Pathophysiology of “cholinoceptor supersensitivity” in affective disorders

doi:10.1016/0006-3223(86)90246-5

Biological Psychiatry

Volume 21, Issues 8–9, July 1986, Pages 813-829

https://doi.org/10.1016/0006-3223(86)90246-5 Get rights and content

Abstract

Phenomenological and physiological variables demonstrate supersensitive changes to cholinergic challenge in affective disorder subjects. Theorists generally assume the primary defect is the postsynaptic muscarinic receptor. However, in addition to defectiveness or up-regulation of this receptor, the appearance of postsynaptic “cholinoceptor super-sensitivity” can result from abnormal presynaptic mechanisms, membrane “pathology,” derangement of intracystolic mechanisms that amplify effects of receptor-agonist coupling, or aberrant cholinergic-monoaminergic interaction. This article discusses abnormalities of the postsynaptic receptor, regulation of postsynaptic receptor density, the presynaptic muscarinic receptor, and other mechanisms regulating the release of acetylcholine, membrane dynamics, and “cascade” mechanisms—specifically the phosphatidylinositol (PI) cycle, Ca²⁺ mobilization, and cyclic guanosine monophosphate (GMP) generation—as causes of cholinergic system “supersensitivity.” It is suggested that an approach to the topic emphasizing site of abnormality will encourage greater clarity of thought in the study of the cholinergic component of the pathophysiology of affective illness.

References (164)

D.D Avery
Intrahypothalamic adrenergic and cholinergic effects on temperature and ingestive behavior in the rat
Neuropharmacology
(1971)
B Baron et al.
Fatty acid incorporation increases the affinity of muscarinic cholinergic receptors for agonists
Biochim Biophys Acta
(1984)
L Beani et al.
Effect of amantadine on cerebral acetylcholine release and content on the guinea pig
Neuropharmacology
(1973)
L Beani et al.
The cerebral acetylcholine release in conscious rabbits with semi-permanently implanted epidural cups
Neuropharmacology
(1968)
L Beani et al.
Noradrenaline inhibition of acetylcholine release from guinea pig brain
Eur J Pharmacol
(1978)
M.C Byrne et al.
Amygdala kindling induces muscarinic cholinergic receptor declines in a highly specific distribution within the limbic system
S.C Dilsaver et al.
An anticholinesterase-like syndrome precipitated by psychotropic withdrawal in a chronic abuser of marijuana
Psychosomatics
(1984)
S.K Fisher et al.
Renewed interest in the polyphosphainositides
Trend Neurosci
(1984)
C Flicker et al.
Behavior during hippocampal microinfusions. I. Norepinephrine and diversive explorations
Brain Res Rev
(1982)
C Flicker et al.
Behavior during hippocampal microinfusion. II. Muscarinic loco-motor activiation
Brain Res Rev
(1982)

C Flicker et al.

Behavior during hippocampal microinfusions. III. Lidocaine versus picrotoxin

Brain Res Rev

(1982)

C Flicker et al.

Behavior during hippocampal microinfusions. IV. Transmitter interactions

Brain Res Rev

(1982)

S Gershon et al.

Psychiatric sequelae of chronic exposure to organophosphorus insecticides

Lancet

(1961)

J.C Gillin et al.

Muscarinic supersensitivity: A possible model for the sleep disturbance of primary depression?

Psychiatry Res

(1979)

D.S Janowsky et al.

A cholinergic adrenergic hypothesis of mania and depression

Lancet

(1972)

D.S Janowsky et al.

Hypothalamic-pituitary-adrenal regulation, neurotransmitters and affective illness

Peptides

(1983)

K Jhamandas et al.

Modification of precipitated morphine withdrawal syndrome by drugs affecting cholinergic mechanisms

Eur J Pharmacol

(1973)

D.L Jones et al.

Biphasic locomotor response to intra-accumbens dopamine in a nonhuman primate

Pharmacol Biochem Behav

(1981)

A Levy et al.

