Beta-endorphin mediates behavioral despair and the effect of ethanol on the tail suspension test in mice

Abstract

Background: The opioid peptide beta-endorphin (beta-E) is synthesized and released in response to stressful stimuli as well as acute alcohol administration. The release of beta-E following exposure to an inescapable aversive situation may mediate behaviors that contribute to allostasis of the stress response. The present study examines the effects of beta-E on immobility in assays involving inescapable stress, both under basal conditions and after acute administration of EtOH.

Methods: Female and male transgenic mice with varying capacities to translate beta-E were subjected to either the forced swim (FST, Experiment 1) or the tail suspension test (TST, Experiment 2). In Experiment 3, mice were divided into three groups based on hormonal status (male, female-estrous, and female-nonestrous) and injected with either 1 g/kg EtOH or equivolume saline 14 minutes prior to behavioral assessment on the TST.

Results: Experiments 1 and 2 demonstrated a direct relationship between beta-E levels and immobility. There were also sex differences in behavior in these tests, with males displaying more immobility than females. A main effect of genotype in Experiment 3 replicated findings in Experiments 1 and 2. There was also an effect of EtOH (increasing immobility) and a significant interaction reflecting a particularly robust effect of the drug in mice with low beta-E. In addition, there were interactions between beta-E, EtOH effects, and hormonal status.

Conclusions: These findings support the contention that beta-E moderates behavioral responses to stressful stimuli and suggest a role for this peptide in coping behavior. Furthermore, the effects of EtOH on the response to stress may be mediated by beta-E. Sex differences in this influence may contribute to sex differences in disease susceptibility and expression.

Fig. 1

Experiment 1 evaluated immobility in wildtype C57BL6/J (B6), heterozygote (HT) and β-E ‘KO’ mice in the forced swim test. The lower panel shows the amount of time mice spent immobile during the 15 min test (data show mean ±SE). βEKO mice differed significantly from B6’s. The inset panel shows sex differences in time immobile, collapsed across strain. Significant differences were determined following ANOVA by post hoc analysis (Tukey’s HSD) test and are designated by an asterisk (all p values ≤ 0.05).

Fig. 2

Experiment 2 evaluated immobility of B6, HT and βEKO mice in the tail suspension test. The lower panel shows the amount of time spent immobile during the 6- min test (data show mean ± SE). There was a tendency for decreased immobility in HTs (p = .068 in Tukey’s post hoc test). The inset panel shows sex differences in immobility time, collapsed across strain. Significant differences from control (B6) or between groups are designated with an asterisk following ANOVA by post hoc analysis (Tukey’s HSD) test.

Fig. 3

Experiment 3 evaluated behavior of B6, HT and βEKO mice in the tail suspension test (data show mean ±SE). The left panel shows time spent immobile during the 6-min test in all genotypes following either saline or 1 g/kg EtOH, in which there were main effects of genotype and drug, as well as a significant interaction, reflecting enhanced drug efficacy in HT mice. The middle panel shows an the number of immobilities in these groups during the same test, which did not depend upon genotype or drug, but again, a significant interaction between these factors reflects a drug effect in HT mice. The right panel shows the latency to become immobile during this test, which did depend upon genotype and drug. Significant differences between groups were determined following ANOVA by post hoc analysis (Tukey’s HSD) and are discussed more fully in the text.

Fig. 4

A triple interaction between genotype, drug and hormonal status on latency to first show immobility in Experiment 3 is shown here (data show mean ±SE). Effects of drug and genotype (depicted in Fig. 3) depended upon hormonal state; with decreased levels of β-E, EtOH effects became more genotype-dependent.