Eli Sørensen

Effects of chronic mild stress on sexual behavior, locomotor activity and consumption of sucrose and saccharine solutions

Many symptoms of human depressive disorders are also observed in animals after exposure to unpredictable stressors. The chronic mild stress (CMS) paradigm was developed in order to better model the human situation by using chronic mild stressors over a longer period. It is claimed that the model induces anhedonia in the animals, a core symptom of depression in humans. Despite the fact that the CMS model has a high degree of face validity, there are a number of laboratories in which the establishment of the model is less reliably observed. We have examined behavior (sexual activity and open field activity) together with hedonic measures (sucrose and saccharine intake) after exposure to CMS. CMS decreased male sexual activity (e.g. reduced capability to ejaculate) and increased activity in an open field test. The hedonic measures showed diverging results after CMS in our laboratory. Sucrose consumption was reduced, while saccharine consumption did not show a comparable change. It is concluded that CMS induces comparable alterations to some depression-like symptoms in humans. Saccharine consumption is not a reliable indicator of the hedonic responsiveness to CMS.

On-line detection of extracellular levels of serotonin in dorsal raphe nucleus and frontal cortex over the sleep/wake cycle in the freely moving rat

We used in vivo microdialysis coupled with polygraphic recording to monitor 5-hydroxytryptamine levels in the dorsal raphe nucleus and frontal cortex across waking, slow-wave sleep and rapid eye-movement sleep. Male Sprague-Dawley rats were prepared with electroencephalogram and electromyogram electrodes. Microdialysis probes were placed in dorsal raphe nucleus and/or frontal cortex. Dialysate samples were manually collected during polygraphically-defined behavioural states and the level of serotonin was assayed by means of microbore high-performance liquid chromatography separation and electrochemical detection. Samples from microdialysis probes histologically localized to the dorsal raphe nucleus and frontal cortex showed different levels of extracellular 5-hydroxytryptamine in waking, slow-wave sleep and rapid eye-movement sleep. In dorsal raphe nucleus the extracellular level of serotonin was highest in waking, decreased in slow-wave sleep to 69% and in rapid eye-movement sleep to 39% of waking mean level (waking 3.2 +/- 0.9; slow-wave sleep 2.2 +/- 0.8; rapid eye-movement sleep 1.3 +/- 0.4 fmol/sample). Mean extracellular levels of serotonin in frontal cortex displayed a similar pattern (waking 1.7 +/- 0.4; slow-wave sleep 1.0 +/- 0.3; rapid eye-movement 0.5 +/- 0.05 fmol/sample). In frontal cortex, rapid eye-movement sleep samples were only obtained in three animals. Our findings are consistent with previous results in cats, and suggest that in rats also, extracellular 5-hydroxytryptamine levels in dorsal raphe nucleus and frontal cortex across the sleep/wake cycle might reflect serotonergic neuronal activity. The findings stress the importance of controlling for behavioural state when investigating neurochemical correlates of serotonergic function.

Chronic mild stress affects sucrose intake and sleep in rats.

Depression in humans is associated with sleep abnormalities of three types: altered rapid eye movement (REM) sleep, fragmented sleep, and reduced delta sleep. In an animal model of depression, chronic exposure to mild stressors (CMS, e.g. periods of soiled cage, reversed light/dark cycle, grouped housing, food and/or water deprivation) causes behavioral and hormonal changes which, in humans, often are associated with depression. In the CMS model, a reduced sucrose intake has been defined as one of the core symptoms of depression, anhedonia, although this finding is not consistent among various laboratories. In the present study, we investigated if the CMS procedure, in our laboratory, would cause decreased sucrose intake and, also, give sleep changes similar to what is found in depressed patients. Exposure to CMS decreased sucrose intake in our rats. The largest effect was obtained after 2 weeks of the stress protocol. CMS rats spent more time in REM sleep and showed more fragmented sleep compared to their baseline recording, while there were no changes in the control rats. Increased sleep fragmentation in CMS rats was particularly evident by increased number of arousals, and increased REM sleep and slow-wave-sleep-1 (SWS-1) episodes. The duration of sleep stage episodes was decreased. The amount of slow-wave-sleep-2 (SWS-2) was not decreased, however SWS-2 in percent of total SWS was reduced. Correlation analysis showed that animals that had less consumption of sucrose spent more time in REM sleep and had increased number of REM sleep episodes. In this study, CMS appears to be a model of depression.

