Inescapable footshock

Historically, inescapable footshock was one of the first stressors used in which investigators reported that exposure to stress was capable of eliciting an increase in alcohol consumption relative to a group of similarly treated controls without shock exposure and/or relative to a period of unstressed baseline ethanol consumption (e.g., Anisman and Waller 1974; Kinney and Schmidt 1979; Mills et al. 1977; Volpicelli et al. 1990). For example, when adult male Holtzman rats were exposed to either 6 or 12 h alternating periods of unsignalled inescapable footshock presented on either a fixed or random interval schedule, alcohol intake was found to significantly increase relative to non-shocked controls (Anisman and Waller 1974). More recently, other studies utilizing footshock exposure have reported a similar stress-induced increase in alcohol intake (Fullgrabe et al. 2007; Siegmund et al. 2005; Vengeliene et al. 2003).

However, upon closer inspection, many of these outcomes were not especially robust. For example, in the Kinney and Schmidt (1979) study, while cued delivery of inescapable footshock significantly increased alcohol intake compared to non-stressed controls, this increase was only significant during one of the four time periods in which footshock and alcohol access were concurrently experienced. Furthermore, another group of animals in the same study that was exposed to unsignalled footshock failed to significantly increase their alcohol consumption. While Mills et al. (1977) also reported that footshock increased alcohol consumption, this effect was only observed for a short time immediately following stress exposure (there was no difference in overall 24-h intake). Although Vengeliene et al. (2003) also demonstrated that three consecutive days of 10-min exposure to footshock increased alcohol intake among several different strains/lines of rats (Wistar, HAD, P, and AA rats), these increases were only observed on one or maximally 2 days of shock exposure.

In contrast, there have been several studies that have utilized inescapable footshock and subsequently found stress-associated decreases in alcohol intake (Bond 1978; Champagne and Kirouac 1987; Darnaudery et al. 2007). For example, when footshock was administered for 6 days to male Sprague–Dawley rats, alcohol intake significantly decreased, returning to prestress levels after stress exposure was terminated (Bond 1978). While Volpicelli et al. (1990) showed that a short period of footshock increased alcohol intake in rats that initially exhibited low preference for alcohol, other findings indicate that rodents exhibiting a relatively high preference for alcohol prior to stress will exhibit footshock-induced decreases in alcohol consumption (Bond 1978; Volpicelli et al. 1990). Adding to these mixed results, there are instances in which no change in alcohol consumption following inescapable footshock treatment has been reported. For example, several studies examining the effects of foot-shock stress reported no appreciable change in alcohol consumption among adult male rats under a variety of circumstances (e.g., Brunell and Spear 2005; Fidler and LoLordo 1996; Myers and Holman 1967; Powell et al. 1966). Similarly, several strains of mice, including DBA/2 and A/J (Matthews et al. 2008), and the high alcohol preferring selectively bred HAP1 line (Chester et al. 2008) have failed to demonstrate footshock-related changes in alcohol intake.

When analyzing the possible variables that may have contributed to differences across studies in regards to the effect of footshock stress on alcohol consumption, there are virtually no clear patterns that would seemingly explain a reliable increase or decrease in consumption. In considering whether the footshock stressor is administered in a predictable vs. unpredictable manner, for example, in two different rat studies (Cicero et al. 1968; Kinney and Schmidt 1979) and one mouse study (Racz et al. 2003), a cued inescapable footshock elicited significant increases in ethanol consumption, whereas random unsignalled foot-shocks did not. It would be tempting to conclude, therefore, that presentation of a cued inescapable shock is more likely to result in increased alcohol intake. Yet, in most studies that reported increased alcohol consumption following footshock (see Table 1), the shock was not signaled. The same could be said for the duration of footshock exposure: studies reporting footshock-induced increases in alcohol intake have used as few as one (Racz et al. 2003) or three repeated days of footshock exposure (e.g., Siegmund et al. 2005; Vengeliene et al. 2003), while others have reported increases in intake after as many as 27 (Kinney and Schmidt 1979) or even 35 (Myers and Cicero 1969) exposures to the stressor. When examining studies reporting no change in intake, both mouse (Matthews et al. 2008) and rat (Brunell and Spear 2005) studies have failed to observe footshock-related increases in intake with as few as 1 day of stress exposure or as many as 24–30 repeated footshock sessions (Cox and Stainbrook 1977; Ng Cheong Ton et al. 1983).

The amount of experience with alcohol consumption prior to stress presentation is another variable that differed greatly across these studies, yet seemed to have no predictive value for determining whether footshock would significantly alter alcohol intake. For instance, studies in which animals had little or no prior opportunity to drink alcohol have reported decreased (e.g., Bond 1978), increased (e.g., Anisman and Waller 1974), or unchanged (e.g., Brunell and Spear 2005; Myers and Holman 1967; Von Wright et al. 1971) alcohol intake following footshock experience. Likewise, studies in which animals were given at least 2 weeks access to alcohol prior to stress administration have reported decreased (Darnaudery et al. 2007), increased (Mills et al. 1977; Vengeliene et al. 2003), or unaltered (Fidler and LoLordo 1996; Ng Cheong Ton et al. 1983) alcohol consumption as a function of footshock exposure.