The effect of chronic lithium treatment in rat brain muscarinic receptor regulation

Neuropharmacology

(1982)

N Anders et al.

Locomotor activity Stimulation in rats produced by dopamine in the nucleus accumbens, potentiation by caffeine

J Pharm Pharmacol

(1975)

K Andersonn et al.

Effects of single injections of nicotine in the ascending dopamine pathways in the rat. Evidence for increases of dopamine turnover in neostriatal and mesolimbic dopamine neurons

Acta Physiol Scand

(1981)

Y Ben-Barak et al.

Scopolamine induces an increase in muscarinic receptor level in rat hippocampus

Brain Res

(1980)

M.J Berridge et al.

Inositol trisphosphate, a novel second messenger in cellular signal transduction

Nature

(1984)

J.C Blosser

β-Adrenergic receptor activation increases acetylcholine receptor number in cultured skeletal unusual myotubes

J Neurochem

(1983)

R.R Bolin

Psychiatric manifestations of artane toxicity

J Nerv Ment Dis

(1960)

M.B Bowers et al.

Some behavioral changes in man following antichol-inesterase administration

J Nerv Ment Dis

(1964)

C.A Briggs et al.

Cholinergic modulation of the release of [³H]-acetylcholine from synaptosomes of the mysenteric plexus

J Neurochem

(1982)

P.L Carlton

Cholinergic mechanisms in the control of behavior by the brain

Psychol Rev

(1967)

F.J Carmichael et al.

Effects of ethanol on neurotransmitter release by rat brain cortical slices

J Pharmacol

(1975)

B.J Carroll et al.

Neurotransmitter studies of neuroendocrine pathology in depression

Acta Psychiatrica Scand

(1980)

T Claudio et al.

Nucleotide and deduced amino acid sequences of Torpedo californica acetylcholine receptor λ subunit

B.M Cohen et al.

Lecithin in the treatment of mania. Double-blind, placebo-controlled trials

Am J Psychiatry

(1982)

B.M Cohen et al.

Lecithin in mania: A preliminary report

Am J Psychiatry

(1980)

B Coastal et al.

The behavioral effects of dopamine applied intracerebrally to areas of the mesolilmbic system

Eur J Pharmacol

(1975)

J.A Crawshaw et al.

A study of Benzhexol abuse

Br J Psychiatry

(1984)

I Creese et al.

Receptor adaptations to centrally acting drugs

Annu Rev Pharmacol Toxicol

(1981)

P Cuatrecasas

Insulin receptor of liver and fat cell membranes

R.M Dashieff et al.

Evidence for an agonist independent down regulation of hippocampal muscarinic receptors in kindling

Brain Res

(1980)

R.M Dashieff et al.

Biochemical evidence of decreased cholinergic neuronal communication following amygdala kindled seizures

Brain Res

(1981)

R.M Dashieff et al.

Seizures down-regulate muscarinic cholinergic receptors in hippocampal formation

Brain Res

(1982)

A Devillers-Thiery et al.

Complete in RNA coding sequence of the acetylcholine binding a subunit of Torpedo inarmonata acetylcholine receptor: A model of the transmembrane organization of the polypeptide chain

S.C Dilsaver

Lithium's effects on muscarinic receptor binding parameters: A possible relationship to therapeutic efficacy?

Biol Psychiatry

(1984)

Dilsaver SC (in press): Pharmacologie induction of cholinergic system up-regulation and super-sensitivity in affective...

S.C Dilsaver et al.

Antidepressant withdrawal syndromes: Evidence for supersensitivity of the cholinergic system as an etiologic factor

J Clin Psychopharmacol

(1983)

S.C Dilsaver et al.

Antidepressant withdrawal phenomena: A review

Biol Psychiatry

(1984)

S.C Dilsaver et al.

The effect of antidepressant withdrawal on the dexamethasone suppression test

Psychiatry Res

(1985)

S.C Dilsaver et al.

