Days Of Swim Stress Research Articles

P.2.031 - The use of light to potentiate antidepressant medication: preclinical evidence

Purpose of the study Major Depression (MD) is the most frequent psychiatric disorders. Despite the large range of available antidepressants, MD treatments remain unsatisfactory due to delayed onset of action and partial therapeutic responsiveness. Hence, more effective antidepressant treatments are urgently required. Recently, an increased awareness of light on mood has been highlighted. Light was shown to synchronize the circadian clock and modulate brain structures involved in sleep regulation, mood and cognition, via light sensitive melanopsin retinal ganglion cells (ipRGCs). Aberrant light cycles and/or disrupted circadian rhythmicity produce depressive states. Inversely, luminotherapy has been proven to be effective in seasonal depression but also in unipolar depression [1]. However, the underlying mechanisms of light are still unknown. Several studies reveal that i) ipRGCs play an important role in mood regulation induced by light [2] and ii) circadian and 5-HT systems are two important interactive regulatory brain networks that modulate mood. The purpose of this study was to decipher the neurobiological mechanisms by which light potentiates the antidepressant response. Methods An original model of treatment resistant depression [3] was used, based on a modified version of the forced swimming test. Briefly, mice were put in a tank filled with water (25°C) during 10 minutes 5 consecutive days (4 hours after lights off). Then, one group of mice were exposed to standard light (100 lux) and another group received add-on one hour of bright light (1000 lux, one hour before lights off) during 9 weeks. Weekly, during 2 months (2 hours after lights off), the immobility time was analyzed during the 4 first minutes of the swimming time. In parallel, the locomotor activity of the mice was assessed in their home-cage using the Circadian Activity Monitoring System. Drugs were injected 30 minutes prior to FST on week 8 and 9. Results In both groups of mice, the immobility time, observed in day 2 to 5, was significantly increased (+40%) and remained stable for at least 8 weeks while a single dose of the NMDA receptor antagonist ketamine (3 mg/kg, i.p) failed to reverse this pseudo-depressive behavior. Interestingly, only the combination of ketamine (3 mg/kg) and the muscarinic antagonist scopolamine (0.1 mg/kg) associated with bright light stimulation was able to decrease the immobility time. No difference was observed in locomotor activity, suggesting that the immobility evaluation corresponds to a behavioral despair. Moreover, a reduced sucrose preference was observed in stressed mice. Conclusion In this novel, validated model of depression [3], we showed that the immobility observed after 5 days of swim stress could remain stable for more than 5 weeks and this mainly because the repeated stress was performed during the dark phase [4]. Repeated bright light exposure, one hour per day during 8 weeks, potentiates the antidepressant effect of a sub-effective combination of ketamine and scopolamine [5]. Together, these results suggest, for the first time in treatment resistant mice, that light, in combination of a pharmacological treatment, can unveil an antidepressant response. Studies are currently ongoing to determine the role of ipRGCs in this surprising response.

Effects of chronic swim stress on EtOH-related behaviors in C57BL/6J, DBA/2J and BALB/cByJ mice

There is a strong clinical relationship between stress and stress-related disorders and the incidence of alcohol abuse and alcoholism, and this relationship appears to be partly genetic in origin. There are marked strain differences in ethanol (EtOH)-related behaviors and reactivity to stress, but little investigation of the interaction between the two. The present study assessed the effects of chronic exposure to swim stress on EtOH-related behavior in three common inbred strains of mice, C57BL/6J, DBA/2J and BALB/cByJ. After establishing baseline (10%) EtOH self-administration in a two-bottle free choice test, mice were exposed to daily swim stress for 14 consecutive days and EtOH consumption was measured as a percent of baseline both during stress and for 10 days afterwards. A separate experiment examined the effects of 14 days of swim stress on sensitivity to the sedative/hypnotic effects of an acute injection of 4g/kg EtOH. Results showed that stress produced a significant decrease in EtOH consumption, relative to pre-stress baseline, in DBA/2J and BALB/cByJ, but not C57BL/6J mice. By contrast, stress increased sensitivity to the sedative/hypnotic effects of EtOH in all three strains. These findings demonstrate that chronic swim stress produces reductions in EtOH self-administration in a strain-dependent manner, and that these effects may be restricted to strains with a pre-existing aversion to EtOH. Present data also demonstrates a dissociation between effects of this stressor on EtOH self-administration and sensitivity to EtOH's sedative/hypnotic effects. In conclusion, strain differences, that are likely in large part genetic in nature, modify the effects of this stressor on EtOH's effects in a behavior-specific manner.

Tyrosine hydroxylase and galanin mRNA levels in locus coeruleus neurons are increased following reserpine administration

The neuropeptide galanin coexists in 80-90% of the norepinephrine-containing neurons in the locus coeruleus. In situ hybridization histochemistry was used to examine the effects of reserpine treatment or swim stress on tyrosine hydroxylase and galanin mRNA concentrations in locus coeruleus neurons. Reserpine administration significantly increased tyrosine hydroxylase and galanin mRNA levels in the locus coeruleus. The reserpine-induced increase in tyrosine hydroxylase mRNA was significantly correlated with the reserpine-induced increase in galanin mRNA. Three consecutive days of swim stress did not significantly alter either tyrosine hydroxylase or galanin mRNA concentrations in the locus coeruleus. These data suggest that both tyrosine hydroxylase and galanin gene expression in locus coeruleus neurons may be regulated by a reserpine-sensitive mechanism.

Chronic stress supersensitizes rats to the inhibition of locomotion produced by arecoline

Chronic inescapable footshock and swim stress supersensitize a hypothalamic muscarinic mechanism which regulates core body temperature. We studied the inhibitory effects of arecoline, a muscarinic agonist, on locomotion in rats before and after chronic swim stress in order to examine the effects of stress on an extra-hypothalamic muscarinic mechanism. We counted crossings in an open field during the days before and after six days of twice-daily swim stress (8 minutes/session at 12C). We first examined the effects of eight doses of ip arecoline (0.01 to 2.0 mg/kg) and normal saline (N = 6 to 8 rats/group) on crossings before and after chronic stress. Doses greater than 0.25 mg/kg inhibited pre-stress crossings relative to saline and did not potentiate the inhibition of locomotion post-stress. The 0.125 mg/kg dose reduced crossings post-stress relative to saline. We reexamined the effects of the 0.125 mg/kg dose saline (N = 20 rats/group) on crossings before and after six days of swim stress. Chronic stress potentiated arecoline-induced inhibition of locomotion. Our results suggest that chronic uncontrollable stressors may supersensitize an extra-hypothalamic muscarinic mechanism involved in the stress response and the pathophysiology of stress-related disease such as major depression.