Reversal by imipramine of β-adrenoceptor up-regulation induced in a chronic mild stress model of depression

doi:10.1016/0014-2999(94)90312-3

European Journal of Pharmacology

Volume 261, Issues 1–2, 11 August 1994, Pages 141-147

https://doi.org/10.1016/0014-2999(94)90312-3 Get rights and content

Abstract

Male Wistar rats were subjected to a chronic mild stress procedure involving different stress stimuli applied for 8 weeks. During this time the consumption of 1% sucrose solution was monitored at weekly intervals. After the first 3 weeks, when stressed animals displayed a reduction of sucrose consumption, the control and stressed groups were divided into subgroups receiving daily placebo or imipramine (10 mg/kg/day) treatment. After 5 weeks of treatment, 24 h after the last injection, the rats were killed and β-adrenoceptor density and affinity in cortical membrane preparations and the accumulation of cycle AMP in cortical slices stimulated with noradrenaline were assessed. While in stressed placebo-treated rats the sucrose consumption remained reduced, in the imipramine-treated group the level of consumption gradually returned to control values. The stressed placebo-treated rats also displayed an increase in cortical β-adrenoceptor density (by 34%) with no changes in affinity, and an increase (22%) in the cyclic AMP response to noradrenaline in cortical slices. Imipramine, which in non-stressed rats did not affect sucrose intake but depressed the β-adrenoceptor density and the cyclic AMP response, reversed the stress-induced decrease in sucrose consumption and the increase in the β-adrenoceptor density; at physiological noradrenaline concentrations it also reduced the enhanced cyclic AMP response. The results suggest that the chronic mild stress procedure produces behavioral and biochemical changes consistent with a realistic model of depression in animals.

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Many studies with chronic stress, a common depression paradigm, lead to inconsistent behavioral results. We are introducing a new model of stress-induced anhedonia, which provides more reproducible induction and behavioral measuring of depressive-like phenotype in mice. First, a 4-week stress procedure induces anhedonia, defined by decreased sucrose preference, in the majority of but not all C57BL/6 mice. The remaining 30–50% non-anhedonic animals are used as an internal control for stress effects that are unrelated to anhedonia. Next, a modified sucrose test enables the detection of inter-individual differences in mice. Moreover, testing under dimmed lighting precludes behavioral artifacts caused by hyperlocomotion, a major confounding factor in stressed mice. Finally, moderation of the stress load increases the reproducibility of anhedonia induction, which otherwise is difficult to provide because of inter-batch variability in laboratory mice. We believe that our new mouse model overcomes some major difficulties in measuring behavior with chronic stress depression models.
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Numerous data from human and animal studies suggest that hippocampal plasticity might be a key element in depression. However, the connection remains loose at best and further data are needed. Human studies are of necessity limited, but animal models can help providing further insight. Unpredictable chronic mild stress (UCMS) is a commonly used model because it mimics depression-like phenotypes satisfactorily. Its rationale is based on the underlying stress-induced difficulties found in many depressed patients. We therefore studied learning and hippocampal neurogenesis in mice from three different inbred strains subjected to UCMS. Learning was assessed in different hippocampus-dependent and independent tasks. The rate of survival of newly generated brain cells was determined in behaviorally-naive animals. Results demonstrated a dramatic reduction of surviving new brain cells in both the hippocampus and the subventricular zone of UCMS-treated animals. This reduction was observed both for neurons and for other cells of the hippocampus. Behavioral data demonstrated an impairment of hippocampus-dependent learning, whereas hippocampus-independent learning was spared. However, the specific results were strongly dependent on strain and sex so that there does not appear to be a direct causative relationship between the deficits in neurogenesis and behavior.
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Reversal by imipramine of β-adrenoceptor up-regulation induced in a chronic mild stress model of depression

Abstract

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Pharmacol. Biochem. Behav.

Prog. Neuropsychopharmacol. Biol. Psychiatry

DSM III R-Diagnostic and Statistical Manual of Psychiatric Disorders

Autoradiographic demonstration of increased serotonin 5-HT2 and beta-adrenergic receptor binding sites in the brain of suicide victims

Arch. Gen. Psychiatry

Development of β-adrenergic receptor subsensitivity by antidepressants

Nature

Autoradiographic demonstration of increased serotonin 5-HT₂ and beta-adrenergic receptor binding sites in the brain of suicide victims