Cholinomimetic and anticholinergic drugs used to investigate an acetylcholine hypothesis of affective disorders and stress

Janowsky, David S.; Risch, S. Craig

doi:10.1002/ddr.430040202

Cited by 126 publications

(45 citation statements)

References 114 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As initially proposed by Janowsky and colleagues in the early 1970s [31], dysfunction of cholinergic transmission (hyperactivity/ hypersensitivity) is likely involved in the pathophysiology of depression. In most animal models, treatment with centrally acting cholinomimetics consistently produces behavioral inhibitory effects including lethargy and hypoactivity, HPA axis activation, decreases in selfstimulation [31,32,33], increases in behavioral despair in the forced swim test, and anhedonia [67]. Treatment with anticholinergic drugs generally reverses these induced phenomena.…”

Section: Discussionmentioning

confidence: 99%

Social defeat, a paradigm of depression in rats that elicits 22-kHz vocalizations, preferentially activates the cholinergic signaling pathway in the periaqueductal gray

Kroes¹,

Burgdorf²,

Otto³

et al. 2007

Behavioural Brain Research

View full text Add to dashboard Cite

Gene expression profiles in the periaqueductal gray (PAG) of adult Long-Evans rats as a function of a stressful social defeat in inter-male fighting encounters were examined. This social subordination model mimics prototypical behavioral changes that parallel aspects of clinical depression, has been postulated to simulate early changes in the onset of depression in the losers, and has been successfully utilized for the evaluation of antidepressant activity. 22-kHz ultrasonic vocalizations (USVs) have been shown to reflect negative emotional states akin to anxiety and depression. Social defeat is the most robust and reliable method of eliciting these calls. The PAG has been shown to be a key brain region for the generation of 22-kHz ultrasonic vocalizations, and 22-kHz USVs have been shown to be controlled by the mesolimbic cholinergic system. In this present study we examined gene expression changes in the PAG of social subordinate rats compared to dominant rats (that do not exhibit 22-kHz USVs). We found that social defeat significantly altered the genes associated with cholinergic synaptic transmission in the PAG. The most robust of these were the increased expression of the β2 subunit of the nicotinic acetylcholine receptor (CHRNB2) and the T-subunit of acetylcholinesterase (ACHE) in the subordinate animals. These changes were corroborated by qRT-PCR and found to be exclusive to the PAG compared to seven other brain regions examined. These data suggest that cholinergic transmission in the PAG is involved in the generation of 22-kHz USVs and provide potential therapeutic targets for the treatment of affective disorders.

show abstract

Section: Discussionmentioning

confidence: 99%

Social defeat, a paradigm of depression in rats that elicits 22-kHz vocalizations, preferentially activates the cholinergic signaling pathway in the periaqueductal gray

Kroes¹,

Burgdorf²,

Otto³

et al. 2007

Behavioural Brain Research

View full text Add to dashboard Cite

show abstract

“…When physostigmine was administered to patients with affective disorders, the symptoms of negative affect were more pronounced and longer lasting. 31,34 Depression-like symptoms have also been observed in normal subjects receiving i.v. physostigmine or arecoline, 35,36 and physostigmine was reported to induce depression in a majority of euthymic bipolar patients maintained on lithium.…”

Section: The Cholinergic-adrenergic Theory Of Depressionmentioning

confidence: 97%

“…For example, central acetylcholine turnover is increased following stress 30 and ACh facilitates the release of several stress-sensitive neurohormones and peptides including corticosterone, ACTH, and CRF. 31 The cholinergic-adrenergic theory of depression hypothesizes a balance between cholinergic and adrenergic systems, suggesting that overactivity of the cholinergic system over the adrenergic system could lead to depressive symptoms. 32 Consistent with this hypothesis, strong evidence supports the presence of exaggerated responses (behavioral, neurochemical, sleep) to cholinergic agents in affective disorder patients relative to controls.…”

Section: The Cholinergic-adrenergic Theory Of Depressionmentioning

confidence: 99%

Nicotinic acetylcholine receptors as targets for antidepressants

et al. 2002

View full text Add to dashboard Cite

While the monoamine deficiency hypothesis of depression is still most commonly used to explain the actions of antidepressant drugs, a growing body of evidence has accumulated that is not adequately explained by the hypothesis. This article draws attention to contributions from another apparently common pharmacological property of antidepressant medications-the inhibition of nicotinic acetylcholine receptors (nAChR). Evidence is presented suggesting the hypercholinergic neurotransmission, which is associated with depressed mood states, may be mediated through excessive neuronal nicotinic receptor activation and that the therapeutic actions of many antidepressants may be, in part, mediated through inhibition of these receptors. In support of this hypothesis, preliminary evidence is presented suggesting that the potent, centrally acting nAChR antagonist, mecamylamine, which is devoid of monoamine reuptake inhibition, may reduce symptoms of depression and mood instability in patients with comorbid depression and bipolar disorder. If this hypothesis is supported by further preclinical and clinical research, nicotinic acetylcholine receptor antagonists may represent a novel class of therapeutic agents for treating mood disorders.

show abstract

“…Thus, there is a discrepancy between animal models of depression and clinical observations in Alzheimer's disease. However, as noted above, the animal models are concordant with clinical observations of increased cholinergic function in depression (Janowsky and Risch, 1984). In fact, recent evidence suggests that cholinergic function may be higher in depressed than in non-depressed Alzheimer's patients (Zubenko et al, 1990).…”

Section: Animal Models and Depression In Old Agementioning

confidence: 70%

Animal models as research tools in depression

Willner

1991

Int J Geriat Psychiatry

View full text Add to dashboard Cite

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.

show abstract

Cholinomimetic and anticholinergic drugs used to investigate an acetylcholine hypothesis of affective disorders and stress

Cited by 126 publications

References 114 publications

Social defeat, a paradigm of depression in rats that elicits 22-kHz vocalizations, preferentially activates the cholinergic signaling pathway in the periaqueductal gray

Social defeat, a paradigm of depression in rats that elicits 22-kHz vocalizations, preferentially activates the cholinergic signaling pathway in the periaqueductal gray

Nicotinic acetylcholine receptors as targets for antidepressants

Animal models as research tools in depression

Contact Info

Product

Resources

About