Novel approaches to alcohol rehabilitation: Modification of stress-responsive brain regions through environmental enrichment

Neuropharmacology xxx (2018) 1e12

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Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm

Invited review

Novel approaches to alcohol rehabilitation: Modification of stress-responsive brain regions through environmental enrichment Terence Y. Pang*, Anthony J. Hannan, Andrew J. Lawrence Florey Institute of Neuroscience & Mental Health, University of Melbourne, Parkville, VIC, Australia

a r t i c l e i n f o

a b s t r a c t

Article history: Received 27 December 2017 Received in revised form 5 February 2018 Accepted 21 February 2018 Available online xxx

Relapse remains the most prominent hurdle to successful rehabilitation from alcoholism. The neural mechanisms underlying relapse are complex, but our understanding of the brain regions involved, the anatomical circuitry and the modulation of specific nuclei in the context of stress and cue-induced relapse have improved significantly in recent years. In particular, stress is now recognised as a significant trigger for relapse, adding to the well-established impact of chronic stress to escalate alcohol consumption. It is therefore unsurprising that the stress-responsive regions of the brain have also been implicated in alcohol relapse, such as the nucleus accumbens, amygdala and the hypothalamus. Environmental enrichment is a robust experimental paradigm which provides a non-pharmacological tool to alter stress response and, separately, alcohol-seeking behaviour and symptoms of withdrawal. In this review, we examine and consolidate the preclinical evidence that alcohol seeking behaviour and stressinduced relapse are modulated by environmental enrichment, and these are primarily mediated by modification of neural activity within the key nodes of the addiction circuitry. Finally, we discuss the limited clinical evidence that stress-reducing approaches such as mindfulness could potentially serve as adjunctive therapy in the treatment of alcoholism. © 2018 Elsevier Ltd. All rights reserved.

Keywords: Alcohol Addiction Animal models Cognitive stimulation Environmental enrichment Mental illness Exercise Physical activity Stress Psychiatric disorder

Contents 1. 2. 3. 4. 5. 6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A range of stressors modulate alcohol drinking behaviour and relapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Environmental enrichment modifies alcohol-seeking behaviour and modulates relapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . EE-modulation of stress response involves brain regions common to stress-induced alcohol relapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cognitive behavioural therapy (CBT) & mindfulness: clinical equivalents and analogues of environmental enrichment . . . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Alcohol abuse is a persistent health pandemic which imposes great socioeconomic cost globally. In the United States, it is estimated that 3% of deaths annually are alcohol-related with many

* Corresponding author. E-mail addresses: terence.pang@florey.edu.au (T.Y. Pang), andrew.lawrence@ florey.edu.au (A.J. Lawrence).

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engaging in excessive drinking (Linden-Carmichael et al., 2017a, 2017b; Rehm et al., 2014). The mortality due to alcohol-abuse in the European Union has been estimated to be similar (Innamorati et al., 2013). The proportion of men and women affected by alcohol abuse in the EU do not differ significantly (Rehm et al., 2013). There is a trend of increasing alcohol consumption across all groups of legal drinking age, but more worryingly this is also accompanied by increasing numbers who engage in high-risk drinking behaviours (Breslow et al., 2017; Grant et al., 2017). In

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Please cite this article in press as: Pang, T.Y., et al., Novel approaches to alcohol rehabilitation: Modification of stress-responsive brain regions through environmental enrichment, Neuropharmacology (2018), https://doi.org/10.1016/j.neuropharm.2018.02.021

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Australia, there has been a steady growth in the numbers of problem drinkers in recent years but, worryingly, there has been a slight decrease in the numbers seeking treatment for alcoholism (Chan et al., 2016; Whiteford et al., 2013). Current attempts to improve upon the diagnostic methodologies and monitoring of treatment effectiveness (Hasin et al., 2017; Shield et al., 2014) have even included a shift in the definition of ‘successful’ treatment from total abstinence to reduced drinking. Besides genetic modifiers and associated pathophysiology (Gelernter et al., 2014; Heath et al., 2011; Heinz et al., 2000, 2005; Laine et al., 1999; Rehm et al., 2016; Treutlein et al., 2009), drinking behaviour and successful rehabilitation are strongly influenced by environmental factors. In Western-based cultures/societies, drinking is often partaken as a sociable activity and the evidence for this comes from several studies which found that drinking patterns of adolescents and young adults are dictated by the actions and perceptions of their immediate social network (Hoffmann, 2017; Mason et al., 2017; Tsakpinoglou and Poulin, 2017; Walther et al., 2017). Participation in rehabilitative programs to address alcohol dependence significantly improves the chance of remission and reduces relapse (Moos and Moos, 2006). A more recent study of a cohort of French subjects replicated the useful nature of social support programs in maintaining abstinence, although relapse rates at 12 months remained high (~60%) (Nalpas et al., 2017). Stress is a major impediment to successful rehabilitation from alcoholism and increases the risk of alcohol relapse (Sinha, 2001). Stress increases alcohol craving (Cooney et al., 2007) and predicts relapse independent of the individuals' history of alcohol misuse (Brown et al., 1990). Early life stress also has a long term impact since adverse childhood experiences are strongly related to initiation of alcohol drinking during adolescence and significantly increase an individual's risk for later alcohol abuse (Dube et al., 2002, 2006). Evidence suggests that the neural circuits involved in stress overlap with the brain systems involved in drug reward, leading to preclinical and clinical research aimed at understanding the link between stress and alcohol consumption/rehabilitation. On the other hand, the neurobiology of stress has also been of great interest for researchers interested in how positive environmental factors modulate stress response and behaviour. There is a large body of evidence that environmental enrichment confers stress resilience, is anxiolytic and anti-depressive in a wide range of preclinical models of disease. Many clinical rehabilitative programs are also based on the stress-reducing principles of enrichment. In this review, we will examine the evidence and discuss how current understanding of environmental enrichment as a non-drug intervention for modulating stress response could hold value by assisting in the promotion of abstinence and facilitate rehabilitation from alcohol dependence. 2. A range of stressors modulate alcohol drinking behaviour and relapse There is strong evidence from both preclinical and clinical studies that stress is a strong motivator for alcohol consumption in alcohol dependent and non-dependent individuals (Becker, 2017; Blaine and Sinha, 2017; Sinha, 2008; Uhart and Wand, 2009), with some interesting gender differences (Chaplin et al., 2008). The neurochemical basis for the upsurge in motivation involves increases in glucocorticoid and catecholamine (e.g. dopamine) levels, both of which are necessary for the reinforcement of the rewarding value of alcohol consumption as a stress-coping action (Belujon and Grace, 2015; Schwabe et al., 2011). Separately, cortisol levels are well-established to be significantly increased by acute psychosocial stress (Berger et al., 2017; Brown et al., 2017; Goncharova and Oganyan, 2018) and following acute alcohol consumption (Frias