Antidepressant withdrawal syndromes: Evidence suporting the cholinergic overdrive hypothesis

J Clin Psychopharmacol

(1983)

P Doerr et al.

Physostigmine-induced escape from dexamethasone in normal subjects

Biol Psychiatry

(1983)

A.C Dolphin et al.

The effects of bromocriptine on locomotor activity and cerebral catecholamines in rodents

J Pharm Pharmacol

(1977)

E.F Domino

Narcotic agonists and Ach

Cited by (87)

The antidepressant efficacy of the muscarinic antagonist scopolamine: Past findings and future directions
2020, Advances in Pharmacology
Citation Excerpt :
Consistent with these data, donepezil, an acetylcholinesterase inhibitor used to manage symptoms of mild cognitive impairment in elderly patients, reportedly increased rates of depressive relapse in patients with a history of MDD (Reynolds et al., 2011). Lastly, patients with MDD show increases in cholinergically mediated neuroendocrine and pupillary responses to physostigmine (Dilsaver, 1986; Janowsky, Risch, Huey, Kennedy, & Ziegler, 1985; Rubin, O'Toole, Rhodes, Sekula, & Czambel, 1999), a finding consistent with a hypersensitive muscarinic cholinergic response. Beyond the implication of the cholinergic system in general in mood disorders, the muscarinic cholinergic receptor system in particular was implicated by evidence of muscarinic receptor supersensitivity (Dulawa & Janowsky, 2019).
Scopolamine is a nonselective muscarinic antagonist that has shown relatively rapid antidepressant effects, although to date the results are from limited clinical studies. Scopolamine reportedly has downstream signaling effects thought to be linked to neuroplasticity within glutamatergic synapses and consequent antidepressant action. In psychiatry, clinically validated pathways are unusual and thus merit further research in an effort develop more effect medicines for patients with mood disorders. Thus, we are faced with a unique opportunity to build on the clinical observation associated with scopolamine through reverse translation to identify of targets that retain the clinical efficacy while reducing the side effect profile. This chapter reviews the clinical antidepressant findings with scopolamine, including discussion of differential response across patient subgroups, as well as a review of biomarkers that predict clinical outcome. The preclinical data associated with scopolamine also are reviewed and convey a vision for narrowing in on the therapeutic muscarinic receptor subtype(s) that support the antidepressant effects to guide the development of next generation antimuscarinic drug targets for depression.
Amygdala response to explicit sad face stimuli at baseline predicts antidepressant treatment response to scopolamine in major depressive disorder
2016, Psychiatry Research - Neuroimaging
The muscarinic antagonist scopolamine produces rapid antidepressant effects in individuals with major depressive disorder (MDD). In healthy subjects, manipulation of acetyl-cholinergic transmission modulates attention in a stimulus-dependent manner. This study tested the hypothesis that baseline amygdalar activity in response to emotional stimuli correlates with antidepressant treatment response to scopolamine and could thus potentially predict treatment outcome. MDD patients and healthy controls performed an attention shifting task involving emotional faces while undergoing functional magnetic resonance imaging (fMRI). We found that blood oxygenation level dependent (BOLD) signal in the amygdala acquired while MDD patients processed sad face stimuli correlated positively with antidepressant response to scopolamine. Amygdalar response to sad faces in MDD patients who did not respond to scopolamine did not differ from that of healthy controls. This suggests that the pre-treatment task elicited amygdalar activity that may constitute a biomarker of antidepressant treatment response to scopolamine. Furthermore, in MDD patients who responded to scopolamine, we observed a post-scopolamine stimulus processing shift towards a pattern demonstrated by healthy controls, indicating a change in stimulus-dependent neural response potentially driven by attenuated cholinergic activity in the amygdala.
Pain sensitivity following loss of cholinergic basal forebrain (CBF) neurons in the rat
2016, Neuroscience
Citation Excerpt :