It is tempting to speculate that biological variables (sex, genotype) may play a significant role in determining the outcome of these studies. Unfortunately, when assessing the role that sex of the animal may have on whether or not footshock stress is likely to result in increases or decreases in intake, limited studies are available. While only a few studies included analysis of female subjects, results from those studies were similarly mixed. Specifically, footshock stress in females was reported to increase (Fullgrabe et al. 2007), decrease (Darnaudery et al. 2007), or not significantly alter (Chester et al. 2008; Cox and Stainbrook 1977; Powell et al. 1966) alcohol consumption.

When considering strain of rat, however, there is some evidence to suggest that certain strains may be more prone to demonstrate footshock stress-induced increases in intake. Specifically, the majority of studies reporting stress-related increases in ethanol intake were experiments that utilized Long–Evans (Mills et al. 1977; Mills and Bean 1978; Myers and Cicero 1969) or Wistar rats (Fullgrabe et al. 2007; Siegmund et al. 2005; Vengeliene et al. 2003). In contrast, with the exception of one case (Volpicelli et al. 1990), studies using Sprague–Dawley rats as subjects have most often found either no change in intake (Brunell and Spear 2005; Casey 1960; Cox and Stainbrook 1977; Fidler and LoLordo 1996) or decreased alcohol consumption (Champagne and Kirouac 1987; Darnaudery et al. 2007) during exposure to footshock stress. To our knowledge, the effects of footshock stress on alcohol consumption have not been directly compared among different outbred or inbred strains of rats. Future studies that directly compare some of these strains of rats will be necessary in order to more firmly establish whether a particular genotype confers greater or lesser susceptibility to footshock-induced changes in alcohol consumption. Unfortunately, since so few studies have assessed the effects of footshock stress on alcohol intake among mice, it is premature to draw conclusions as to genetic contributions to the outcome of such studies. Only one study directly compared three inbred mouse strains for the ability of footshock stress to alter drinking. Results from this study indicated that C57BL/6J mice increased alcohol intake in the 24 h following a single acute 15-min footshock exposure, while no change in intake was reported in DBA/2J and A/J mouse strains (Matthews et al. 2008). Given the extensive literature regarding genetic influences on alcohol consumption and stress response in mice (Crabbe 2008; Crabbe et al. 2006; Holmes 2008; Mozhui et al. 2010), systematic evaluation of the influence of footshock stress on alcohol consumption among different genetic mouse models is certainly warranted.

Restraint

Another popularly explored stressor in rodent studies is restraint or immobilization stress. As with footshock stress, some studies employing restraint have reported this stressor to significantly increase alcohol consumption (Derr and Lindblad 1980; Lynch et al. 1999; Ploj et al. 2003; Roman et al. 2004). For example, Lynch et al. (1999) found male Wistar rats that experienced repeated immobilization stress increased alcohol intake compared to non-stressed controls. However, in this study, rats were exposed to several phases of forced access to alcohol, which may have impacted the effects of stress on “choice” drinking. Additionally, while 4 days of repeated restraint were shown to significantly increase alcohol intake in both adult male (Ploj et al. 2003) and female (Roman et al. 2004) Wistar rats, this effect was dependent upon whether the animals were earlier exposed to maternal separation stress, and the interaction of this variable on drinking outcome differed for males and females. There are, alternatively, numerous studies in the literature that have reported either restraint stress-induced decreases in alcohol intake (e.g., Chester et al. 2004; Ng Cheong Ton et al. 1983; Sprague and Maickel 1994) or no change in alcohol consumption following exposure to this type of stressor (e.g., Bertholomey et al. 2011; Bowers et al. 1997; Rockman et al. 1987; Roman et al. 2003).

Upon examination of the many variables that could potentially influence the manner in which restraint stress impacts alcohol drinking, there appears to be no clear factor that emerges as a primary determinant of the outcome of such studies. For example, if considering the influence of amount of restraint stress exposure, studies have shown increased (Ploj et al. 2003; Roman et al. 2004), decreased (Haleem 1996; Sprague and Maickel 1994), or no change (Roman et al. 2003; Tambour et al. 2008) in alcohol consumption with as few as 1–4 days of restraint treatment. Similarly, studies involving more extensive restraint stress exposure (2–8 weeks) have reported increased (Derr and Lindblad 1980; Lynch et al. 1999), decreased (Chester et al. 2004; Krishnan et al. 1991), or unaltered (Nash and Maickel 1985; Ng Cheong Ton et al. 1983) alcohol intake.

Another variable to consider is the duration of restraint during each stress session. For this variable, there is again no clear pattern that emerges as to whether duration/intensity of restraint relates to an increase or decrease in alcohol consumption. For example, relatively short exposures (~15–30 min restraint) have been shown to increase (Lynch et al. 1999) or have little effect (Ng Cheong Ton et al. 1983; Roman et al. 2003) on alcohol intake. Likewise, studies that employed relatively long durations of daily restraint (≥18 h) reported increased (Derr and Lindblad 1980) or decreased (Abraham and Gogate 1989) levels of alcohol consumption. Variable unpredictable restraint has been utilized as well, with several studies reporting decreased (Chester et al. 2004; Krishnan et al. 1991; Sprague and Maickel 1994) or unaltered (Nash and Maickel 1985; Rockman et al. 1987) alcohol intake.

