A Cholinergic-Adrenergic Hypothesis of Mania and Depression

Davidson, Jonathan

doi:10.1016/s0140-6736(72)93021-8

Cited by 1,017 publications

(380 citation statements)

References 33 publications

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“…An enhanced ratio of cholinergic to adrenergic function has been hypothesized to play a role in mania and depression (Fritze, 1993;Janowsky et al, 1972b). Cholinergic challenge studies lend support to this theory.…”

Section: Discussionmentioning

confidence: 93%

A Potential Cholinergic Mechanism of Procaine's Limbic Activation

Benson

Carson

Kiesewetter

et al. 2004

Neuropsychopharmacol

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The local anesthetic procaine, when administered to humans intravenously (i.v.), yields brief intense emotional and sensory experiences, and concomitant increases in anterior paralimbic cerebral blood flow, as measured by positron emission tomography (PET). Procaine's high muscarinic affinity, together with the distribution of muscarinic receptors that overlaps with brain regions activated by procaine, suggests a muscarinic contribution to procaine's emotional and sensory effects. This study evaluates the effects of procaine on cerebral muscarinic cholinergic receptors in the anesthetized rhesus monkey. Whole brain and regional muscarinic receptor binding was measured before and after procaine administration on the same day in three anesthetized rhesus monkeys with PET and the radiotracer 3-(3-(3[ 18 F]fluoropropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine ([ 18 F]FP-TZTP), a cholinergic ligand that has preferential binding to muscarinic (M 2 ) receptors. On separate days each animal received six different doses of i.v. procaine in a randomized fashion. Procaine blocked up to B90% of [ 18 F]FP-TZTP specific binding globally in a dose-related manner. There were no regional differences in procaine's inhibitory concentration for 50% blockade (IC 50 ) for [ 18 F]FP-TZTP. Tracer delivery, which was highly correlated to cerebral blood flow in previous monkey studies, was significantly increased at all doses of procaine with the greatest increases occurring near procaine's IC 50 for average cortex. Furthermore, anterior limbic regions showed greater increases in tracer delivery than nonlimbic regions. Procaine has high affinity to muscarinic M 2 receptors in vivo in the rhesus monkey. This, as well as a preferential increase of tracer delivery to paralimbic regions, suggests that action at these receptors could contribute to i.v. procaine's emotional and sensory effects in man. These findings are consistent with other evidence of cholinergic modulation of mood and emotion.

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Section: Discussionmentioning

confidence: 93%

A Potential Cholinergic Mechanism of Procaine's Limbic Activation

Benson

Carson

Kiesewetter

et al. 2004

Neuropsychopharmacol

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“…Several lines of evidence implicate the brain cholinergic system in negative affectivity and depression. 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].…”

Section: Discussionmentioning

confidence: 98%

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

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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.

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“…89 The Flinders sensitive line (FSL) rats and their corresponding controls, the Flinders resistant line (FRL) rats, were established by selective breeding for high and low sensitivity, respectively, to the anticholinesterase agent, diispopropyl fluorophosphate. 90 This rat line was originally developed based on the fact that an overactive cholinergic system seems to be associated with depression-like behavior, 91 and some data support the claim that patients with affective disorder display increased sensitivity to cholinergic agonists. 92,93 Early maternal separation that induces a response characterized by reduced activity and other depressiverelated behaviors in adult life has also been used.…”

Section: Bdnf and Animal Models Of Depressionmentioning

confidence: 99%

BDNF in schizophrenia, depression and corresponding animal models

2005

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Understanding the etiology and pathogenesis schizophrenia and depression is a major challenge facing psychiatry. One hypothesis is that these disorders are secondary to a malfunction of neurotrophic factors. Inappropriate neurotrophic support during brain development could lead to structural disorganisation in which neuronal networks are established in a nonoptimal manner. Inadequate neurotrophic support in adult individuals could ultimately be an underlying mechanism leading to decreased capacity of brain to adaptive changes and increased vulnerability to neurotoxic damage. Brain-derived neurotrophic factor (BDNF) is a mediator involved in neuronal survival and plasticity of dopaminergic, cholinergic, and serotonergic neurons in the central nervous system (CNS). In this review, we summarize findings regarding altered BDNF in schizophrenia and depression and animal models, as well as the effects of antipsychotic and antidepressive treatments on the expression of BDNF. Molecular Psychiatry (2005) 10, 345-352.

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A Cholinergic-Adrenergic Hypothesis of Mania and Depression

Cited by 1,017 publications

References 33 publications

A Potential Cholinergic Mechanism of Procaine's Limbic Activation

A Potential Cholinergic Mechanism of Procaine's Limbic Activation

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

BDNF in schizophrenia, depression and corresponding animal models

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