Anxiety and fear of pain are predictive of exaggerated pain and pain sensitivity over time (Turk and Wilson, 2010; Parr et al., 2012; Belfer et al., 2013; Castillo et al., 2013; Zale et al., 2013). ( 3) Another negative mood state, depression, is often associated with chronic pain, is enhanced by cholinergic agonists and is ameliorated by cholinergic antagonists (Janowsky et al., 1974; Dilsaver, 1986; Furey et al., 2010). ( 4) Cholinergic antagonism shifts electroencephalographic activity toward high-voltage, slow rhythms (Ebert and Kirch, 1998) and produces drowsiness (Longo, 1966).
Flexion/withdrawal reflexes are attenuated by spinal, intracerebroventricular (ICV) and systemic delivery of cholinergic agonists. In contrast, some affective reactions to pain are suppressed by systemic cholinergic antagonism. Attention to aversive stimulation can be impaired, as is classical conditioning of fear and anxiety to aversive stimuli and psychological activation of stress reactions that exacerbate pain. Thus, in contrast to the suppressive effects of cholinergic agonism on reflexes, pain sensitivity and affective reactions to pain could be attenuated by reduced cerebral cholinergic activation. This possibility was evaluated in the present study, using an operant test of escape from nociceptive thermal stimulation (10 °C and 44.5 °C) before and after destruction of basal forebrain cholinergic neurons. ICV injection of 192 IgG-saporin produced widespread loss of basal forebrain cholinergic innervation of the cerebral cortex and hippocampus. Post-injection, escape from thermal stimulation was decreased with no indication of recovery for upto 19 weeks. Also, the normal hyperalgesic effect of sound stress was absent after ICV 192-sap. Effects of cerebral cholinergic denervation or stress on nociceptive licking and guarding reflexes were not consistent with the effects on operant escape, highlighting the importance of evaluating pain sensitivity of laboratory animals with an operant behavioral test. These results reveal that basal forebrain cholinergic transmission participates in the cerebral processing of pain, which may be relevant to the pain sensitivity of patients with Alzheimer’s disease who have prominent degeneration of basal forebrain cholinergic neurons.
Changes in the cholinergic system between bipolar depression and euthymia as measured with [<sup>123</sup>I]5IA single photon emission computed tomography
2013, Biological Psychiatry
The cholinergic system is substantially altered in individuals with major depression and is partially restored when depression remits. We quantified the availability of β₂-subunit-containing nicotinic acetylcholine receptors (β₂*-nAChR) in subjects with bipolar disorder.
Twenty-five subjects with bipolar disorder (15 depressed, 10 euthymic) and 25 sex- and age-matched control subjects had a [¹²³I]5IA-85380 single photon emission computed tomography scan to quantify β₂*-nAChR V_T/f_P (total volume of distribution, corrected for individual differences in metabolism and protein binding of the radiotracer). Average V_T/f_P was compared between groups and correlated with clinical characteristics. Postmortem analysis of β₂*-nAChRs was conducted using equilibrium binding with [¹²⁵I]5IA in subjects with bipolar disorder and matched control subjects.
We showed significantly lower β₂*-nAChR availability (20%–38%) in subjects with bipolar depression compared with euthymic and control subjects across all brain regions assessed (frontal, parietal, temporal, and anterior cingulate cortex, hippocampus, amygdala, thalamus, striatum). The postmortem binding study in which endogenous acetylcholine was washed out did not show a statistically significant difference in β₂*-nAChR number in temporal cortex of the bipolar depressed and control groups (15% difference; p = .2).
We show that the alteration in the cholinergic system observed during a depressive episode appears to resolve during euthymia. We suggest that lower V_T/f_P observed in vivo may be due to a combination of higher endogenous acetylcholine levels during depression, which could compete with radiotracer binding to the receptor in vivo, and lower receptor number in bipolar depression. Identification of differences in cholinergic signaling in subjects with bipolar depression may improve our understanding of its etiology and reveal new treatment targets.
Antidepressant effects of the muscarinic cholinergic receptor antagonist scopolamine: A review
2013, Biological Psychiatry
Citation Excerpt :