As was the case for studies employing footshock stress, there is little indication that the amount of experience with alcohol prior to stress exposure predicts the manner in which restraint stress subsequently modifies drinking behavior. Specifically, studies in which animals were given a relatively short period of “baseline” drinking prior to stress (i.e., ≤1 week) have reported increased (Derr and Lindblad 1980) or no change (Nash and Maickel 1985) in alcohol intake subsequent to restraint exposure. Likewise, studies in which animals were provided access to alcohol for longer periods of time prior to stress exposure (≥2 weeks) report increased (Ploj et al. 2003; Roman et al. 2004), decreased (Abraham and Gogate 1989; Chester et al. 2004; Krishnan et al. 1991), or no change (Bertholomey et al. 2011; Roman et al. 2003; Tambour et al. 2008) in alcohol consumption once restraint stress was administered.

Examining the influence of sex on restraint stress-induced changes in alcohol drinking is difficult due to the fact that so few studies have included analysis of female subjects. To our knowledge, only three such studies have been conducted: one demonstrating restraint-induced increases (Roman et al. 2004) and two reporting unchanged alcohol consumption (Bertholomey et al. 2011; Tambour et al. 2008) after restraint stress. Finally, it is difficult to draw conclusions regarding the influence of genetics on the ability of restraint stress to modulate alcohol drinking. While it is the case that three of the four studies reporting restraint stress-induced increases in alcohol intake used Wistar rats (Lynch et al. 1999; Ploj et al. 2003; Roman et al. 2004), studies reporting unchanged or decreased intake were conducted across a variety of strains, including Wistar rats. Again, very few studies have systematically examined the effects of restraint stress on alcohol consumption in different strains/lines of mice.

Forced swim

More recently, researchers have begun to explore the potential of other stressors such as forced swim to influence alcohol consumption. Generally, the forced swim test (FST) consists of inescapable exposure to a tank of room temperature water for a session ranging from 6 to 15 min in duration. Currently, there are a limited number of studies in which repeated exposure to the FST is reported to significantly elevate alcohol intake and, in most instances, the change in alcohol consumption was modest and transient in nature. This is true for studies conducted with rats (Fullgrabe et al. 2007; Siegmund et al. 2005) and mice (Cowen et al. 2003a, b; Sperling et al. 2010). On the other hand, there are several instances in which forced swim stress exposure either did not alter alcohol intake during the stress exposure phase in rats (Sommer et al. 2008; Vengeliene et al. 2003) and mice (Boyce-Rustay et al. 2007; Lowery et al. 2008) or even resulted in decreased alcohol intake (Boyce-Rustay et al. 2008). It is important to note that a few reports have observed significant FST-induced increases in alcohol intake long after the stress exposure ended, with these post-stress increases not emerging until at least 3 weeks later and only in certain mouse strains (e.g., BALB/cJ but not C57BL/6N, in Lowery et al. 2008) or genetic models (e.g., CRFR1 knockouts but not wild-type mice, in Sillaber et al. 2002).

Since duration of the swim test is relatively short, generally 5–10 min, and varies little across studies, this variable is unlikely to have contributed to the discordant results noted above. Additionally, it is difficult to conclude that the number of FST stress sessions relates to a particular outcome in these studies since alcohol drinking was typically assessed in the context of FST exposure being repeated over 2–5 days. For example, FST stress-induced increases in alcohol intake have been reported in both rats and mice following two (Cowen et al. 2003a, b) and three (Fullgrabe et al. 2007; Siegmund et al. 2005) days of repeated forced swim testing. Other studies, however, have indicated little change in alcohol consumption after a single acute FST session (Boyce-Rustay et al. 2007), or when FST testing was repeated for 3 days (Sillaber et al. 2002; Sommer et al. 2008; Vengeliene et al. 2003) or five consecutive days (Lowery et al. 2008; Mutschler et al. 2010). Although one study that used a more protracted period of FST exposures (14 consecutive days) reported stress-related decreases in consumption, this reduction was strain dependent, being significant in DBA/2J and BALB/cByJ strains but not in C57BL/6J mice (Boyce-Rustay et al. 2008). Furthermore, in another study by the same group (Boyce-Rustay et al. 2007), the same 14-day regimen of repeated FST exposures did not alter alcohol consumption, suggesting that a longer period of stress presentations in and of itself will not necessarily lead to an observation of FST-induced decreased alcohol intake. Taken together, it is difficult to attribute a specific effect of this stressor on alcohol drinking to the amount of forced swim stress exposure.

Since all of the studies examining FST exposure in Table 1 have involved providing animals with access to alcohol for at least 2 weeks prior to accessing the effects of the stressor on alcohol drinking, it is unlikely that this variable can effectively sort out the discrepant outcomes reported in these studies. Further, as noted above for footshock and restraint stressors, it is difficult to gauge the role of sex in defining the effects of restraint stress on alcohol consumption because so few studies have examined such effects in female subjects. Despite the relatively small number of studies conducted with rats, Wistar rats were shown to exhibit slight increases in alcohol intake following FST exposure (Fullgrabe et al. 2007; Siegmund et al. 2005; Vengeliene et al. 2003). Interestingly, FST exposure did not significantly alter alcohol intake in several lines of rats selectively bred for high alcohol preference (P, HAD, AA lines) (Vengeliene et al. 2003). Therefore, as with sex of the animal, strain of rat used is a variable that has not yet been systematically examined in the literature.

