Research report
The effect of isolation rearing on volitional ethanol consumption and central CCK/dopamine systems in Fawn-Hooded rats

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Abstract

Numerous studies have demonstrated that socially isolating rats (from weaning) produces a sustained anxious phenotype and an enhanced response to psychostimulant drugs such as amphetamine and cocaine. In addition, isolation rearing has been shown to induce significant changes in the mesolimbic dopamine system. These data indicate that isolation rearing not only induces an anxiogenic phenotype but also induces neurochemical changes in reward nuclei of the brain, which is correlated with an enhanced response to psychostimulants. For these reasons, the effect of isolation rearing on volitional ethanol consumption was examined in Fawn-Hooded (FH) rats and correlated with neurochemical changes in central dopamine and cholecystokinin systems.

Social isolation from weaning produced an anxiogenic phenotype as measured by a decreased time spent on the open arms of an elevated plus-maze. Interestingly, isolation-rearing induced a greater proportion of FH rats to acquire preference for ethanol while having no effect on the amount of ethanol consumed by alcohol-preferring rats. In addition, isolation rearing induced a number of changes in central CCK/dopamine systems.

Introduction

Alcohol is one of the most widely used drugs throughout western society and its abuse is the cause of much social, medical and economic problems [34]. For this reason, there has been extensive research into the neurochemical actions of ethanol and the underlying pathophysiology of alcoholism. One major area of research has focused on the anxiolytic property of ethanol and it has been demonstrated that ethanol can decrease experimental anxiety in a number of different species, including humans [6], [12], [14], [64] due to its actions as an allosteric modulator of the GABAA receptor [26], [61]. For this reason, it has been suggested that an anxious phenotype may be associated with a pre-disposition to consume ethanol [60]; indeed, a correlation between high basal levels of experimental anxiety and high voluntary ethanol consumption has been demonstrated [60]. In addition, amygdaloid lesions and micro-injections of GABA agents into the amygdala reduce experimental anxiety and produce a reduction in ethanol consumption [21], [43].

Numerous studies have demonstrated that socially isolating rats (from weaning) produces a sustained anxious phenotype [67] and an enhanced response to psychostimulant drugs, such as amphetamine and cocaine [49], [54], [59]. More specifically, amphetamine administration has been shown to produce an enhanced increase in locomotor activity in socially isolated rats [49], [54], [59] and this is correlated with an enhanced increase in dopamine release from the nucleus accumbens septi (Acb) compared to group-housed rats [22]. These data indicate that isolation rearing not only induces an anxiogenic phenotype but also induces neurochemical changes in reward nuclei of the brain that are correlated with an enhanced response to psychostimulants.

Another potent modulator of behavioural state is the neuropeptide cholecystokinin (CCK) which has been implicated in the modulation of a number of central processes including anxiety [50], cardiovascular [15] and respiratory [16] control, satiety [66], body weight regulation [41], and central reward processing [62]. The ability of CCK agents to modulate behavioural state has been widely reported and attributed to an action at the central CCK-B (CCK2) receptor subtype [58]. Thus, selective CCK-B agonists such as t-BOC-CCK-4 and BC 197 are potent anxiogenics in a number of different species [2], [11], [51], [52]; while selective CCK-B antagonists such as Ci-988 and L-365,260 display an anxiolytic profile [42], [57]. In addition, CCK has been implicated in the actions of abused drugs, such as cocaine [23], [40], amphetamines [24], [62] and ethanol [8], [9], [65]. Moreover, CCK is co-localised with dopamine in primary reward neurones of the rat brain [7], [28], [55], [56] and it has been demonstrated that CCK can modulate dopaminergic neurotransmission in these neurones [27], [37], [39]. In addition, recent studies have demonstrated receptor–receptor interactions between the dopamine D2 and CCK-B receptors, with CCK agonists altering the affinity of the dopamine D2 receptor in vitro and ex vivo [1], [32], [33].

Therefore, the aim of the present study was to examine the effects of isolation rearing on the acquisition and maintenance of volitional ethanol consumption in alcohol-preferring Fawn-Hooded (FH) rats [5], [53]. In addition, the effects of isolation rearing on the central CCK and dopamine systems were characterised with particular emphasis on the dopamine D2 and CCK-B receptors and the mRNA encoding preproCCK and tyrosine hydroxylase (TH, the rate limiting enzyme in dopamine/catecholamine synthesis).

Section snippets

Animals

All experiments were performed in accordance with the Prevention of Cruelty to Animals Act 1986 under the guidelines of the National Health and Medical Research Council Code of Practice for the Care and Use of Animals for Experimental Purposes in Australia.

All rats were housed in the Department of Pharmacology, Monash University Animal House and kept at constant temperature and humidity with lights on from 07:00 to 19:00 h, and free access to food (standard rat chow) and water. FH rats were from

Behavioural effects of isolation rearing

Isolation rearing induced an anxious phenotype in the FH rats as characterised by a decrease in the time spent (−43%) in the open arms of an elevated plus-maze relative to group-housed rats (Fig. 1A). Interestingly, isolation rearing also decreased locomotor activity as seen by a decrease in the total number of entries into the arms of the plus-maze (Fig. 1B). In addition to spending less time on the open arms of the elevated plus-maze, all of the rats reared in isolation acquired an

Discussion

This study is the first to examine the effects of isolation rearing on volitional ethanol consumption and the central CCK and dopamine systems of alcohol-preferring, FH rats. Social isolation from weaning induced an anxiogenic phenotype as determined by a decrease in the time spent and the number of entries into the open arms of an elevated plus-maze compared to group-housed rats, consistent with previous observations [67]. Interestingly, isolation rearing also decreased the number of total arm

Conclusion

This study reports for the first time on the effects of isolation rearing on volitional ethanol consumption and the central CCK and dopamine systems of alcohol-preferring, FH rats. Social isolation from weaning induced an anxiogenic phenotype and induced a greater proportion of FH rats to consume ethanol, while having no effect on the average daily ethanol consumption. These data further suggest that behavioural state may play a role in the acquisition, but not in the maintenance of ethanol

Acknowledgements

The authors wish to thank Dr. L. Iversen for the generous gifts of L-364,718 and L-365,260, and Astra Pharmaceuticals for the gifts of NCQ 634 and raclopride. This work was supported by the Australian Brewers’ Foundation and the National Health and Medical Research Council (Australia) of which A.J. Lawrence is a Senior Research Fellow.

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      Increased ethanol consumption after chronic adolescent social isolation, usually assessed in adulthood, is associated with increased reward sensitivity and anxiety, which are potential mediators. For example, isolation-rearing increased ethanol preference in ethanol preferring male fawn hooded rats (Hall et al., 1998b; Lodge and Lawrence, 2003c), which was associated with anxiety (Djouma et al., 2006; Hall et al., 1998a). Consistent with this role for isolation-induced increases in anxiety driving ethanol consumption in these rats, both diazepam and the CRFR1 Antagonist CP-154,526 reduced ethanol consumption in isolation-reared fawn hooded rats (Lodge and Lawrence, 2003b).

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