Researchers showed that increasing cholinergic activity using the anticholinesterase inhibitor, physostigmine, provided a challenge uniquely capable both of exacerbating depressive symptoms in currently depressed subjects with major depressive disorder (MDD) and inducing depressive symptoms and reversing manic symptoms in manic subjects with bipolar disorder (BD) (6–10). The neuroendocrine and pupillary responses to physostigmine (11–13) also were abnormally increased in depressed individuals. The muscarinic cholinergic receptor system specifically was implicated by evidence showing that polysomnographic responses to selective muscarinic agonists (14–16) were exaggerated in depressed versus control samples, suggesting that muscarinic receptor supersensitivity exists in depressed individuals.
The muscarinic cholinergic receptor system has been implicated in the pathophysiology of depression, with physiological evidence indicating this system is overactive or hyperresponsive in depression and with genetic evidence showing that variation in genes coding for receptors within this system are associated with higher risk for depression. In studies aimed at assessing whether a reduction in muscarinic cholinergic receptor function would improve depressive symptoms, the muscarinic receptor antagonist scopolamine manifested antidepressant effects that were robust and rapid relative to conventional pharmacotherapies. Here, we review the data from a series of randomized, double-blind, placebo-controlled studies involving subjects with unipolar or bipolar depression treated with parenteral doses of scopolamine. The onset and duration of the antidepressant response are considered in light of scopolamine’s pharmacokinetic properties and an emerging literature that characterizes scopolamine’s effects on neurobiological systems beyond the cholinergic system that appear relevant to the neurobiology of mood disorders. Scopolamine infused at 4.0 μg/kg intravenously produced robust antidepressant effects versus placebo, which were evident within 3 days after the initial infusion. Placebo-adjusted remission rates were 56% and 45% for the initial and subsequent replication studies, respectively. While effective in male and female subjects, the change in depression ratings was greater in female subjects. Clinical improvement persisted more than 2 weeks following the final infusion. The timing and persistence of the antidepressant response to scopolamine suggest a mechanism beyond that of direct muscarinic cholinergic antagonism. These temporal relationships suggest that scopolamine-induced changes in gene expression and synaptic plasticity may confer the therapeutic mechanism.
Strategies to achieve clinical effectiveness: Refining existing therapies and pursuing emerging targets
2011, Journal of Affective Disorders
Citation Excerpt :
In addition it has also been found to rapidly increase adult neurogenesis (Mayer et al., 2006), and blocks corticosterone-induced 5HT2A receptor upregulation in preclinical models (Trajkovska et al., 2009). Although there has been consistent evidence demonstrating that overstimulation of the cholinergic system results in symptoms reflective of melancholic depression (Dilsaver, 1986; Janowsky et al., 1994), the cholinergic system has received less attention as an antidepressant target. Evidence has shown that currently available antidepressants antagonize nicotinic acetylcholine receptors (nAChRs), supporting the hypothesis that antagonism may result in antidepressant effects (Shytle et al., 2002).
Clinical effectiveness reflects a balance between efficacy and tolerability as well as patient satisfaction and overall improvement in quality of life and function. This is of particular importance when considering the long term use of antidepressant therapies for relapse prevention.
The purpose of this review is to explore methods to enhance the modest efficacy and effectiveness outcomes reported with current antidepressant strategies. Two strategies are addressed: a) Doing better with existing treatments and b) pursuing novel targets beyond the monoamine system for new antidepressant drug development.
In the first instance, it is important to consider the balance between antidepressant efficacy and tolerability for individual patients and also be aware of evidence supporting superiority of one agent over others. Both sequential and concurrent combination therapies with existing antidepressants are also reviewed. The second approach involves a review of emerging novel pharmacological treatments based on biomarker research. Unique targets where antidepressant treatments appear effective include the melatonergic, glutamatergic, neurotrophic, cytokine, and neuropeptide systems.
While agomelatine represents an example of a clinically available antidepressant that targets melatonin receptors, drugs that act on other candidate systems are still in the development phase.

