Chronic mild stress-induced anhedonia model of depression

Moreau, J.‐L.; Scherschlicht, R.; Jenck, F.; Martin, J.R.

doi:10.1097/00008877-199511000-00003

Cited by 126 publications

(12 citation statements)

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“…Rats could interrupt a convergent light beam by poking their noses into the hole to trigger a rewarding intracranial electrical stimulation via an electrode stereotaxically implanted within the mesolimbic system at the level of the ventral tegmental area. Thresholds for self-stimulation behavior were determined as described (27). A group of 16 Wistar rats (300-350 g) were implanted for the study.…”

Section: Methodsmentioning

confidence: 99%

A synthetic agonist at the orphanin FQ/nociceptin receptor ORL1: Anxiolytic profile in the rat

Jenck

Wichmann²,

Dautzenberg³

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

262

249

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The biochemical and behavioral effects of a nonpeptidic, selective, and brain-penetrant agonist at the ORL1 receptor are reported herein. This low molecular weight compound {(1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one} has high affinity for recombinant human ORL1 receptors and has 100-fold selectivity for ORL1 over other members of the opioid receptor family. It is a full agonist at these receptors and elicits dose-dependent anxiolytic-like effects in a set of validated models of distinct types of anxiety states in the rat (i.e., elevated plus-maze, fear-potentiated startle, and operant conflict). When given systemically, the compound has an efficacy and potency comparable to those of a benzodiazepine anxiolytic such as alprazolam or diazepam. However, this compound is differentiated from a classical benzodiazepine anxiolytic by a lack of efficient anti-panic-like activity, absence of anticonvulsant properties, and lack of effects on motor performance and cognitive function at anxiolytic doses (0.3 to 3 mg͞kg i.p.). No significant change in intracranial self-stimulation performance and pain reactivity was observed in this dose range. Higher doses of this compound (>10 mg͞kg) induced disruption in rat behavior. These data confirm the notable anxiolytic-like effects observed at low doses with the orphanin FQ͞nociceptin neuropeptide given locally into the brain and support a role for orphanin FQ͞nociceptin in adaptive behavioral fear responses to stress.T he ORL1 orphan receptor was identified from a human cDNA library on the basis of close homology (Ϸ65% in the transmembrane domains) with the -, ␦-, and -opioid receptors (1, 2). Classical opioid ligands do not bind to ORL1, but orphanin FQ͞nociceptin (OFQ͞N), a 17-amino acid neuropeptide purified from brain extracts, was found to be the natural ligand of the G protein-coupled receptor ORL1 (3, 4). OFQ͞N, its precursor peptide, and its receptor ORL1 are located in corticolimbic regions involved in the integration of the emotional components of fear and stress as well as in the spinal cord, with a pattern distinct from that of opioid peptides and receptors in rodents (5-9). The expression of OFQ͞N or its receptor in the amygdaloid complex, septohippocampal region, periaqueductal gray matter, locus coeruleus, and dorsal raphe nucleus suggests that major brain neuronal systems may be sensitive to the action of OFQ͞N. Such sensitivity has widespread implications for many aspects of behavior including arousal, attention, neuroendocrine control, fear, and anxiety (10). In brain slices, OFQ͞N has potent inhibitory actions on neurons in the dorsal raphe nucleus, the locus coeruleus, the periaqueductal gray matter, and the amygdala (11)(12)(13)(14). In general, OFQ͞N plays an inhibitory role on synaptic transmission in the central nervous system and thereby may contribute to a reduction in responsiveness to stress. When given intracerebroventricularly to rodents, OFQ͞N reduces elementary stress-induced physiological respon...

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Section: Methodsmentioning

confidence: 99%

A synthetic agonist at the orphanin FQ/nociceptin receptor ORL1: Anxiolytic profile in the rat

Jenck

Wichmann²,

Dautzenberg³

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

262

249

View full text Add to dashboard Cite

show abstract

“…In line with this, it was recently shown in rodents that chronic unpredictable stress affects suprachiasmatic nucleus (SCN) functionality, the central pacemaker of the circadian system in mammals, by dampening the amplitude of circadian PERIOD2 (PER2) protein expression, one of the main clock proteins involved in internal rhythm generation (Jiang et al 2011). In addition, various biological diurnal rhythms generated and fine-tuned by the SCN such as locomotor activity (Gorka et al 1996), body temperature (Ushijima et al 2006), heart rate (Grippo et al 2003), sleep (Moreau et al 1995), and plasma glucocorticoid (GC) levels (Ottenweller et al 1994) are also affected by repeated exposure to non-psychosocial stressors.…”