Extracellular levels of serotonin and GABA in the hippocampus after chronic mild stress in rats. A microdialysis study in an animal model of depression

One of the most established hypotheses of depression focuses on alteration of the serotonergic (5-HT) function. Recent evidence suggests that serotonergic involvement in depression may be modulated by the action of gamma-hydroxybutyric acid (GABA). Furthermore, altered GABAergic function is also evident in depressed patients and in animal models of depression. Disturbed sleep is characteristic of patients with mood disorders. The most pronounced changes of the 5-HT firing activity occur during sleep. Hence, the present paper reports a study on simultaneously measurement of hippocampal levels of serotonin and GABA during waking and sleep in the chronic mild stress (CMS) animal model of depression. The neurotransmitter findings are accompanied by depression-like symptoms (e.g. sleep alterations and reduced sucrose intake, a putative indicator of anhedonia in rodents). Our results show that animals exposed to CMS had lower hippocampal GABA levels compared to controls. In addition, after CMS there was a lack of 5-HT stage-dependency. A subgroup (five out of eight animals) showed a consistent increase in 5-HT levels in slow wave sleep and REM sleep. We also observed that this increase occurred in those animals regarded as most anhedonic (lowest intake of sucrose solution). Moreover, REM sleep was positively correlated with anhedonia. No interaction between 5-HT and GABA was found in the hippocampus. The data suggest that both GABAergic and serotonergic systems may be simultaneously but independently involved in depression. The alteration in 5-HT function may represent a link between depression-like behaviour and sleep abnormalities found in depressed patients.

Effects of sleep deprivation on extracellular serotonin in hippocampus and frontal cortex of the rat.

Sleep deprivation improves the mood of depressed patients, but the exact mechanism behind this effect is unclear. An enhancement of serotonergic neurotransmission has been suggested. In this study, we used in vivo microdialysis to monitor extracellular serotonin in the hippocampus and the frontal cortex of rats during an 8 h sleep deprivation period. These brain regions were selected since both have been implicated in depression. The behavioral state of the animal was continuously monitored by polygraphic recordings during the experiment. Sleep deprivation produced a gradual decline in extracellular serotonin levels, both in the hippocampus and in the frontal cortex. In order to investigate whether the reduction in serotonin was due to other factors than sleep deprivation, i.e. time of day effect, another experiment was performed. Here animals were allowed to sleep during most of the recording period. This experiment showed the expected changes in extracellular serotonin levels: consistently higher levels in the awake, non-sleep deprived animals compared to during sleep, but no time of day effect. The reduction in extracellular serotonin during sleep deprivation may suggest that serotonin does not play a major role in the mood-elevating effect of sleep deprivation. However, since 5-HT levels are strongly behavioral state dependent, by eliminating sleep, there may be a net increase in serotonergic neurotransmission during the sleep deprivation period.

Objective measures of sleep and dim light melatonin onset in adolescents and young adults with delayed sleep phase disorder compared to healthy controls.

Delayed sleep phase disorder is characterized by a delay in the timing of the major sleep period relative to conventional norms. The sleep period itself has traditionally been described as normal. Nevertheless, it is possible that sleep regulatory mechanism disturbances associated with the disorder may affect sleep duration and/or architecture. Polysomnographic data that may shed light on the issue are scarce. Hence, the aim of this study was to examine polysomnographic measures of sleep in adolescents and young adults with delayed sleep phase disorder, and to compare findings to that of healthy controls. A second aim was to estimate dim light melatonin onset as a marker of circadian rhythm and to investigate the phase angle relationship (time interval) between dim light melatonin onset and the sleep period. Data from 54 adolescents and young adults were analysed, 35 diagnosed with delayed sleep phase disorder and 19 healthy controls. Results show delayed timing of sleep in participants with delayed sleep phase disorder, but once sleep was initiated no group differences in sleep parameters were observed. Dim light melatonin onset was delayed in participants with delayed sleep phase disorder, but no difference in phase angle was observed between the groups. In conclusion, both sleep and dim light melatonin onset were delayed in participants with delayed sleep phase disorder. The sleep period appeared to occur at the same circadian phase in both groups, and once sleep was initiated no differences in sleep parameters were observed.