et al., 2002; Ireland et al., 1984; Lex et al., 1991). When both events are concurrent, the experience of stress and drinking alcohol co-activate the HPA axis to increase glucocorticoid release and potentiate normal dopaminergic neurotransmission to impact motivation, and reinforce goal (alcohol)-directed behaviour (Bjork and Gilman, 2014; Levita et al., 2009). To further demonstrate that HPA axis activity regulates alcohol seeking behaviour, Vendruscolo et al. (2015) administered the selective GR antagonist, CORT113176, which significantly decreased alcohol drinking in alcohol dependent rats (Vendruscolo et al., 2015). This modulatory effect was attributed to an increase in glucocorticoid receptor (GR) signalling in the central amygdala (CeA) during alcohol dependence since antagonism of GR with mifepristone (which also inhibits progesterone receptor function) decreased alcohol intake while increasing phosphorylation of GR at Ser232 - a molecular marker of GR nuclear localization and transactivation. Indeed, discrete microinjection of mifepristone into the CeA reduced stress-induced reinstatement of alcohol-seeking behaviour in male Long Evans rats (Simms et al., 2012). The clinical utility of these findings was investigated in a group of alcohol-dependent (paid) volunteers who were administered mifepristone during abstinence. Compared to placebo, mifepristone treatment was associated with a greater reduction in alcohol-cued craving (tested in a laboratory environment) and greater reductions in the self-reported number of drinks per day. Alternative approaches and novel pharmacotherapy targets to modify drinking behaviour are currently being investigated and stem from attempts to gain a better understanding of the complex neurochemical processes involved in promoting the development of resilience or susceptibility to addiction (Srinivasan et al., 2013). For example, genetic variants of the CRH binding protein (CRH-BP) confer greater risk for alcoholism and anxiety in humans, and selective reduction of CRH-BP expression in the CeA robustly decreases alcohol consumption in dependent rats (HaassKoffler et al., 2016). HPA axis dysregulation is evident in heavy drinkers as they have higher baseline levels of cortisol compared to moderate drinkers, but is not detected in those with current and remitted alcohol dependence (Boschloo et al., 2011). This finding is evidence that pathophysiology of the HPA axis differs for a heavy drinker and an alcohol-dependent individual. It is important to be aware, however, that pseudo-Cushing's syndrome is also linked to excessive alcohol consumption (Groote Veldman and Meinders, 1996; Jeffcoate, 1993; Kirkman and Nelson, 1988). The differential diagnosis of this idiopathic condition is somewhat challenging, but patients typically record normal midnight cortisol levels within five days of alcohol abstinence (Newell-Price et al., 1998). Since alcohol elicits cortisol production and a normal functioning HPA axis would have selfregulatory capacity to maintain homeostasis, transitioning into a state of alcohol dependence likely involves persistent desensitization of the HPA axis due to chronic stimulation resulting in the down-regulation of glucocorticoid production. This alcoholimpaired HPA axis is maintained during withdrawal and is evident from the blunted cortisol response to naltrexone, compared to healthy non-dependent controls (Besirli et al., 2014). The most recent evidence confirms progressive adaptation of the HPA axis through transitions into alcohol dependence, acute withdrawal and finally protracted abstinence. Over a period of 8 weeks of chronic self-administering 10% v/v ethanol, the peak plasma corticosterone levels (measured 1 h before dark cycle) of male Wistar rats (grouphoused 2e3 per cage) progressively increased while basal levels remained unaffected (measured 2 h before light phase) (Somkuwar et al., 2017). During acute withdrawal (first 11 days), a suppression (flattening) of the typical diurnal rhythm of corticosterone was observed before the re-emergence of pre-withdrawal peak levels after 19 days of abstinence. Together, these findings suggest gradual

Please cite this article in press as: Pang, T.Y., et al., Novel approaches to alcohol rehabilitation: Modification of stress-responsive brain regions through environmental enrichment, Neuropharmacology (2018), https://doi.org/10.1016/j.neuropharm.2018.02.021