Section: Introductionmentioning

confidence: 93%

Time matters: pathological effects of repeated psychosocial stress during the active, but not inactive, phase of male mice

Bartlang¹,

Neumann²,

Slattery³

et al. 2012

Journal of Endocrinology

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Recent findings in rats indicated that the physiological consequences of repeated restraint stress are dependent on the time of day of stressor exposure. To investigate whether this is also true for clinically more relevant psychosocial stressors and whether repeated stressor exposure during the light phase or dark phase is more detrimental for an organism, we exposed male C57BL/6 mice to social defeat (SD) across 19 days either in the light phase between Zeitgeber time (ZT)1 and ZT3 (SDL mice) or in the dark phase between ZT13 and ZT15 (SDD mice). While SDL mice showed a prolonged increase in adrenal weight and an attenuated adrenal responsiveness to ACTH in vitro after stressor termination, SDD mice showed reduced dark phase home-cage activity on observation days 7, 14, and 20, flattening of the diurnal corticosterone rhythm, lack of social preference, and higher in vitro IFNg secretion from mesenteric lymph node cells on day 20/21. Furthermore, the colitis-aggravating effect of SD was more pronounced in SDD than SDL mice following dextran sulfate sodium treatment. In conclusion, the present findings demonstrate that repeated SD effects on behavior, physiology, and immunology strongly depend on the time of day of stressor exposure. Whereas physiological parameters were more affected by SD during the light/inactive phase of mice, behavioral and immunological parameters were more affected by SD during the dark phase. Our results imply that repeated daily SD exposure has a more negative outcome when applied during the dark/active phase. By contrast, the minor physiological changes seen in SDL mice might represent beneficial adaptations preventing the formation of those maladaptive consequences.

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“…Thus, CMS suppresses the consumption of and preference for palatable sweet solutions (Willner et al 1987), and the rewarding properties of food pellets, sweet solutions, and amphetamine, as assessed by the place preference conditioning procedure (Papp et al 1991). CMS furthermore increases thresholds for ventral tegmental self-stimulation, indicating a decreased responsiveness to rewarding stimuli (Moreau et al 1995). This decrease in sensitivity to reward is assumed to model human anhedonia.…”

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confidence: 99%

Proteomic Investigation of the Ventral Rat Hippocampus Links DRP-2 to Escitalopram Treatment Resistance and SNAP to Stress Resilience in the Chronic Mild Stress Model of Depression

Bisgaard¹,

Jayatissa²,

Enghild

et al. 2007

J Mol Neurosci

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The development of depression as well as recovery from depression is most likely accompanied by a change in protein expression profiles. The purpose of the present study was to quantitatively investigate global protein expression differences independent of any hypothesis describing depression etiology and recovery. Thus two-dimensional differential in-gel electrophoresis was employed to compare the ventral hippocampal proteomes between different treatment groups in the chronic mild stress (CMS) model of depression. The CMS paradigm induces anhedonic behaviour, which is a major symptom of depression, by exposing rats to a series of mild stressors for 7 weeks, with antidepressant treatment during the last 4 weeks. In the CMS model, animals were split into six different groups at the end of treatment; unchallenged control escitalopram (n = 12), unchallenged control vehicle (n = 12), CMS vehicle (n = 12), CMS escitalopram responders (n = 11), CMS escitalopram non-responders (n = 13) and CMS resilient (stress resistant) (n = 12). Protein levels in the ventral rat hippocampus were compared between the groups to provide putative markers of anhedonia, escitalopram resistance, and stress resilience. Twenty-eight candidate protein spots were selected, of which 13 were successfully identified using tandem mass spectrometry. DRP-2 (dihydropyrimidinase-related protein-2) was a potential marker for escitalopram resistance, whereas alpha-SNAP and beta-SNAP were associated with stress resilience. Furthermore, several molecular chaperones and cytoskeleton organisers were identified as being differentially expressed. Our data indicate that neuronal adaptation is an essential element of depression etiology and recovery, suggesting the involvement of cellular plasticity in the underlying molecular mechanism.

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Chronic mild stress-induced anhedonia model of depression

Cited by 126 publications

References 0 publications

A synthetic agonist at the orphanin FQ/nociceptin receptor ORL1: Anxiolytic profile in the rat

A synthetic agonist at the orphanin FQ/nociceptin receptor ORL1: Anxiolytic profile in the rat

Time matters: pathological effects of repeated psychosocial stress during the active, but not inactive, phase of male mice

Proteomic Investigation of the Ventral Rat Hippocampus Links DRP-2 to Escitalopram Treatment Resistance and SNAP to Stress Resilience in the Chronic Mild Stress Model of Depression

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