For studies that have utilized different mouse strains/genotypes, again, it is difficult to directly ascertain whether particular lines are more or less susceptible to the effects of FST on alcohol intake since so few studies have been conducted to specifically address this issue. For instance, though results from a few studies would suggest that C57BL/6 mice may be relatively insensitive to the effects of FST exposure on alcohol drinking (e.g., Boyce-Rustay et al. 2007, 2008; Lowery et al. 2008), another study recently reported that FST exposure increased alcohol consumption in this same inbred mouse strain (Sperling et al. 2010). Clearly, more studies are needed that directly compare the effects of FST stress on alcohol drinking in several mouse genotypes.

It is noteworthy that a unique feature of the forced swim stressor is that, as opposed to other stressors such as footshock and restraint, the FST procedure enables assessment of behavioral responsiveness to the stressor during its application. This is attractive because it provides an opportunity to gain insight about how individual differences in coping strategies exhibited during FST exposure may relate to subsequent avidity for alcohol. Unfortunately, to our knowledge, none of the studies examining the effects of an FST stressor on alcohol intake have attempted to relate behavioral (coping) response exhibited during FST exposure with later levels of alcohol intake. In a few instances, behavioral response during FST exposure was recorded in studies involving different age groups (e.g., Fullgrabe et al. 2007) or genetically manipulated lines (e.g., Cowen et al. 2003a, b; Sperling et al. 2010; Vengeliene et al. 2003). However, in these few cases, group differences that were either present or absent in FST-related behavior failed to explain later group differences in alcohol consumption. It is important to note that in these studies, individual relationships between FST behavior and later drinking within a group were not analyzed. Using a different approach, Weiss and his colleagues have shown that rats selectively bred for stress-induced suppression of struggling behavior in the FST procedure (the “stress susceptible” or “SUS” line) demonstrated increased levels of alcohol intake under basal (unstressed) conditions compared to a stress-resistant line and non-selected control line of rats. Further, the increased alcohol consumption in SUS rats, measured in a two-bottle choice situation, approached levels of intake and preference exhibited by rats selectively bred for high alcohol consumption (Weiss et al. 2008; West and Weiss 2006). In a similar vein, another study involving outbred CD1 mice examined the relationship between stress response in a related procedure (tail suspension test; TST) and later alcohol drinking. After characterizing mice as exhibiting high vs. low immobility in the TST, it was shown that the more stress-responsive mice consumed more alcohol in a two-bottle choice situation compared to mice that displayed less immobility (more struggling) in the task (Pelloux et al. 2005). This effect was only observed in females. Nevertheless, these latter findings suggest that more rigorous examination of individual differences in behavioral (coping) response to stressors such as the FST might provide additional insight into the complex relationship between stress responsiveness and propensity to drink. Clearly, this is an area of research that warrants further investigation.

Social defeat

This stressor is particularly ethologically relevant to rodents, containing both physical and psychological components (Miczek et al. 2008). Generally, experimental subjects are placed into the home cage of a “resident” (who has been shown to consistently display aggressive behavior towards intruders) for a short period of time, allowing for the resident to physically chase and attack the experimental subject. In some instances, a perforated divider is then placed in the cage to prevent the animals from physically interacting with each other, yet allowing the intruder to still see, smell, and hear the aggressive resident for a certain period of time. Studies investigating the effects of social defeat stress on the intruder rodent have shown that this stressor reduces both home cage (van Erp and Miczek 2001; van Erp et al. 2001) and operant self-administration (Funk et al. 2005; van Erp and Miczek 2001) of alcohol in rats. A few experiments that have investigated the effects of social defeat stress in mice have generally found little change in alcohol consumption during the stressor phase of the study (Croft et al. 2005; Sillaber et al. 2002). Interestingly, in both of these mouse studies post-stress increases in intake were observed, but not until several weeks after the conclusion of the social defeat experience. Since such a limited number of studies using social defeat stress have been conducted, elucidating the variables responsible for discrepancies across studies is not possible at this time. While evidence from rat studies might suggest that more intense social defeat sessions result in an even greater reduction in ethanol intake (e.g., van Erp et al. 2001), future research would need to validate and expand on this relationship between stressor duration/intensity and ethanol consumption before more firm conclusions are drawn.

Social isolation

Although the effects of individual housing on subsequent alcohol consumption have generally been examined following long-term periods of social isolation (see below), there have been a few instances in which shorter periods of isolation were investigated in rats. Not surprisingly, results regarding the effects of brief periods of social isolation have been mixed as well, with increased (Mediratta et al. 2003; Nunez et al. 2002, 1999), decreased (Doremus et al. 2005; Sprague and Maickel 1994), and unaltered alcohol intake (Nash and Maickel 1985) relative to non-stressed (group-housed) controls reported during the period of stressor exposure. It is important to note that in most of the studies in the literature that have examined the relationship between stress exposure and alcohol consumption, animals are individually housed in order to easily and more accurately assess alcohol intake of individual animals during the experiment. Since the few available studies that have examined the effects of social isolation for more brief periods after weaning have provided such conflicting results, future studies examining the influence of social isolation stress on alcohol consumption would be beneficial as they would help to inform researchers designing future studies regarding the potential influence that isolate housing may have on the results obtained.

Other stressors

In addition to the types of stressors utilized as described above, there are several other stress procedures that researchers have used to examine the relationship between stress and alcohol consumption. For example, tail pinch (Adams 1995), fear-conditioned memories (Bertotto et al. 2010), food restriction (Schroff et al. 2004), shock probe exposure (Sandbak and Murison 2001), saline injections (Little et al. 1999), repeated cage changes (O'Callaghan et al. 2002), ultrasonic noise (O'Callaghan et al. 2002) and overcrowding (Weisinger et al. 1989) are all stressors which have been studied for their ability to influence alcohol consumption, with again, these stressors varying in the direction of their effects on intake (see Table 1 for details).

