Sensitization to the Actions of Antidepressant Drugs

Willner, Paul

doi:10.1007/978-1-59259-464-1_8

Cited by 11 publications

(10 citation statements)

References 171 publications

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“…The noradrenergic basis of the attentional de®cit caused by acute exposure to uncontrollable stress has already been mentioned; other animal models of depression display symptoms that are attributable to disturbances of serotonergic function. 39 These ®ndings provide strong support for the view that the analysis of the neurobiological mechanisms underlying psychopathology is more readily addressed at the level of symptoms rather than syndromes.…”

Section: Neurobiological Mechanisms Underlying Depressive Symptomatologymentioning

confidence: 70%

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Stress and Depression: Insights from Animal Models

Willner

1997

Stress Med.

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The largest group of animal models of depression comprises procedures in which stress causes antidepressant‐reversible behavioural abnormalities. Two models that have been extensively investigated are learned helplessness and a more recently developed paradigm in which anhedonia is induced by exposure to chronic mild stress. The problem of validating animal models is discussed, and several applications of animal models of depression are described, with particular reference to the chronic mild stress procedure. Areas in which animal models can provide valuable insights include the aetiology of depression, the neurobiological mechanisms underlying depressive symptomatology and mechanisms of antidepressant action. © 1997 John Wiley & Sons, Ltd.

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Section: Neurobiological Mechanisms Underlying Depressive Symptomatologymentioning

confidence: 70%

“…39 Current evidence suggests that this sensitization of postsynaptic D2/D3 receptors is the mechanism by which antidepressants reverse CMS-induced anhedonia. The decreased number of D2/D3 receptors seen in anhedonic chronically stressed animals was reversed in animals chronically treated with imipramine.…”

Section: Mechanisms Of Antidepressant Actionmentioning

confidence: 99%

Stress and Depression: Insights from Animal Models

Willner

1997

Stress Med.

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“…Since sub-sensitivity to reward appears to reflect anhedonia (inability to experience pleasure), a core symptom of major depressive disorders, the CMS procedure may represent a uniquely useful research tool. Numerous studies have shown that the CMSinduced sub-sensitivity to reward can be reversed by chronic treatment with antidepressant drugs, including tricyclics, atypical antidepressants, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAOI), as well as repeated electro convulsive shock (ECS) [Willner, 1987[Willner, , 1997.…”

Section: Introductionmentioning

confidence: 99%

Effects of the novel antidepressant milnacipran in a chronic mild stress model of depression

Papp

Panconi

Gruca

2004

Drug Development Research

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The chronic mild stress (CMS) model of depression may serve as a suitable research tool for studying the action of novel antidepressants (i.e., both efficacy and onset of action). The CMS-induced sub-sensitivity to reward is reversed by chronic treatment with antidepressant drugs. The effect of the serotonin and norepinephrine reuptake inhibitor (SNRI), milnacipran, was investigated on the CMS model in rats in comparison with imipramine. The CMS model of depression consisted in subjecting rats to several mild stressors for a prolonged period of time, which resulted in a decrease in their responsiveness to rewarding stimuli. This deficit was monitored by a decrease in the consumption of a 1% sucrose solution. Stressed and control animals received daily for 5 weeks injections of vehicle, imipramine (10 mg/ kg) or milnacipran (3, 10, and 30 mg/kg). CMS caused a decrease in the consumption of the 1% sucrose solution. The deficit in sucrose consumption in stressed animals was reversed by imipramine and milnacipran. The effect of milnacipran was gradual, dose-dependent, and was maintained for one week after stopping drug treatment. Neither imipramine nor milnacipran modified the behavior of control animals. Milnacipran is active in the CMS model of depression as expected from its clinically demonstrated antidepressant effect. Drug Dev.

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“…There are indications of this differentiation in earlier studies (reviewed by Willner, 1989b). For example, following one week of treatment, the effect of tricyclic antidepressants in the forced swim test may be blocked by catecholamine antagonists (Borsini and Meli, 1988), while their effect in olfactory bulbectomized animals was reversed by the 5HT antagonist metergoline (Broekkamp et al, 1980).…”

Section: Mechanisms Of Antidepressant Actionmentioning

confidence: 90%

“…We now know that following chronic administration, antidepressants cause multiple changes in the functioning of a variety of neuronal systems (reviewed by Willner, 1989b). Animal models of depression can be used to establish the functional significance of these effects.…”

Section: Mechanisms Of Antidepressant Actionmentioning

confidence: 98%

Animal models as research tools in depression

Willner

1991

Int J Geriat Psychiatry

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KEY woms-Animal models, research, depression, old age.Animal models of depression are often thought to be of little relevance for understanding the clinical disorder, since the behaviours involved frequently carry little conviction as analogues of human behaviour. However, to dismiss animal models on these grounds is to misunderstand their purpose-or rather purposes. The most familiar usage of animal models of depression is within the pharmaceutical industry, as screening tests in the development of novel antidepressants. As the only purpose of drug screening is to produce new drugs, the extent to which the procedures used resemble the clinical disorder is largely irrelevant: the major issue is whether a test successfully predicts clinical efficacy. This article is concerned with a different aspect of animal models of depression, their use as simulations for investigating the psychobiology of depression. Many of the available models were developed primarily as predictive drug screening tests, without regard to their validity as simulations of depression. However, a minority of models have been developed explicitly for this purpose; and less valid models can also provide useful corroborative insights.The procedures for validating animal models of psychiatric disorders have been discussed in detail elsewhere (Willner, 1984(Willner, , 1986(Willner, , 1991; they include consideration of predictive validity (which concerns primarily the correspondence between drug actions in the model and in the clinic), face validity (phenomenological similarities between the model and the disorder), and construct validity (a sound theoretical rationale). Some desirable features in a simulation of depression are that the model should respond to antidepressant drugs; should employ realistic inducing conditions; and should model a core symptom of the disorder. In addition, for many purposes, such as investigating mechanisms of antidepressant action over a clinically relevant time scale, a prolonged time course is also desirable.

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Sensitization to the Actions of Antidepressant Drugs

Cited by 11 publications

References 171 publications

Stress and Depression: Insights from Animal Models

Stress and Depression: Insights from Animal Models

Effects of the novel antidepressant milnacipran in a chronic mild stress model of depression

Animal models as research tools in depression

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