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and sustained impairment of the negative feedback mechanisms (largely mediated by glucocorticoid receptor signalling) which regulate circulating concentrations of corticosterone. Although a systematic characterisation of the expression patterns of glucocorticoid receptors during the transition to alcohol dependence has yet to be conducted, pharmacological targeting of glucocorticoid receptors could potentially limit alcohol drinking during the rehabilitative process. As a demonstration of the viability of this strategy, the gradual escalation of alcohol drinking can be prevented following administration of mifepristone during the withdrawal period (Somkuwar et al., 2017). There is increased GR signalling in the medial prefrontal cortex as measured by increased total GR and phosphorylated GR protein expression, but it remains to be determined whether mifepristone-induced inhibition of alcohol drinking behaviour also involves altering GR expression and signalling of the HPA axis itself (i.e. hypothalamus and adrenal glands). Social isolation is a situation that is strongly linked to excessive alcohol consumption, but is also separately associated with significant modifications to the physiological stress response e.g. reduced cortisol awakening response (Jandackova et al., 2017; Schutter et al., 2017). The detrimental impact of social isolation on HPA axis activity is not limited to humans and is also observed in other species (Guesdon et al., 2015; Hennessy et al., 2017; Pisu et al., 2016; Ross et al., 2017; Taylor et al., 2015). Interestingly, individuals with Type D personality, a non-pathological personality trait class closely linked with social inhibition and poorer mental health, have been identified by at least two independent studies to be at greater risk of substance and alcohol misuse (Bruce et al., 2013; Michal et al., 2011). One group of particularly susceptible individuals are the homeless, who are arguably socially isolated with reduced opportunities for social interaction. Substance misuse including alcohol dependence is much more prevalent among homeless people than in the general population (Fazel et al., 2008; Grant et al., 2004). While there are many factors contributing to this increased prevalence, perhaps one of the primary reasons is being stressed by their personal situation of housing instability. Studies have documented many reasons for homeless people to engage in alcohol drinking, whether it is for the positive or negative psychological effects, or even for social engagement with other homeless counterparts (Collins et al., 2017). The stress associated with social instability of homelessness is partially modelled in rodents through a procedure involving constant changing of cage mates with short intervals of social isolation (McCormick, 2010). This form of chronic stress elicits behavioural changes including increased anxiety and reduced sociability (Hodges et al., 2017; Roeckner et al., 2017) which are likely attributable to changes in gene expression of key genes involved in stress response and HPA axis activity (crhr1, pomc, avpr1a, oxtr) throughout the brain (Nowacka-Chmielewska et al., 2017). It is therefore unsurprising that in this model of social instability stress, the stressed rats develop increased ethanol preference (Roeckner et al., 2017). Drinking in social isolation has been reported on for several decades (Neff, 1997; Singer et al., 1964). While drinking is often a social activity, solitary drinking is a common activity to cope with trauma, anxiety and stress (Horyniak et al., 2016; Morita et al., 2015; Mowbray et al., 2014). However, this only serves to worsen the existing health issues facing the individual as separate research has found that drinking to cope with depression potentiates events of social isolation and is predictive of future alcohol abuse (Collins et al., 2018). Interestingly, the hypothalamic neuropeptide oxytocin which is strongly linked to sociability traits (Haas et al., 2016; Staes et al., 2014) and reverses social deficits in rodent models of autism (Bales et al., 2014; Teng et al., 2016) has been proposed as a potential modulator of alcoholism (Bowen and Neumann, 2017; Lee

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and Weerts, 2016). Its potential to treat substance abuse disorders stems from reports that adolescent pretreatment with oxytocin diminishes methamphetamine-seeking behaviour and the prevention of morphine reinstatement with an oxytocin analogue carbetocin (Georgiou et al., 2015; Hicks et al., 2016). In rats, isolation-housing changes HPA axis function through shrinkage of the adrenal glands while group-housing protects against stress-induced adaptations (Huzard et al., 2015). Despite the likely possibility that HPA axis pathophysiology is secondary to chronic alcohol drinking, it could be a roadblock to successful rehabilitation and therefore deserves much closer scrutiny. Social isolation of rats from weaning also modifies alcohol-drinking behaviour and consistently escalates alcohol preference (Lodge and Lawrence, 2003b). Single-housed adolescent rodents display escalated alcohol consumption and elevated anxiety, a common comorbidity of alcohol dependence (Butler et al., 2014a, 2016). In one of the first studies of this, juvenile male Long-Evans rats which were weaned into single-housing conditions were reported to have increased ethanol preference on 2 of the 5 days of free-choice drinking, as well as displaying increased anxiety behaviour on the elevated-plus maze (but not in the light-dark box) (McCool and Chappell, 2009). There appears to be an equivocal impact of social isolation on alcohol intake in females since a similar study of single-housed 3-week-old adolescent female Long-Evans rats observed greater alcohol intake and 2-bottle choice preference over 5 days compared to group-housed (4 per cage) counterparts (Butler et al., 2014b). Interestingly, there was no difference in anxiety behaviour in the light-dark box, which suggests that isolationinduced increases in alcohol drinking involve neurobiological processes which are dissociable from those which underlie the development of anxiety. This is supported by the findings of Lodge & Lawrence who reported that the CRF1 receptor antagonist antalarmin, but not diazepam, reduced ethanol consumption of isolation-housed rats (Lodge and Lawrence, 2003a). The apparent male-specific anxiogenic impact involving an interaction of social isolation with alcohol consumption (Skelly et al., 2015) warrants further investigation to better understand why females may be protected from this effect. The well-established sex difference in stress response could be one reason. It has been reported that HPA axis activity and corticosterone production are suppressed in male rats by chronic alcohol exposure (Allen et al., 2016) and this could well account for the anxiogenic observation. However, a corresponding study in female rats would be required to confirm that was indeed the reason for the different behavioural outcomes. Isolation-induced increases in alcohol-drinking behaviour are also observed in mice. Male and female single-housed C57Bl/6 J mice display greater voluntary alcohol intake compared to group-housed mice (Lopez and Laber, 2015), and also manifest alcohol-induced enhancements of sociable behaviours (Kent et al., 2014). It should be noted that the impact of social isolation is not limited to alcoholdrinking behaviour as it also leads to increased consumption of saccharin-sweetened water (Panksepp et al., 2017). Therefore the impact of isolation is presumably on the reward-regulating neural networks rather than preference for a single palatable substance. Besides chronic stress, acute traumatic stress is also a significant risk factor for alcohol abuse, which for certain individuals may be potentiated by the impact of trauma-related social withdrawal and other psychopathologies. Clinically, increased alcohol intake and social withdrawal are commonly considered as avoidant coping strategies to trauma. However, whether social withdrawal (or other co-morbid psychopathologies such as apathy, depression and anxiety) is a causal factor for alcohol drinking is unclear. In a recent study of vehicular crash survivors, social withdrawal behaviour detected at 3 months after the accident was predictive of the patient developing PTSD (Thompson et al., 2018). It would be

