Pathophysiology of "cholinoceptor supersensitivity" in affective disorders

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.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26130/1/0000206.pd

Amitriptyline and cholinergic supersensitivity

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27429/1/0000467.pd

Cholinergic-monoamine systems, depression, and panic

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26185/1/0000264.pd

Amitriptyline-induced supersensitivity of a central muscarinic mechanism: Lithium blocks Amitriptyline- induced supersensitivity

Chronic treatment with amitriptyline produces dose-dependent supersensitivity of a central muscarinic cholinergic mechanism involved in the regulation of core body temperature. The authors demonstrated that chronic treatment with lithium prevents the induction of this response. The potential clinical and theoretical significance of this finding is set forth.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27190/1/0000193.pd

Chronic treatment with lithium produces supersensitivity to nicotine

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28017/1/0000453.pd

Fluoxetine subsensitizes a nicotinic mechanism involved in the regulation of core temperature

Fluoxetine HCl, 10 mg/kg ip, twice daily produced subsensitivity to the hypothermic effects of nicotine (base), 1 mg/kg ip, after 1 (pp<0.002) weeks of treatment. Phenelzine sulfate, desipramine HCl and bright artificial light produced the same effect. The capacity of three chemically distinct classes of antidepressants and bright artificial light (a treatment for seasonal depression) to produce this result suggestss that effects on nicotinic mechanisms may be involved in the mechanism of action of these treatments.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26608/1/0000149.pd

Cholinergic properties of desipramine and amoxapine: Assessment using a thermoregulation paradigm

1. 1. The withdrawal of tricyclic antidepressants (TCAs) produces symptoms suggesting cholinergic rebound.2. 2. Amitriptyline (AMI), the most potent antimuscarinic agent among this class of drugs, produces supersensitivity to the muscarlnic agonist, oxotremorine.3. 3. Enhancement of the sensitivity of cholinoceptive neurons to acetylcholine as a consequence of treatment with TCAs would account for many of the symptoms following the withdrawal of these drugs.4. 4. Desipramine (DMI) is the least potent antimuscarinic compound among the TCAs, yet its withdrawal produces withdrawal symptoms.5. 5. Recently, it was reported that amoxapine (AMX) weakly binds to muscarinic acetylcholine receptors (mAchR) . This may indicate that this drug lacks the effects antimuscarinic effects . and that it will not supersensitize cholinergic networks.6. 6. A thermoregulation paradigm was used to assess the sensitivity of a central muscarinic mechanism to oxotremorine before and after treatment with DMI and AMX. Treatment with either drug increased the hypothermic response to this agonist.7. 7. Mechanisms whereby drugs can produce cholinergic system supersensitivity, and the use of thermoregulation paradigms in assessing the properties of therapeutic agents is discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26971/1/0000538.pd

Cold stress and cholinergic supersensitivity

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26634/1/0000176.pd

Effects of placebo (saline) injections on core temperature in the rat

1. Core temperature was telemetrically measured in 15 rats before (i.e., at baseline) and at 10-min intervals for 120 min following the injection of normal saline (1 ml/kg ip) or "no injection."2. The sample exhibited a mean temperature increase of 0.60 +/- 0.10[deg]C(mean +/- SEM) following injection.3. This differed significantly from the mean increase of 0.13 +/- 0.03[deg]C following "no injection" (p 4. The injection of saline (1 ml/kg) affected a mean rise in core temperature of 0.55 +/- 0.07[deg]C (p > 0.000001) in 46 animals in a second experiment.5. These data indicate that routine handling and a simple injection comprise significant and measurable stress which must be controlled in neuropharmacological studies employing a thermoregulation paradigm.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28880/1/0000716.pd

Chronic treatment with ethanol produces supersensitivity to oxotremorine

1. The effect of chronic treatment with ethanol (14% v:v in drinking water) on the physiological endpoint core temperature which is partially regulated by a muscarinic mechanism was measured in adult male rats (n = 8).2. One and two weeks of treatment were associated with enhancement of the hypothermie response to oxotremorine, 0.25 mg/kg ip ((p = 0.0005 and p = 0.0001, respectively).3. The sample remained supersensitive to this muscarinic agonist 48 and 96 hours after the discontinuation of treatment (p = 0.0014 and p = 0.013 respectively).4. Repeated injections of oxotremorine, 0.25 mg/kg ip, every other day for 10 days did not produce carry-over effects in a control experiment.5. The results suggest that ethanol renders muscarinic mechanisms supersensitive during chronic treatment and that Supersensitivity remains up to 96 hours following withdrawal.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28878/1/0000713.pd