Post-stress increases in alcohol consumption

When examining the literature concerning the effects of acute/sub-chronic stress exposure on alcohol intake, there have been several instances in which post-stress increases in intake have been observed (e.g., Casey 1960; Croft et al. 2005; Lynch et al. 1999; Nash and Maickel 1985; Volpicelli et al. 1986, 1990). In one study, the effect was reported to last for as many as 6 months after stress exposure (Sillaber et al. 2002). However, other groups have failed to observe delayed effects of stress on alcohol consumption (Boyce-Rustay et al. 2007; Fidler and LoLordo 1996; Tambour et al. 2008) or have found that post-stress elevations in intake are only observed under limited conditions—in certain genotypes and/or only one sex (e.g., Chester et al. 2006; Sillaber et al. 2002). Specifically, of the 78 individual citations listed in Table 1, 59 monitored ethanol intake for a period of time following the termination of stressor exposure. Of these 59 studies, only 41% (24 studies) reported a significant post-stress increase in intake, while the remaining 35 studies reported a decrease or no change in alcohol consumption. Therefore, a more general overview of the literature would indicate that increases in alcohol consumption during a period of time following termination of stress exposure are not observed in as many studies as is often thought.

Summary

Over several decades, a large body of work has been conducted in animals examining the influence of acute/sub-chronic stress experience on alcohol consumption. Various stress procedures have been employed using numerous models and a wide variety of experimental conditions. Despite a general perception in the field that stress is associated with increased alcohol drinking, as shown in Table 1, an overview of this literature reveals equivocal findings, with studies indicating increased, decreased, or no change in alcohol consumption under a variety of stress conditions. There have been multiple proposed hypotheses as to why models of acute/sub-chronic stress exposure do not always increase alcohol intake, and many of these revolve around specific experimental parameters that are thought to favor a particular outcome. These include, but are not limited to, the context in which the stressor is experienced in relation to drinking access (Caplan and Puglisi 1986; Volpicelli et al. 1982), controllability of the stressor (Volpicelli and Ulm 1990), and whether the stressor is signaled or unsignalled (Kinney and Schmidt 1979). While there may be general trends in the influence of these variables on stress-induced changes in alcohol consumption, there are exceptions in nearly every case, and these observations may no longer remain true when considering different species, strains, or stressors.

The factors contributing to stress-induced decreases in alcohol consumption are not entirely clear, although numerous explanations have been hypothesized. In some studies, it has been suggested that rats exhibiting a higher alcohol preference due to such factors as sweetening of the alcohol solution (Bond 1978), induction of drinking via forced consumption (Bond 1978), naturally occurring individual differences in consumption (Darnaudery et al. 2007), or genetic selection for high alcohol intake (Chester et al. 2004) are more likely to express stress-induced reductions in intake. However, this explanation may be too simplistic since there are other circumstances in which initial high alcohol preference was not associated with stress-related suppression of alcohol consumption (Boyce-Rustay et al. 2008; Fidler and LoLordo 1996; Powell et al. 1966). Finally, it should be noted that as indicated in Table 1, there are a substantial number of studies that report no change in alcohol consumption following acute/sub-chronic exposure to various stressors. No doubt, many factors including prior alcohol experience, predictability of the stressor, duration of stressor application, as well as the nature and intensity of the stressor contribute to these equivocal findings in the literature. In surveying this body of work, it is difficult to draw consensus about factors that contribute to a particular outcome (increased vs. decreased alcohol intake) because these variables do not seem to account for differences in results across studies in a systematic or reliable manner.

Maternal separation

Most of the studies that examined effects of early maternal separation in rodents reported decreased alcohol intake or no change in later drinking (for a review see Roman and Nylander 2005). This is especially the case when the duration of daily maternal separation was relatively short (<60 min; usually about 15 min). For example, except for one study (Lancaster 1998), daily separation of rat pups from their mothers for short time intervals during the first 3 weeks of life have generally resulted in decreased alcohol intake during adulthood (e.g., Ploj et al. 2003; Roman et al. 2005, 2003). In contrast, relatively long-term daily maternal separation (60–360 min per day) resulted in increased alcohol intake later in life (Huot et al. 2001; Ploj et al. 2003; Roman et al. 2005), although other studies reported no change in alcohol consumption (e.g., Jaworski et al. 2005; Marmendal et al. 2004). In these studies, maternal separation was repeated for several days, which varied across studies (7–20 days). However, it is the duration of each episode of maternal separation (short vs. long) that appears to determine the direction of the effect (increase vs. no change) rather than the number of days that maternal deprivation was experienced by the pups.

Maternal separation studies in rats have included use of several strains (e.g., Wistar, Long–Evans) as well as lines selectively bred for high alcohol intake (alcohol accepting; AA line). The only study that reported elevated alcohol intake following short duration maternal separation was conducted with Long–Evans rats (Lancaster 1998). The remaining studies cited in Table 2 that involved short-duration maternal separation reported either no change or decrease in alcohol intake, and none of these studies used Long–Evans rats. Thus, increased alcohol consumption following short-duration maternal separation may be unique to this particular strain of rats. In the case of long-duration maternal separation, increased alcohol consumption was observed across different strains of rats: Wistar (Ploj et al. 2003), Long–Evans (Huot et al. 2001), and AA (Roman et al. 2005). In most cases, the effect of maternal separation exposure on later alcohol consumption was similar in both male and female offspring. The one exception was an apparent sex-dependent increase in drinking observed only in male AA rats following long-duration maternal separation (Roman et al. 2005).