Please cite this article in press as: Pang, T.Y., et al., Novel approaches to alcohol rehabilitation: Modification of stress-responsive brain regions through environmental enrichment, Neuropharmacology (2018), https://doi.org/10.1016/j.neuropharm.2018.02.021

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interesting if a follow-up study was able to determine and compare the subsequent incidence of alcohol misuse developed by patients with and without PTSD, taking into account their pre-accident alcohol history. Early life trauma is another form of chronic stress strongly linked to social withdrawal, anxiety disorders (Heim and Nemeroff, 2001) and a greater risk for developing alcohol use disorders (Schwandt et al., 2013). In the maternal separation model of early life trauma, male C57Bl/6 J mice display increased free-choice alcohol intake during adolescence and early adulthood (Cruz et al., 2008; Garcia-Gutierrez et al., 2016). However how it changes voluntary alcohol consumption of female mice has not been examined and it would be important to establish this because a separate study has reported that female mice which had experienced early life separation stress were faster to develop behavioural sensitization to ethanol (Kawakami et al., 2007). It has been proposed that sex-specific effects of early life stress on the physiological stress response, i.e. HPA axis activity, likely account for the sex differences observed in terms of chronic alcohol-drinking behaviours (Kawakami et al., 2013). Interestingly though, the modification of alcohol-drinking behaviour following stress is in itself modulated by the individual's history of alcohol consumption. Mice dependent on alcohol following chronic intermittent ethanol exposure were found to increase their ethanol consumption after forced-swim stress, in contrast to non-dependent mice which reduced their ethanol intake (Anderson et al., 2016; Lopez et al., 2016). The severity of the stress experience is an additional influence on stress-induced drinking behaviour because social defeat reduced acute ethanol consumption (the longer term drinking pattern has yet to be investigated). However, a separate study of outbred mice did find that alcohol consumption decreased initially after social defeat, which was then followed by an increase 20-days post stress (Norman et al., 2015). However, at least in the chronic social defeat model of trauma, there is no alleviation of social withdrawal by acute alcohol administration (Favoretto et al., 2017) which suggests that other psychosocial/environmental factors are likely to motivate the higher incidence of alcohol misuse for trauma patients. These other environmental factors should therefore be the targets of therapeutic interventions to reduce alcohol intake and alleviate alcohol-seeking behaviours. Since the environment is more than a mere contextual cue and is just as significant a factor in influencing the likelihood of successful rehabilitation and maintenance of abstinence (in part through avoidance of the environments where the individual participated in drinking), it is vital that there is continuing research to understand the interplay between different aspects of the environment and the particular neurobiological processes which drive excessive alcohol-drinking behaviours. 3. Environmental enrichment modifies alcohol-seeking behaviour and modulates relapse The effectiveness of non-pharmacological approaches to modify the behavioural and physical symptoms of drug withdrawal continues to be actively explored in a variety of rodent models, amongst which the paradigm of environmental enrichment appears to bear particular promise (Hajheidari et al., 2015; Li et al., 2015a; Peck et al., 2015). The anti-depressive and cognitive enhancing benefits of environmental enrichment (EE) are welldemonstrated in multiple rodent models of neurological conditions (Bondi et al., 2014; Jankowsky et al., 2005; Nithianantharajah and Hannan, 2006; Pang et al., 2009) and there is growing evidence that EE has the capacity to modify drug-seeking behaviour. The provision of EE housing during forced abstinence attenuates cue-

induced cocaine-seeking behaviour (Thiel et al., 2010) and reverses conditioned place preference (Chauvet et al., 2011), although it does not prevent drug-primed reinstatement (Li and Frantz, 2017). The constant provision of environmental stimulation is necessary to maintain those benefits since suppression of cocaine craving was lost after rats were removed from their enriched cages and returned to standard-housing conditions (Chauvet et al., 2012). This is particularly important when considered alongside the evidence that cue-induced drug-seeking behaviour is enhanced by social isolation (Thiel et al., 2010) because a combination of both is common to drug addicts who are affected by social withdrawal/ isolation and are frequently in situations of unstable housing conditions. The benefits of EE are well-accepted to be driven primarily through increased neuronal plasticity. This broadly involves alterations to the physiological properties of neurons, enhanced LTP, firing rates and network rhythms, most of which are wellcharacterised by studies of the hippocampus and cortical regions (Alwis and Rajan, 2013; Nichols et al., 2007; Rema et al., 2006). The impact of EE on neuronal networks and region-to-region signalling could account for enrichment-mediated modifications of drugseeking behaviour, e.g. the prevention of drug-induced reinstatement attributed to the modulation of infralimbic cortex activity (Solinas et al., 2008) and reduced cue-induced reinstatement associated with increased perineuronal net intensity within the medial prefrontal cortex (Slaker et al., 2016). However, there is still uncertainty regarding the exact brain regions involved in abstinence, and if these are subject to further modulation by environmental stimulation. One approach to identify such regions would be to examine the pattern of Fos expression, an immediate-early gene product which is routinely used as a molecular correlate of cellular activity. For example, compared to isolation and pairhoused conditions, environmentally enriched cocaine-abstaining rats have reduced Fos expression in the paraventricular nucleus of the hypothalamus (PVN), nucleus accumbens (NAc) shell, bed nucleus of the stria terminalis (BNST), the ventral tegmental area (VTA) and anterior cingulate cortex (Chauvet et al., 2011; Thiel et al., 2010). Interestingly, Fos expression in the nigrostriatal dopaminergic regions (substantia nigra and caudate putamen) remained unaltered by enrichment which suggests that the attenuation of drug-seeking behaviour does not necessitate manipulation of dopaminergic signalling. In this section, we will review the current evidence that EE modifies alcohol-seeking behaviour during withdrawal, then discuss the brain regions where the benefits of EE might converge. It is now common knowledge that the housing conditions into which rodents are weaned significantly modify their proclivity for alcohol. Social isolation of Fawn-Hooded rats from weaning leads to a greater proportion of them acquiring alcohol preference but this is reversible with the CRF1 receptor antagonist, antalarmin (Djouma et al., 2006; Lodge and Lawrence, 2003a). Isolationhoused Long Evans rats displayed greater alcohol preference and make more alcohol lever presses compared to pair-housed rats, though enrichment housing did not alter operant responding for 10% ethanol (Deehan et al., 2007). In a similar study of alcoholpreferring P rats, environmental enrichment decreased their natural preference for alcohol as evident from lower volumes of selfadministered alcohol (Deehan et al., 2011) which does suggest the potential for environmental interventions to override an existing genetic preference for alcohol. Similar EE-mediated modulations of alcohol-associated behaviours have been reported in mice. For example, standard-housed male Swiss-Webster mice receiving 20% v/v ethanol injections daily for 15 days displayed behavioural sensitization to alcohol administration but this response was prevented in enrichment-housed mice (Rueda et al.,