View all citing articles on Scopus

^☆: Supported in part by Physician Scientist Career Development Award (Muscarinic Receptor Abnormalities in Affective Illness), Grant SRC1K11 MH0055301.

View full text

CommentPathophysiology of “cholinoceptor supersensitivity” in affective disorders☆

Abstract

Neuropharmacology

Biochim Biophys Acta

Neuropharmacology

Neuropharmacology

Eur J Pharmacol

Psychosomatics

Trend Neurosci

Brain Res Rev

Brain Res Rev

Brain Res Rev

Brain Res Rev

Lancet

Psychiatry Res

Lancet

Peptides

Eur J Pharmacol

Pharmacol Biochem Behav

Neuropharmacology

Locomotor activity Stimulation in rats produced by dopamine in the nucleus accumbens, potentiation by caffeine

J Pharm Pharmacol

Effects of single injections of nicotine in the ascending dopamine pathways in the rat. Evidence for increases of dopamine turnover in neostriatal and mesolimbic dopamine neurons

Acta Physiol Scand

Scopolamine induces an increase in muscarinic receptor level in rat hippocampus

Brain Res

Inositol trisphosphate, a novel second messenger in cellular signal transduction

Nature

β-Adrenergic receptor activation increases acetylcholine receptor number in cultured skeletal unusual myotubes

J Neurochem

Psychiatric manifestations of artane toxicity

J Nerv Ment Dis

Some behavioral changes in man following antichol-inesterase administration

J Nerv Ment Dis

Cholinergic modulation of the release of [3H]-acetylcholine from synaptosomes of the mysenteric plexus

J Neurochem

Cholinergic mechanisms in the control of behavior by the brain

Psychol Rev

Effects of ethanol on neurotransmitter release by rat brain cortical slices

J Pharmacol

Neurotransmitter studies of neuroendocrine pathology in depression

Acta Psychiatrica Scand

Nucleotide and deduced amino acid sequences of Torpedo californica acetylcholine receptor λ subunit

Lecithin in the treatment of mania. Double-blind, placebo-controlled trials

Am J Psychiatry

Lecithin in mania: A preliminary report

Am J Psychiatry

The behavioral effects of dopamine applied intracerebrally to areas of the mesolilmbic system

Eur J Pharmacol

A study of Benzhexol abuse

Br J Psychiatry

Receptor adaptations to centrally acting drugs

Annu Rev Pharmacol Toxicol

Insulin receptor of liver and fat cell membranes

Evidence for an agonist independent down regulation of hippocampal muscarinic receptors in kindling

Brain Res

Biochemical evidence of decreased cholinergic neuronal communication following amygdala kindled seizures

Brain Res

Seizures down-regulate muscarinic cholinergic receptors in hippocampal formation

Brain Res

Complete in RNA coding sequence of the acetylcholine binding a subunit of Torpedo inarmonata acetylcholine receptor: A model of the transmembrane organization of the polypeptide chain

Lithium's effects on muscarinic receptor binding parameters: A possible relationship to therapeutic efficacy?

Biol Psychiatry

Antidepressant withdrawal syndromes: Evidence for supersensitivity of the cholinergic system as an etiologic factor

J Clin Psychopharmacol

Antidepressant withdrawal phenomena: A review

Biol Psychiatry

The effect of antidepressant withdrawal on the dexamethasone suppression test

Psychiatry Res

Antidepressant withdrawal syndromes: Evidence suporting the cholinergic overdrive hypothesis

J Clin Psychopharmacol

Physostigmine-induced escape from dexamethasone in normal subjects

Biol Psychiatry

The effects of bromocriptine on locomotor activity and cerebral catecholamines in rodents

J Pharm Pharmacol

Narcotic agonists and Ach

Comment
Pathophysiology of “cholinoceptor supersensitivity” in affective disorders☆

Cholinergic modulation of the release of [³H]-acetylcholine from synaptosomes of the mysenteric plexus