Persistent suppression of ethanol self-administration by brief social stress in rats and increased startle response as index of withdrawal
Introduction
In humans, excessive alcohol drinking is often linked to the experience of stress [1], [2]. The popular tension-reduction hypothesis posits that alcohol is consumed in order to reduce the effects of stress, as a form of self-medication, but empirical support is inconsistent [3]. Animal research has tried to elucidate the connection between stress and alcohol use or abuse, using mice, rats, and monkeys as models for human alcohol consumption (see [4], [5]). The initial problem with studying stress effects on alcohol consumption is the reluctance of most animals to drink alcoholic fluids. Several protocols have been developed to induce animals to self-administer alcohol, and these methodologies have reduced the stressful nature of involuntary alcohol administration [6], [7]. A second problem pertains to the nature of the stressor, since specific stress response profiles appear to exist, and each type of stress may have its distinctive relevance to the human situation [8]. A multiphasic time course and an inverted U-shaped function characterize the relationship between intensity and timing of stress on endocrine and behavioral stress responses [9]. These characteristics highlight the relevance of the interval between the experience of stress and alcohol consumption.
The experimental analysis of the events and processes through which stress, in particular, social stress, impacts on alcohol intake has generated a complex pattern of results. Under most conditions, alcohol intake actually decreases during and after exposure to footshock or restraint stress (e.g., [10], [11]). Yet, several studies have shown an increase in alcohol intake after various types of laboratory stress such as footshock or restraint [12], [13], [14], [15] and others again have seen no consistent change in intake (e.g., [16], [17], [18]). Among the variables that contribute to these results are many variations in experimental procedures such as housing conditions, choice of alcohol solution, forced consumption vs. free choice, type of stress exposure, or duration and timing of stress with respect to alcohol consumption (see review in Ref. [19]). In addition to showing an increase or decrease in alcohol consumption after being subjected to stress, the effects of stress depend on initial alcohol preference or concurrent availability of alternative fluids [15], [20], [21]. In some cases, the increase in alcohol appeared after discontinuation of the stress exposure, possibly as a rebound phenomenon (e.g., [15], [17], [22]). In order to delineate the stress conditions that result in either decreased or increased alcohol consumption in laboratory animals, it is of paramount significance to attend to the different methods of alcohol self-administration, the different models of stress exposure including their physical or psychological features, and the differences in duration of alcohol access, the exact stress parameters, and the precise timing of stress relative to access.
Among the social variables affecting alcohol consumption are simply different housing conditions. Early studies showed that singly housed rodents tended to consume more alcohol [23], [24]. On the other extreme, crowded housing also increased alcohol intake [25], [26], [27]. As a result, alcohol consumption under several housing conditions, such as pair- and colony-housing, have been investigated. In these studies, individual differences have been reported, presumably due to differences in dominance status [28]. In general, subordinate rats or monkeys tended to drink more alcohol than dominant animals [26], [29], [30]. In addition, the nature of the housing environment seems to play a role, in that animals in impoverished living conditions (e.g., steel wire hanging cages) consume more alcohol than animals in enriched environments [21]. For the present experiments, singly housed male rats subjected to brief episodes of defeat stress were selected as a model to produce stress-induced changes in alcohol consumption, since this type of social stress facilitates acquisition and maintenance of cocaine self-administration and sensitizes animals to psychomotor stimulants [31], [32], [33]. A limited access protocol was selected, in order to allow precise measurements of intake relative to the stress exposure without ensuing compensatory intake.
The current experiments investigated the effects of short-term social defeat stress, i.e., brief exposure to an aggressive conspecific, under precisely controlled conditions, on alcohol consumption. The first aim was to investigate how the timing of stress relative to the alcohol access period determined the subsequent alcohol intake. In addition to the acute effects immediately after exposure to stress, animals were studied at 4 h after stress, when heart rate and temperature have normalized, and at 24 h after stress when changes in anticipation of the next stress episode can occur [34]. The second aim was to compare the effects of stress on alcohol intake in two different access situations: (1) home cage alcohol drinking and (2) alcohol as reinforcer of operant responding. The third aim was to assess the changes in defensive responses during social stress exposure in animals that were under the influence of self-consumed alcohol. In all experiments, a sucrose-fading technique was used to initiate alcohol self-administration [6].
Section snippets
Subjects
Male Long–Evans rats, weighing 225–250 g upon arrival, were housed in standard stainless steel hanging cages (20×24×18 cm). Animals were kept in a temperature (20–22°C) and humidity (45–55%) controlled environment under a reversed light cycle (lights on between 2000 and 0800 h). Food and water were available during the dark period, and food was removed during the light period to ensure an empty stomach for the 8:00 a.m. ethanol access period (see below). Body weight was monitored daily and ca.
Acquisition of ethanol self-administration
Animals with access to ethanol in the home cage acquired stable intake of ethanol solution after about 30 days (Fig. 1, top). The average intake was 7.3±0.5 g fluid (10% ethanol), which corresponds to 1.3±0.1 g/kg ethanol. The water-drinking control groups underwent a simultaneous fading procedure, from 10% sucrose to tap water, without ethanol being introduced. After 30 days, their intake was lower and more variable than the intake of the ethanol groups, at 5.4±1.7 g fluid (water)
Discussion
In these experiments, brief social stress episodes consistently decreased ethanol consumption, confirming similar evidence with footshock and restraint stress (e.g., [10], [11]). Whether animals were exposed to the mild stress of being placed in an unfamiliar animal's territory or the more intense stress of an aggressive encounter, the outcome was suppressive. Stress-induced decreases were similar whether animals were consuming ethanol in the home cage or as reinforcer of operant behavior, and
Acknowledgements
We would like to acknowledge the contributions of Ann Sheffield, Robert Micucci, and Molly Castille to the daily experimental routine. We thank Dr. Gene Heyman for discussing the limitations and possibilities of sweetened alcohol self-administration procedures. J. Thomas Sopko was indispensable in preparing the manuscript. The research was supported by USPHS research grants AA05122 and DA02632 (KAM, PI).
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