Please cite this article in press as: Pang, T.Y., et al., Novel approaches to alcohol rehabilitation: Modification of stress-responsive brain regions through environmental enrichment, Neuropharmacology (2018), https://doi.org/10.1016/j.neuropharm.2018.02.021

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2012). Male C57Bl/6 J mice housed in enriched conditions during the extinction phase after conditioned place preference are reported to be non-responsive to ethanol-induced reinstatement (Li et al., 2015b). Collectively, these reports are consistent in the positive modification of alcohol seeking behaviour in rodent species reflecting the benefits of environmental enrichment. Physical activity is often investigated as an easily dissociable component of environmental enrichment and elevating the level of physical activity has consistently been reported to modify alcoholdrinking behaviour. In mice, voluntary wheel-running for a subchronic 16-day period reduced alcohol preference in a two-bottle free-choice paradigm (Darlington et al., 2016), although this effect does appear to be selective for female mice (Ehringer et al., 2009; Gallego et al., 2015). In contrast, Lewis rats permitted two-bottle free-choice alcohol drinking for 5 weeks before alcohol was withdrawn persisted in their increased alcohol preference after 2 weeks of voluntary wheel-running (Werme et al., 2002). However this was attenuated in the group of abstinent rats after 4 weeks of running which again highlights that an extended treatment period might be necessary for robust behavioural modifications during withdrawal. Male Wistar rats which had undergone 10 weeks of operant alcohol self-administration and a separate group with an additional exposure to 7 weeks of chronic intermittent alcohol vapour exposure all displayed positive signs of being protected against cue-induced reinstatement after being provided running wheels during a 23day period of abstinence (Somkuwar et al., 2016). It would be interesting for future studies to examine whether running could also prevent the emergence of dysphoria-like behaviours associated with forced-abstinence in dependent animals (Bruijnzeel et al., 2010). Social interaction is another key factor in the environmental enrichment paradigm. This has been indirectly examined in the studies of social isolation and its impact on drinking behaviour. According to a recent study, single-housed male C57Bl/6 J mice showed greater preference for ethanol compared to group-housed mice (3e5 per cage) (Holgate et al., 2017). Social enrichment (group-housing only) is sufficient to protect against chronic stressinduced behavioural and corticosterone changes (Liu et al., 2013), and prevents stress-induced increases in daily ethanol intake and alcohol preference in male Wistar rats (Vazquez-Leon et al., 2017). Our group previously investigated the common psychiatric comorbidities of alcohol withdrawal using the two-bottle freechoice paradigm in female C57Bl/6 J mice. Additionally, we attempted to rescue those behavioural deficits through environmental manipulations. We showed that daily running for 2 weeks normalised abstinence-associated reduction in saccharin drinking and rescued abstinence-induced depressive-like effects in the novelty-suppressed feeding and forced-swim tests (Pang et al., 2013b). In a follow-up study, the provision of environmental enrichment (without running-wheels) during the 2-week forcedabstinent period similarly prevented the development of anhedonic behaviour (decreased saccharin preference) and prodepressive behaviour (increased immobility in the forced-swim test) which were observed in the standard-housed abstinent mice (Pang et al., 2013a). Therefore, the collective evidence suggests that positive environments potentially benefit the rehabilitative process by suppressing alcohol preference and preventing co-morbid depression. The dysregulation of HPA axis activity is documented in individuals undergoing withdrawal. Abstinent male alcoholics show a blunted response to an acute pharmacological stressor at several levels of HPA axis function (Adinoff et al., 1998; Costa et al., 1996), and this blunting has been shown to be predictive of relapse (Junghanns et al., 2003). During withdrawal, there is nonsuppression of cortisol by dexamethasone but greater cortisol and

