Cholinergic properties of desipramine and amoxapine: assessment using a thermoregulation paradigm.
1. The withdrawal of tricyclic antidepressants (TCAs) produces symptoms suggesting cholinergic rebound. 2. Amitriptyline (AMI), the most potent antimuscarinic agent among this class of drugs, produces supersensitivity to the muscarinic agonist, oxotremorine. 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. Desipramine (DMI) is the least potent antimuscarinic compound among the TCAs, yet its withdrawal produces withdrawal symptoms. 5. Recently, it was reported that amoxapine (AMX) weakly binds to muscarinic acetylcholine receptors (mAchR) in vitro. This may indicate that this drug lacks the effects antimuscarinic effects in vivo, and that it will not supersensitize cholinergic networks. 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. Mechanisms whereby drugs can produce cholinergic system supersensitivity, and the use of thermoregulation paradigms in assessing the properties of therapeutic agents is discussed.
Department of Psychiatry, University of Michigan, Ann Arbor.
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Dilsaver
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Davidson
D000657:Amoxapine / Q000494:pharmacology*; D000818:Animals; D001833:Body Temperature Regulation / Q000187:drug effects*; D003891:Desipramine / Q000494:pharmacology*; D003989:Dibenzoxazepines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007031:Hypothalamus / Q000187:drug effects; D008297:Male; D010095:Oxotremorine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011950:Receptors, Cholinergic / Q000187:drug effects; D011976:Receptors, Muscarinic / Q000187:drug effects*
D003989:Dibenzoxazepines; D011950:Receptors, Cholinergic; D011976:Receptors, Muscarinic; D010095:Oxotremorine; D000657:Amoxapine; D003891:Desipramine