurons implicated in different aspects of alcohol-seeking; are orexins implicated in motivational properties of alcohol; how and when do orexins interact with other peptide and non-peptide systems to regulate alcohol-seeking; are orexins implicated in neural adaptations following chronic intermittent alcohol use and/or withdrawal? Clearly this list of questions is far from exhaustive, yet it indicates the need for concerted endeavour to improve our understanding of the fundamental neurobiology of the orexin system and how it pertains to alcohol use, abuse, dependence and withdrawal.
Acknowledgment The author is grateful to the National Health and Medical Research Council of Australia for ongoing support. REFERENCES
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