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ACTH release upon a CRH challenge which signifies impairment of GR-mediated negative feedback regulation of the HPA axis concurrent with hyper-responsivity of the pituitary (Hundt et al., 2001; Sher, 2006). In an attempt to understand how enrichment is beneficial, we investigated the responsivity of the HPA axis and expression patterns of relevant genes given the well-documented stress-reducing effects of EE (Du et al., 2012; Morley-Fletcher et al., 2003; Skwara et al., 2012; Welberg et al., 2006). Despite no differences in serum corticosterone levels at baseline and after forced-swim stress exposure, we found that the alcohol-abstinent mice had an exaggerated corticosterone response to CRH stimulation (consistent with clinical observations) but this was not observed in abstinent mice under EE conditions (Pang et al., 2013a). In addition, expression levels of the glucocorticoid receptor were up-regulated in the hypothalamus in abstinent mice and this was normalised in the enriched mice. Our findings collectively suggest that EE regulates HPA axis response to correct an abnormal physiological stress response which manifests during alcohol abstinence. Further evidence of this comes from a recent study which found that EE during abstinence prevented acute restraint stressinduced escalation of alcohol intake in abstinent male C57Bl/6 J mice that had been subject to two-bottle free-choice drinking-inthe-dark for 15 days followed by intermittent 2-h weekly access (Marianno et al., 2017). Therefore, there is mounting evidence that EE alters behaviour during alcohol abstinence by modulating stress response, but a comprehensive characterisation of HPA axis regulation is still required. 4. EE-modulation of stress response involves brain regions common to stress-induced alcohol relapse Besides modulating corticosterone production in the periphery, environmental enrichment also regulates stress response by affecting central brain regions. Evidence of this can be gleaned from a study which took a reductive approach to environmental enrichment and exposed rodents to daily handling (itself a common protocol to habituate animals prior to behavioural testing). Male and female rats exposed to daily handling during the first 3 weeks of life or during adulthood have different patterns of neural activation post-stress, compared to non-handled controls (Abraham and Kovacs, 2000). In staining for Fos protein, stress elicited reduced neural activation in the paraventricular nucleus (PVN) of the hypothalamus, the bed nucleus of the stria terminalis (BNST), the central amygdala (CeA) and the hippocampus of handled rats. Therefore, this form of physical enrichment appears to dampen the activity of these stress-sensitive neural nodes. More conventional approaches to enrichment through a combination of social interaction and provision of novel objects and cage configurations also impact on those brain regions. EE dampens CeA neuronal activation in rats, which is up-regulated following exposure to novelty and water avoidance stress (Matsuda et al., 2017; Reichmann et al., 2013). Besides the CeA, the basolateral amygdala (BLA) is also involved in the emergence of stress-induced anxiety behaviour that is prone to environmental modulation. Gene expression of CRHR1 is significantly increased while that of the NPY-Y1 receptor is significantly decreased in the BLA after exposure to inescapable foot shock (another model of PTSD), and both are normalised by EE in parallel with rescue of anxiety-related behaviours (Hendriksen et al., 2012). Acute restraint stress also stress promotes a rapid increase in the nuclear translocation of GR in the BLA, an effect that is prevented by EE (Novaes et al., 2017). The effect of EE on stress resiliency also involves modulation of PVN hypothalamic CRH signalling since neural activity (reflected in the number of FosB þ cells) is markedly reduced in enriched mice following social defeat stress, compared to standard-housed

Please cite this article in press as: Pang, T.Y., et al., Novel approaches to alcohol rehabilitation: Modification of stress-responsive brain regions through environmental enrichment, Neuropharmacology (2018), https://doi.org/10.1016/j.neuropharm.2018.02.021

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stressed animals (Lehmann and Herkenham, 2011). EE also alters activity of the transcription factor CREB by reducing levels of phospho-CREB (the active form of the protein) in the nucleus accumbens (NAc) (Green et al., 2010). However, further validation and characterisation of how EE impacts on neuronal activity across these regions in the absence of a stressor is also warranted. How are these brain regions relevant to a brain which is undergoing alcohol withdrawal and is there potential for EE to attenuate stress-induced relapse? Firstly, all the above mentioned brain regions are implicated in alcohol dependence and relapse. Fos expression is up-regulated in the NAc core, dorsolateral striatum and orbitofrontal cortex of adult Sprague-Dawley rats after undergoing chronic intermittent alcohol drinking (Li et al., 2010). The number of Fos-positive neurons is also increased in the CeA of male Wistar rats following 24 h abstinence after a period of intermittent alcohol drinking (George et al., 2012). Interestingly, George et al., also found that abstinence led to selective recruitment of CRFpositive GABAergic interneurons in the medial prefrontal cortex, and this is further support of the hypothesis that abstinence behaviour is modulated by stress. Fos expression determined after cue-induced reinstatement of alcohol-seeking reveals increased activity in the anterior cingulate cortex, NAc core and shell, and PVN (Dayas et al., 2007). Targeting the NAc shell (and its major output targets eg. VTA, LH) could be particularly crucial to regulating alcohol-craving, given that there has been an attempt to reproduce the benefits of environmental enrichment through viralmediated overexpression of DFosB in the NAc shell which successfully decreased cocaine self-administration and relapse (Zhang et al., 2014). The acute phase of withdrawal is often marked by the highest incidence of relapse. After only 5 days of withdrawal, increased Fos expression is also observed in the VTA of alcohol non-sensitized Swiss mice compared to mice exhibiting alcohol-induced locomotor sensitization (De Pauli et al., 2014). The VTA is also implicated in fear response (Abraham et al., 2014; Tovote et al., 2015) so it is not surprising that during withdrawal from two-bottle free-choice alcohol drinking, rats display hypersensitivity to fear memory recall by escalating alcohol intake along with increased Fos expression in the basolateral amygdala, periaqueductal gray and dentate gyrus of the hippocampus (Bertotto et al., 2010). Increased glutamatergic neurotransmission in the VTA regulates cocaine-primed drugseeking behaviour and blockade of this prevents reinstatement (Sun et al., 2005), therefore further attempts to manipulate VTA dopaminergic neurons could still be pursued as a means of facilitating negative reinforcement during abstinence. As a side note, it is worth mentioning a recent report that context-induced relapse for cocaine is not dependent on activation of the NAc, CeA or VTA (Pelloux et al., 2018) which would suggest drug-specific patterns of neuronal activation during abstinence from a particular substance. How could we gauge whether these same brain regions would be involved in mediating EE-induced modification of the alcoholseeking behaviours during abstinence? One approach would be to examine the activation patterns in the brains of animals which have been administered a drug known to reduce alcohol intake and craving behaviour. Naltrexone is an FDA-approved opioid receptor antagonist which is used clinically to treat alcohol dependence. Administration of Naltrexone to rats with chronic intermittent access to alcohol reduces the Fos expression in the dorsolateral striatum, orbitofrontal cortex, NAc core, and also in the NAc shell (Li et al., 2010). As mentioned, the NAc shell is a prime target for environmental and pharmaco-modulation and as further support of this, a recent study successfully demonstrated that a novel GABAB receptor positive allosteric modulator prevented stressinduced alcohol drinking in part by dampening neuronal activation in the NAc shell (Augier et al., 2017).

