Comparison of Rats Selectively Bred for High and Low Ethanol Intake in a Forced-Swim-Test Model of Depression: Effects of Desipramine

doi:10.1016/S0031-9384(97)00171-6

Physiology & Behavior

Volume 62, Issue 4, October 1997, Pages 729-733

https://doi.org/10.1016/S0031-9384(97)00171-6 Get rights and content

Abstract

This investigation examined if there is a relationship between selective breeding for high or low alcohol intake and immobility in a forced-swim-test (i.e., “behavioral despair”) model of depression. Time spent immobile in a water-filled cylinder was measured in the alcohol-preferring (P) and nonpreferring (NP) lines of rats, and in the high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) lines. Each rat was tested for 2 10-min trials administered 24 h apart, and pretreatment with saline or desipramine (10.0 or 20.0 mg desipramine/kg b.wt. IP) also was evaluated. Drug was administered immediately after Trial 1 and again 1 h before Trial 2. When tested without pretreatment in Trial 1 or with saline pretreatment in Trial 2, NP rats spent significantly more time immobile than did P rats, but no comparable line differences were found when HAD and LAD rats were tested. Desipramine pretreatment reduced the time spent immobile in rats of the 2 alcohol-nonpreferring lines (i.e., the NP and LAD rats), but had no significant effect in rats of the 2 alcohol-preferring lines (the P and HAD rats). These findings do not support the hypothesis that there is a functional relationship between high alcohol drinking and susceptibility to “behavioral despair” as measured by the forced-swim test. The results with desipramine suggest that selection for high alcohol intake may be associated with insensitivity to desipramine.

Section snippets

Swim Test

The swim test was conducted using a water-filled circular 30-gallon plastic cylinder (50 cm diameter × 70 cm high). The sides were smooth, so that escape from the water was not possible. A water depth of 35 cm ensured that the rat was unable to touch the bottom. The water was maintained near the ambient room temperature (22 ± 1°C). Each rat was placed in the cylinder and observed for 2 10-min trials administered 24 h apart. The trials were videotaped, and the cumulative length of time each rat

Comparison of P and NP Rats

Fig. 1 shows that the NP rats spent significantly more time immobile than did the P rats during Trial 1, which was carried out prior to administration of drug or saline (t₂₈ = 5.74, p < 0.001). Fig. 2 top panel, shows the time spent immobile for rats of the P and NP lines during Trial 2. The ANOVA yielded significant effects of line [F(1,23) = 9.31, p < 0.005], desipramine dose [F(2,23) = 6.30, p < 0.006], and a significant Line × Dose interaction [F(2,23) = 5.27, p < 0.01]. Post hoc

Discussion

When rats from the P and NP lines were tested in the absence of drug, NP rats spent more time immobile than did P rats. This finding was consistent and reliable because it was seen when all of the rats were tested in Trial 1 and again in rats receiving saline in Trial 2. This finding also replicates similar comparisons of P and NP rats in the swim test that were conducted by this laboratory and others 6, 22, 31. However, no line difference in time spent immobile was found when rats of the HAD

Acknowledgements

The authors thank David Sinclair for encouragement and advice during early stages of this work and the late James Norton for statistical consultation. This research was supported by grants AA08312, AA08553, AA10709, and AA07611 from the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health.