Studies examining the effects of maternal separation on alcohol self-administration in mice are more limited. In one study, repeated maternal separation prior to weaning did not alter subsequent alcohol intake in C57BL/6J mice, although increased alcohol consumption was reported in female offspring that experienced maternal separation and then were housed in isolation prior to testing (Advani et al. 2007). In another study, daily maternal separation (180 min) in outbred CFW mice produced higher levels of drinking and operant self-administration in adulthood, but progressive ratio testing did not reveal an apparent alteration in the reinforcing efficacy of alcohol (Cruz et al. 2008). Taken together, although there is limited evidence from studies conducted with mice, a similar pattern emerges in that short-duration maternal deprivation produces little change in later alcohol intake (Advani et al. 2007), while more prolonged maternal deprivation favors an outcome of increased alcohol consumption (Cruz et al. 2008).

Studies conducted with nonhuman primates have shown that maternal deprivation has long-lasting effects on behavioral and biological indices of stress and anxiety (Higley et al. 1991b). For example, peer-reared rhesus monkeys show profound alterations in neuroendocrine stress response (chronic elevation of cortisol and ACTH levels) when compared to mother-reared controls. Peer-reared monkeys also showed elevated voluntary alcohol intake in daily 1-h sessions, with intake achieving significantly higher blood alcohol concentrations compared to mother-reared monkeys (Higley et al. 1991a). In another study conducted with rhesus monkeys, although peer-reared and mother-reared subjects did not differ in magnitude of the stress response to social isolation during adulthood, altered stress responsiveness was related to voluntary alcohol consumption. That is, monkeys exhibiting a higher cortisol response to social separation consumed significantly more alcohol in a limited access (1 h) drinking situation (Fahlke et al. 2000). More recently, female macaques that were peer-reared were reported to evidence elevated alcohol intake compared to mother-reared subjects, with the effect modulated by genetic variation in genes related to serotonin regulation of the HPA axis (Barr et al. 2009, 2004).

Chronic isolation

Several studies have examined the effects of prolonged social isolation (typically accomplished by individual housing) on subsequent alcohol consumption. Although one study using rats reports decreased alcohol intake (Fahlke et al. 1997) and a few others report no effect of chronic isolation on later alcohol intake (e.g., Lodge and Lawrence 2003b; Rockman et al. 1988), the large preponderance of studies indicate that chronic isolation increases subsequent alcohol consumption in mouse, rat, and monkey species (see Table 2). For example, several studies conducted with different rat strains (e.g., Hall et al. 1998; Juarez and Vazquez-Cortes 2003) and rats selectively bred for high alcohol preference (Ehlers et al. 2007) have reported that chronic social isolation during adolescence leads to higher alcohol self-administration in adulthood. In a recent study, Long–Evans rats that were chronically isolated during adolescence were shown to exhibit higher levels of alcohol self-administration along with elevated behavioral measures of anxiety (McCool and Chappell 2009). Likewise, studies in mice have shown that chronic social isolation during adolescence results in increased alcohol consumption (Advani et al. 2007). In a recent study conducted in our laboratory, chronic social isolation during early development (14 days, starting at weaning) produced significantly higher voluntary alcohol consumption in male and female C57BL/6J mice compared to group-housed controls (Lopez et al. 2011). A common factor across all of these studies in rats and mice is that chronic social isolation during a critical period of development results in elevated alcohol intake later in adulthood. It is not clear whether chronic isolation during adulthood also affects alcohol intake. To our knowledge, only one study in rats (Schenk et al. 1990) and one study in mice (Lopez et al. 2011) have directly compared the effect of chronic social isolation exposure experience during adolescence vs. adulthood, and these results indicated that isolation housing for the same duration during adulthood did not alter subsequent alcohol intake. This suggests that the timing of chronic isolation stress experience is key, and that interactions with dynamic developmental changes (neural, endocrine) may underlie subsequent enhanced avidity for alcohol in rodents. Clearly, this issue deserves more experimental attention.

A couple of studies have evaluated the effects of chronic isolation on alcohol consumption in nonhuman primates. In one study, adult rhesus monkeys that were socially isolated intermittently (every other week) consumed more alcohol while isolated than during periods of group housing (Kraemer and McKinney 1985). Interestingly, monkeys that experienced intermittent (weekly) separations consumed more alcohol than those continuously isolated prior to and during alcohol access. Despite some methodological issues (alcohol intake when monkeys were together was estimated based on the group consumption from a single bottle), this study showed that social isolation induced higher alcohol intake (Kraemer and McKinney 1985). Other studies conducted with adult male and female squirrel monkeys showed that while acute (20 min) social separation resulted in reduced alcohol intake (and reduced intake of a control fluid) along with anxiety-like behavior, extending social isolation for a week produced selective elevation of alcohol consumption in the male subjects (McKenzie-Quirk and Miczek 2008; Miczek et al. 2008). This increase in alcohol intake returned to baseline levels when monkeys returned to their social housing conditions (McKenzie-Quirk and Miczek 2008; Miczek et al. 2008). Collectively, results from these studies indicate that the timing and duration of social isolation are critical factors that influence impact on alcohol drinking in adult monkeys. To our knowledge, the effects of chronic social isolation during early developmental periods (adolescence) on subsequent alcohol self-administration have not been systematically studied in monkeys.