Collectively, these brain regions are well-established to regulate stress response and behaviour, particularly relevant to pathological conditions such as PTSD where high co-morbidity of alcohol abuse is reported (see reviews by Bains et al., 2015; Chattarji et al., 2015; McEwen et al., 2015). In the process of stress-induced reinstatement of alcohol-seeking behaviour in Long Evans rats, increased Fos expression in the BNST correlates significantly with alcoholseeking behaviour (lever pressing) (Le et al., 2018). Inactivation of the central amygdala neuronal ensemble during abstinence curtails alcohol drinking behaviour (de Guglielmo et al., 2016) and this could translate into a second site of therapeutic interest to be targeted in conjunction with the NAc shell. Several of these brain regions were also identified in a separate study aimed at understanding the environmental modulation of sucrose-seeking behaviour (Grimm et al., 2016). Significant reductions of Fos expression were observed in the anterior cingulate cortex, the NAc shell, and CeA of enriched sucrose-abstinent rats, but only after 30 days of environmental enrichment (compared to only 1 day of enrichment housing). The finding again implies that a minimum period of therapeutic exposure is likely necessary before the cellular benefits of environmental enrichment can be observed. This could directly impact on the extent of behavioural modification so future studies evaluating the effectiveness of environmental enrichment during abstinence should factor this into their experimental design. Incidentally, 1 week of EE is reportedly sufficient to elicit increased cell proliferation and differentiation in the amygdala of adult non-drinking mice, resulting in greater numbers of oligodendrocytes and astrocytes (Okuda et al., 2009). Environmental enrichment of Long Evans high-anxiety (HAn) rats reduces their anxiety on the elevated-plus maze and yields greater numbers of BDNF-positive cells in the central amygdala and hippocampus compared to their isolation housed counterparts (Ravenelle et al., 2014). The enriched rats also had decreased sensitivity to amphetamine-induced hyperlocomotion which reflects environmental modulation of drug response. However the direct interaction with objects and changing housing configurations appear to be crucial for the benefits of environmental enrichment in this case since social housing alone (compared to isolation housing) produced no observable benefits. 5. Cognitive behavioural therapy (CBT) & mindfulness: clinical equivalents and analogues of environmental enrichment There have been several studies reporting on the potential benefits of providing psychosocial-centric therapy as an adjunct to pharmacological treatment for alcoholism. It is worth noting that a recent meta-analysis of 13 studies covering almost 2000 patients concluded that no single psychosocial intervention has the proven capacity to maintain abstinence successfully, but a reduction in recidivism is possibly achieved with a combination of CBT and pharmacology interventions (Khan et al., 2016). In a study of almost 300 outpatients, 12 weeks of CBT with adjunctive Naltrexone treatment (63%) achieved a greater rate of abstinence compared to CBT alone (36%) (Walters et al., 2009), demonstrating an effectiveness of this approach. However that success was over a relatively short 3-month period and examining patterns of abstinence over an extended time period is probably more relevant to the longterm health of the patient. A subsequent meta-analysis suggested that the combined treatment approach with CBT and naltrexone provides no additional benefit for the patient (compared to CBT/ placebo-treated patients) if relapse rate was taken as the sole measurement of success (Agosti et al., 2012). Despite improving the patient's quality of life (Laaksonen et al., 2013), it would appear that

Please cite this article in press as: Pang, T.Y., et al., Novel approaches to alcohol rehabilitation: Modification of stress-responsive brain regions through environmental enrichment, Neuropharmacology (2018), https://doi.org/10.1016/j.neuropharm.2018.02.021

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CBT alone may have limited use for the long term rehabilitative process, and additional interventions are required to maintain abstinence and prevent relapse. The inconsistent treatment outcomes associated with CBT could also be due to the heterogeneous nature of the study group such as whether they engage in low or high-risk drinking patterns, thus influencing the outcome (Vuoristo-Myllys et al., 2014). Another possible reason for unsuccessful outcomes of CBT could be the absence of follow-up support provided to the patient in order to ensure continuity of the rehabilitative process. This is evident from recent studies trialling a variety of technologies to enable cost-effective long-term monitoring of a patient's progress. One such randomised controlled study provided patients with daily interactive phone call (Alcohol Therapeutic Interactive Voice Response, ATIVR) compared to standard care, and at 12-months follow-up these patients achieved higher rates of continuous abstinence, reported no increase in drinking over time, and had lower incidence of relapse (Rose et al., 2012, 2015). Therefore, the perceived limitations of CBT could simply be due to having not provided therapy for a sufficient length of time (beyond the 3e6 months most studies have utilised) and/or the absence of follow-on monitoring of the patient post-CBT. These are important considerations for future studies should the effectiveness of CBT be the subject of further investigation. More recently, in a study of treatment-seeking abstaining patients who were receiving CBT, it was found that greater stress was significantly associated with more frequent and greater cravings, and a predictor of relapse (Law et al., 2016). That finding suggests that there exists an indirect association between the state of HPA axis functionality and the success of CBT treatment. Interestingly, in a separate study of panic disorder patients, CBT was not effective in improving the anxiety symptoms of patients who had the greatest hypo-responsiveness in their stress response (Wichmann et al., 2017). It is not known if the severity of HPA axis pathology could predict the likely outcome of CBT for alcoholics. If so, it would then be possible to identify the best candidates for receiving CBT during rehabilitation. Future studies could examine this issue by conducting an initial assessment of HPA axis function in an attempt to predict the most likely outcome of CBT treatment. In recent years, mindfulness has emerged as an alternative