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However, it is important to note that baseline negative affect in HAD-1 rats is not likely due to depression, as shown by an animal model of depression (forced swim test). According to this study, HAD-1 and LAD-1 rats showed no difference in time spent immobile during a forced swim test, indicating that there is no functional relationship between High Alcohol Drinking and susceptibility to behavioral despair or depression, at least for this animal model [58]. The HAD-1 rat line meets most of the criteria proposed for an animal model of alcoholism, but has not yet been studied as extensively as the alcohol-preferring P rat, which meets all of the criteria proposed for an animal model of alcoholism [31,32,34].
Heightened emotional states increase impulsive behaviors such as excessive ethanol consumption in humans. Though positive and negative affective states in rodents can be monitored in real-time through ultrasonic vocalization (USV) emissions, few animal studies have focused on the role of emotional status as a stimulus for initial ethanol drinking. Our laboratory has recently developed reliable, high-speed analysis techniques to compile USV data during multiple-hour drinking sessions. Since High Alcohol Drinking (HAD-1) rats are selectively bred to voluntarily consume intoxicating levels of alcohol, we hypothesized that USVs emitted by HAD-1 rats would reveal unique emotional phenotypes predictive of alcohol intake and sensitive to alcohol experience. In this study, male HAD-1 rats had access to water, 15% and 30% EtOH or water only (i.e., Controls) during 8 weeks of daily 7-h drinking-in-the-dark (DID) sessions. USVs, associated with both positive (i.e., 50–55 kHz frequency-modulated or FM) and negative (i.e., 22–28 kHz) emotional states, emitted during these daily DID sessions were examined. Findings showed basal 22–28 kHz USVs were emitted by both EtOH-Naïve (Control) and EtOH-experienced rats, alcohol experience enhanced 22–28 kHz USV emissions, and USV acoustic parameters (i.e., mean frequency in kHz) of both positive and negative USVs were significantly suppressed by chronic alcohol experience. These data suggest that negative affective status initiates and maintains excessive alcohol intake in selectively bred HAD-1 rats and support the notion that unprovoked emissions of negative affect-associated USVs (i.e., 22–28 kHz) predict vulnerability to excessive alcohol intake in distinct rodent models.
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For instance, rats selectively bred for high susceptibility to forced swim (i.e., high immobility) have been shown to drink more ethanol under non-stress situations (Bertholomey et al., 2011). However, P rats (selectively bred for high ethanol preference) demonstrate less immobility than non-preferring (NP) rats in the forced swim test, indicating that there is no simple genetic link between the two behaviors (Bertholomey et al., 2011; Godfrey, Froehlich, Stewart, Li, & Murphy, 1997; Viglinskaya et al., 1995). Another study reported that rats that were chronically exposed to ethanol displayed greater immobility during forced swim stress (Walker et al., 2010).
Several animal models have evaluated the effect of stress on voluntary ethanol intake with mixed results. The experiments reported here examined the effects of different stressors on voluntary ethanol consumption in dependent and nondependent adult male C57BL/6J mice. In Experiment 1, restraint, forced swim, and social defeat stress procedures all tended to reduce ethanol intake in nondependent mice regardless of whether the stress experience occurred 1 h or 4 h prior to ethanol access. The reduction in ethanol consumption was most robust following restraint stress. Experiment 2 examined the effects of forced swim stress and social defeat stress on drinking in a dependence model that involved repeated cycles of chronic intermittent ethanol (CIE) exposure. Repeated exposure to forced swim stress prior to intervening test drinking periods that followed repeated cycles of CIE exposure further increased ethanol consumption in CIE-exposed mice while not altering intake in nondependent mice. In contrast, repeated exposure to the social defeat stressor in a similar manner reduced ethanol consumption in CIE-exposed mice while not altering drinking in nondependent mice. Results from Experiment 3 confirmed this selective effect of forced swim stress increasing ethanol consumption in mice with a history of CIE exposure, and also demonstrated that enhanced drinking is only observed when the forced swim stressor is administered during each test drinking week, but not if it is applied only during the final test week. Collectively, these studies point to a unique interaction between repeated stress experience and CIE exposure, and also suggest that such an effect depends on the nature of the stressor. Future studies will need to further explore the generalizability of these results, as well as mechanisms underlying the ability of forced swim stress to selectively further enhance ethanol consumption in dependent (CIE-exposed) mice but not alter intake in nondependent animals.
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Several sets of selectively bred alcohol preferring and non-preferring lines of rats have been described, including the ALKO alcohol/non-alcohol (AA/ANA) lines (Sommer et al., 2006; Roman et al., 2012), the Sardinian alcohol preferring/alcohol non-preferring (sP/sNP) lines (Colombo et al., 1995, 2006), the Indiana University lines [alcohol preferring/alcohol non-preferring (P/NP) and high alcohol-drinking/low alcohol-drinking (HAD/LAD) rats (Murphy et al., 2002; McBride et al., 2013)], and the Warsaw alcohol high-preferring/Warsaw alcohol low-preferring (WHP/WLP) lines (Dyr and Kostowski, 2008). The alcohol preferring and non-preferring lines can be useful not only for studying alcohol drinking but also for delineating mechanisms of co-occurrence of alcohol use and psychiatric disorders (Godfrey et al., 1997; Roman et al., 2012). A positive association between high alcohol intake and depressive-like traits was observed in alcohol-naïve sP and AA rats, which spent more time immobile in the Porsolt forced swim test as compared to sNP and ANA rats, respectively (Ciccocioppo et al., 1999; Viglinskaya et al., 1995).
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Comparison of Rats Selectively Bred for High and Low Ethanol Intake in a Forced-Swim-Test Model of Depression: Effects of Desipramine

Abstract

Section snippets

Swim Test

Comparison of P and NP Rats

Discussion

Acknowledgements

Physiol. Behav.

Alcohol

Alcohol

Alcohol

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Biol. Psychiat.

Eur. J. Pharmacol.

Brain Res. Bull.

Physiol. Behav.

Pharmac. Ther.

Drugs and the treatment of psychiatric disorders

Is the forced swimming test a suitable model for revealing antidepressant activity?

Psychopharmacology

An improved t-table for simultaneous control on g contrasts

J. Am. Stat. Assn.

Animal models of psychiatric disorders