Overcrowding

Several studies have evaluated the effect of overcrowding on voluntary alcohol intake in rodents. Results have been mixed and, unfortunately, in some cases methodological problems (e.g., using average group intake as dependent variable) have obscured study outcomes (Deatherage 1972; Heminway and Furumoto 1972). Studies in Wistar rats have shown that 7 or 14 days of overcrowding resulted in elevated alcohol intake when rats were subsequently individually housed for testing (Nagaraja and Jeganathan 2002, 2003). However, the overcrowding housing condition decreased food intake, leaving open the possibility that rats increased their alcohol consumption to compensate for reduced caloric intake (Nagaraja and Jeganathan 2002). Similar results were reported in another study conducted with Sprague–Dawley rats (Hannon and Donlon-Bantz 1976). In this study, overcrowding induced high alcohol intake in both male and female rats. Unlike the previously cited study (Nagaraja and Jeganathan 2002), overcrowding did not affect water or saccharin intake. However, the increase in alcohol intake was transient (5–7 days) and the authors speculate that once rats adapted to the housing situation, alcohol intake returned to baseline levels (Hannon and Donlon-Bantz 1976). Thus, while few studies have examined the effects of overcrowding on alcohol consumption, existing results do not suggest robust or durable effects in rodents.

Social status

A number of studies have examined the influence of dynamic social interactions in group-housed animals on alcohol consumption. In one study, Long–Evans rats housed in a colonial and environmentally enriched housing condition consumed less alcohol than rats housed in groups or individually in standard cages (Kulkosky et al. 1980). Whether an enriched housing environment and/or its interaction with opportunities for social interaction contribute to this outcome was not (and has not been) directly examined. Other studies using Long–Evans rats found that despite similar overall amount of alcohol consumed, intake was much more variable in group-housed rats compared to those individually housed. Further analysis revealed that the greater heterogeneity in alcohol intake among group-housed rats was attributed to higher levels of alcohol consumption in subordinate subjects (Blanchard et al. 1987). These results are congruent with an earlier study showing reduced alcohol intake in dominant Wistar rats (Wolffgramm and Heyne 1991). More recent studies evaluating the effect of social rank on alcohol intake using triads of Long–Evans rats also showed reduced alcohol intake in dominant rats relative to intake in the sub-dominant and subordinate animals (Pohorecky 2006, 2008, 2010). Studies in mice have generally shown similar results. For example, in one study, Swiss mice were housed in groups to determine social rank based on aggressive behavior (mice that evidenced wounds were identified as subordinates). Mice were then individually housed for alcohol intake assessment and results indicated that mice presenting with wounds showed the highest level of alcohol intake (Hilakivi-Clarke and Lister 1992). Similar results were obtained with C57BL/6J mice that were either identified and categorized based on expression of aggressive or submissive behavior (Kudryavtseva et al. 1991) or C57BL/6J mice that were continuously tested for social aggressive interaction while alcohol intake was assessed (Kudryavtseva et al. 2006). In both cases, mice that exhibited more submissive behavior or were defeated in social interaction tests consumed more alcohol. It should be noted that the effect of pairing the aggressive and subordinate mice on intake was not immediate and was observed only during the second week of pair housing (Kudryavtseva et al. 1991). Also, this effect was observed in C57BL/6J mice but not in CBA/lac mice (Kudryavtseva et al. 1991).

Only a very limited number of studies have examined the relation between social dominance and alcohol intake in nonhuman primates, and results have been mixed. Some studies have reported higher alcohol consumption in dominant monkeys (Crowley and Andrews 1987; Crowley et al. 1990), while other studies reported elevated drinking in monkeys with a lower social rank (McKenzie-Quirk and Miczek 2008; Miczek et al. 2008). There are several factors that might explain the opposing results observed in this set of studies. For example, two different species of monkeys were used: male Japanese Snow monkeys (Crowley and Andrews 1987; Crowley et al. 1990) and both male and female squirrel monkeys (McKenzie-Quirk and Miczek 2008). However, perhaps the most influencing factor was the procedure used to evaluate alcohol intake. In one case, monkeys had shared access to the alcohol bottle and, as might be predicted, dominant monkeys were able to gain more access to the alcohol bottles (Crowley and Andrews 1987; Crowley et al. 1990). However, when competition for alcohol access was relaxed and all monkeys had similar access to the drinking bottles, the differences in alcohol intake between dominant and subordinate monkeys disappeared (Crowley et al. 1990). Studies involving squirrel monkeys involved first determining social rank based on a dominance index and then the animals were individually given access to alcohol (McKenzie-Quirk and Miczek 2008).