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approach to achieving long-term abstinence. Mindfulness interventions are typically stress-reducing, though the precise physiological underpinnings remain unclear. The current understanding is that it triggers re-adaptation of the stress response resulting in lower cortisol levels, blood pressure and inflammatory cytokines (Pascoe et al., 2017). In normal healthy individuals, engaging in mindfulness (e.g. yoga and meditation) decreases feelings of anxiety and depressed mood, increases the cortisol awakening response (improved state of arousal) and plasma levels of BDNF (Cahn et al., 2017). While some of these behavioural and physiological benefits are reported to be sustained for up to 6 months (Wetherell et al., 2017), extended longitudinal studies are still required. However, since stress is a prime trigger for relapse and there is a growing body of evidence that mindfulness improves stress response, mindfulness might be an important component to the rehabilitation from substance abuse disorders. However there may be limitations to its efficacy as was in the case of patients with chronic recurring depression (Gex-Fabry et al., 2012), suggesting that mindfulness is ineffective if the current disorder was sufficiently severe. The number of studies investigating the effectiveness of mindfulness in rehabilitation from alcohol abuse has been growing in number and cohort size. In an early study of 19 patients provided mindfulness-based therapy 4e6 times per week, the majority (15/ 19) successfully completed a 30 day abstinent period (Zgierska et al., 2008). Not unexpectedly, patients also reported reduced anxiety, depression and stress, along with reductions of their basal plasma levels of cortisol and IL-6 at 16-week follow-up. Mindfulness has been trialled for various diseases and has consistently been reported to reduce stress and correct abnormalities in salivary or serum cortisol concentrations (Ardito et al., 2017; Sandler et al., 2017). As part of a larger study of 286 subjects with various substance abuse disorders including alcoholism found that a program of mindfulness-based relapse prevention led to significantly lower rates of relapse at 12-month follow-up (Bowen et al., 2014). Interestingly, it has been suggested that a positive change to the patient's own temperament (arguably improved due to less stress) is a significant predictive factor for the effectiveness of mindfulness to prevent relapse (Crescentini et al., 2015). It also appears that a

Fig. 1. Neural activity in brain regions implicated in alcohol relapse which are modulated by environmental enrichment and naltrexone treatment. Note the directional differences in neural activation after relapse (red arrows) and pharmacological (yellow arrows) or environmental (green arrows) interventions.

Please cite this article in press as: Pang, T.Y., et al., Novel approaches to alcohol rehabilitation: Modification of stress-responsive brain regions through environmental enrichment, Neuropharmacology (2018), https://doi.org/10.1016/j.neuropharm.2018.02.021

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formal, regimented mode of delivery of the mindfulness activity is necessary for successful limitation of craving (Enkema and Bowen, 2017), and this could be related to issues of motivation and overcoming craving during the initial phases of abstinence and rehabilitation. Unlike CBT which has been examined in combination with pharmacotherapy, studies of mindfulness as an adjunctive therapy with naltrexone have yet to be conducted. These studies will be required to establish the effectiveness of this combination of treatments in achieving long-term reductions of drinking, abstinence and impact on relapse rates. 6. Summary In recent years, significant advances have been made in our understanding of the neurobiology of alcohol addiction leading to the re-examination of current approaches to rehabilitation and therapy. Part of this improvement is driven by better understanding of the diverse non-genetic environmental factors such as stress and social isolation which influence alcohol-drinking behaviour and propensity for relapse. Preclinical studies have been essential in identifying the discrete parts of the brain (see Fig. 1) which respond to these external factors and this information is currently being used to pursue more targeted and effective treatment approaches. In identifying that environmental enrichment impacts on neural activity in brain regions similarly modulated under conditions of stress-induced relapse, the collective evidence supports the recommendation of adjunctive stress-reducing therapies in addition to treating the primary behavioural symptoms of alcohol addiction. Acknowledgements The authors would like to thank Gina Cocos for conducting the initial literature search. The authors declare no conflicts of interest in the preparation of this work. AJH (1117148) and AJL (1116930) are NHMRC Principal Research Fellows. TYP, AJH and AJL are also supported by NHMRC Project Grants (TYP & AJH: 1083468, 1138321; AJL: (1079893, 1105741, 1120576). We also acknowledge the Victorian State Government's Operational Infrastructure Program. References Abraham, A.D., Neve, K.A., Lattal, K.M., 2014. Dopamine and extinction: a convergence of theory with fear and reward circuitry. Neurobiol. Learn. Mem. 108, 65e77. Abraham, I.M., Kovacs, K.J., 2000. Postnatal handling alters the activation of stressrelated neuronal circuitries. Eur. J. Neurosci. 12, 3003e3014. Adinoff, B., Iranmanesh, A., Veldhuis, J., Fisher, L., 1998. Disturbances of the stress response: the role of the HPA axis during alcohol withdrawal and abstinence. Alcohol Health Res. World 22, 67e72. Agosti, V., Nunes, E.V., O'Shea, D., 2012. Do manualized psychosocial interventions help reduce relapse among alcohol-dependent adults treated with naltrexone or placebo? A meta-analysis. Am. J. Addict. 21, 501e507. Allen, C.D., Grigoleit, J.S., Hong, J., Bae, S., Vaughan, J., Lee, S., 2016. Exposure to alcohol during adolescence exerts long-term effects on stress response and the adult brain stress circuits. Neuroscience 339, 64e71. Alwis, D.S., Rajan, R., 2013. Environmental enrichment causes a global potentiation of neuronal responses across stimulus complexity and lamina of sensory cortex. Front. Cell. Neurosci. 7, 124. Anderson, R.I., Lopez, M.F., Becker, H.C., 2016. Forced swim stress increases ethanol consumption in C57BL/6J mice with a history of chronic intermittent ethanol exposure. Psychopharmacology (Berlin) 233, 2035e2043. Ardito, R.B., Pirro, P.S., Re, T.S., Bonapace, I., Menardo, V., Bruno, E., Gianotti, L., 2017. Mindfulness-based stress reduction program on chronic low-back pain: a study investigating the impact on endocrine, physical, and psychologic functioning. J. Alternative Compl. Med. 23, 615e623. Augier, E., Dulman, R.S., Damadzic, R., Pilling, A., Hamilton, J.P., Heilig, M., 2017. The GABAB positive allosteric modulator ADX71441 attenuates alcohol selfadministration and relapse to alcohol seeking in rats. Neuropsychopharmacology 42, 1789e1799.

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Please cite this article in press as: Pang, T.Y., et al., Novel approaches to alcohol rehabilitation: Modification of stress-responsive brain regions through environmental enrichment, Neuropharmacology (2018), https://doi.org/10.1016/j.neuropharm.2018.02.021