Granule containing cells and fibres in the sinus venosus of elasmobranchs.

SummaryThe concentrations of catecholamines in the heart chambers of elasmobranchs were measured by the fluorimetric method of Bertler et al. (1958). Noradrenaline (NA) can be detected in all the chambers, but the sinus venosus is by far the richest in NA. This can either be due to the presence of storage sites for this amine in the sinus wall, or to a transport of amine to the sinus venosus from the anterior chromaffin bodies. The sinus wall contains large numbers of “granule containing cells” and axon-like processes, both with numerous dense-core vesicles of about 1800 Å diameter. The dense-core vesicles contain a uranophilic matrix indicating the presence of protein, phospholipids and/or nucleic acid. The reactions failed to demonstrate amine, which may be due to a loss of amine by diffusion, to a relatively low intravesicular amine concentration, or, to the absence of amines in these granule-containing cells and processes. Heavy accumulations of granule-containing processes occur in the subendothelial area. The endothelium contains fenestrae and pores through which granule-containing fibres protrude into the venous cavity. Granule-containing cells are innervated by presumed cholinergic nerve endings. It is suggested that the granule-containing cells and fibres belong to a neurosecretory system with a cholinergic input, releasing the contents of the dense-core vesicles into the blood stream at the level of the venous cavity.

Sleep and waking following microdialysis perfusion of the selective 5-HT1A receptor antagonist p-MPPI into the dorsal raphe nucleus in the freely moving rat

The aim of this study was to examine the involvement of the dorsal raphe nucleus (DRN) presynaptic serotonergic 5-HT1A autoreceptors on sleep and waking parameters, in particular rapid eye movement (REM) sleep. In a previous study, the systemic administration of the selective 5-HT1A receptor antagonist p-MPPI reduced REM sleep in a dose-dependent manner suggesting a blockade of the 5-HT1A autoreceptors. In the present study, a blockade by microdialysis perfusion of 10 microM and 100 microM of p-MPPI for 7 h into the DRN in freely behaving rats influenced vigilance state only to a small extent. The administration of 10 microM of p-MPPI induced a reduction of total REM sleep mainly due to a suppression of REM sleep during the third 2 h period of the recording of sleep and waking. Perfusion of 100 microM of p-MPPI decreased total transition type sleep (TRANS) but the effect on REM sleep did not reach significance. There was no change in waking or slow wave sleep (SWS) following any of the doses. The data suggest that 5-HT1A receptor-mediated mechanisms in the DRN may be only moderately important in the serotonergic modulation of REM sleep.

The Personality Profile of Young Adults With Delayed Sleep Phase Disorder

Delayed sleep phase disorder (DSPD) is a circadian rhythm sleep disorder characterized by a substantial delay in the major sleep period, resulting in difficulties falling asleep and awakening at a socially desirable time in the morning. This study is the first to investigate the NEO-Personality Inventory-Revised profile of young adults with DSPD. The study includes 40 patients diagnosed with DSPD (mean age = 20.7) and 21 healthy controls (mean age = 21.1). Results showed that young adults with DSPD scored higher on Neuroticism, lower on Extroversion, and much lower on Conscientiousness than the control group. Assessing the personality profile of young adults with DSPD before initiating treatment might provide useful clinical guidance regarding the individual needs for follow up during treatment. Trial registration: ClinicalTrials.gov identifier: NCT00834886.

Increased extracellular 5-HT but no change in sleep after perfusion of a 5-HT1A antagonist into the dorsal raphe nucleus of rats

Aim:  The 5‐HT1A receptor antagonist 4‐Iodo‐N‐[2‐[4‐(methoxyphenyl)‐1‐piperazinyl]ethyl]‐N‐2‐pyridinyl‐benzamide hydrochloride (p‐MPPI) (10 μm) was perfused into the dorsal raphe nucleus (DRN) to study simultaneously the effects of the drug on the DRN and frontal cortex extracellular serotonin (5‐hydroxytryptamine, 5‐HT) levels and concurring behavioural states.