Shifts in circadian cycle

When rodents are given free 24 h access to alcohol, consumption follows the pattern of water and food intake, with higher levels of consumption during the dark phase of the circadian cycle (Hiller-Sturmhofel and Kulkosky 2001; Spanagel et al. 2005). The introduction of a shift in the normal light/dark cycle has been proven to be stressful in rodents, adversely affecting the overall health of the subjects (Kort and Weijma 1982; Penev et al. 1998; Tsai et al. 2005). Only a few studies have examined the influence of circadian shifts on alcohol consumption. In one study, adult male Sprague–Dawley rats that experienced a single 8-h shift in the light/dark schedule as well as repeated changes in the lights-on schedule showed a significant increase in voluntary alcohol intake (Gauvin et al. 1997). Other studies conducted with male and female Fisher and Lewis rats (Rosenwasser et al. 2010) or male and female HAD1 rats (Clark et al. 2007) showed a significant decrease in alcohol intake when the animals were subjected to 6-h shifts in the light/dark cycle. In another study, male Wistar rats kept constantly in the dark or with the lights on showed reduced alcohol intake as well (Goodwin et al. 1999). Similar results were obtained with C57BL/6J mice that were switched from a 12:12-h light/dark cycle to a 6:6-h light/dark cycle (Millard and Dole 1983). Additionally, C57BL/6J mice, and the selectively bred high alcohol-preferring (HAP2) and low alcohol-preferring (LAP2) mice that experienced significant changes in their light/dark cycle schedules showed reduced alcohol intake (Trujillo et al. 2011). Taken together, most studies examining the effect of shifts in circadian cycles on voluntary alcohol drinking in rats and mice have shown significant reductions in alcohol intake. An explanation for this general outcome remains to be determined.

Chronic variable stress

Several studies that have shown that experience with chronic variable and unpredictable stress has long-lasting effects on HPA axis regulation and stress responsiveness (Flak et al. 2009; Jankord and Herman 2008; Ostrander et al. 2009; Zurita et al. 2000). There is also evidence from studies conducted with rats indicating that experience with chronic variable stress affects later responsiveness to drugs of abuse such as cocaine (Lepsch et al. 2005), morphine, (Molina et al. 1994) and amphetamine (Kabbaj et al. 2002; Lin et al. 2002). However, the effect of chronic variable stress on voluntary alcohol intake remains largely unexplored. In a recent study, exposure to variable and unpredictable mild stressors for 14 days during early development (starting at weaning) resulted in elevated alcohol intake in adult C57BL/6J mice using a two-bottle choice (alcohol vs. water) limited access (2 h/day) testing procedure (Lopez et al. 2011). Additional studies are needed to determine the generality of these effects, and whether similar findings are obtained if chronic variable stress is administered during adulthood.

Summary

A large portion of the studies presented in this section demonstrate that chronic stress exposure, especially when experienced during early life, can subsequently produce increased propensity to self-administer alcohol later in adulthood. Evidence in support of such observations come from studies involving mice, rats, and nonhuman primates, and they are based on the general premise that stressful conditions during early development induce long-lasting epigenetic, physiological, and behavioral alterations that impact motivation to drink alcohol (Higley et al. 1991a; Holmes et al. 2005). A review of this literature indicates that a number of procedural variables have significant modulating effects on the outcome. For example, studies involving maternal separation manipulations suggest that effects on subsequent alcohol drinking are dependent on the duration of the maternal separation episode as well as sex of the test subjects (Ploj et al. 2003; Roman et al. 2005). Most of the studies that used long periods of maternal separation reported higher voluntary ethanol intake, and this effect was observed in rats, mice, and nonhuman primates (see Table 2). In some instances, the strain of rats (Lancaster 1998) or the combination of a particular strain and sex (Roman et al. 2005) appeared to modulate the effect of maternal separation. Additionally, in the case of social isolation, the timing of chronic stress exposure appears important, but may be dependent on the species studied. For example, chronic social isolation in rodents can induce higher alcohol intake when the stress is experienced during early (but not later) development (Lopez et al. 2011; Schenk et al. 1990). However, in nonhuman primates, chronic isolation during adulthood also produced increases in voluntary alcohol intake (McKenzie-Quirk and Miczek 2008; Miczek et al. 2008). When considering the social status of rodents housed in groups, most studies have indicated either reduced intake in social dominant subjects (e.g., Pohorecky 2010; Wolffgramm and Heyne 1991) and/or elevated intake in subordinates (e.g., Hilakivi-Clarke and Lister 1992; Kudryavtseva et al. 2006). These results in rodent studies suggest there may be an inverse relationship between social rank and alcohol intake. However, studies conducted with nonhuman primates do not entirely support such a relationship. Specifically, some studies in monkeys have shown that dominant subjects drink more (Crowley and Andrews 1987; Crowley et al. 1990) while other studies indicate subordinate subjects drink more (McKenzie-Quirk and Miczek 2008; Miczek et al. 2008). Differences in monkey species and methods for assessing alcohol consumption may contribute to the mixed results. However, since so few studies have been conducted with nonhuman primates, it is difficult to discern which factors may contribute to higher or lower drinking in dominant subjects. Another issue to be considered relates to the persistence of effects on alcohol drinking. In some cases, the effects of maternal separation and chronic social isolation on later alcohol drinking were transient (Advani et al. 2007; Lancaster 1998; Lopez et al. 2011), while in other cases, the effects were more durable (Ehlers et al. 2007; Roman et al. 2005). At present, it is not known whether it is the characteristics of the stress experience, intervening variables, or an interaction of these factors that play a role in determining not only the direction, but also the persistence of changes in alcohol drinking. As a growing body of evidence suggests that various chronic stress procedures, especially when administered early in development, result in later increased alcohol drinking, more studies focused on examining (epi)genetic, physiological, and neural mechanisms underlying the phenomena are certainly warranted.