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

Abstract

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.

Effects of neuronal norepinephrine uptake blockade on baroreflex neural and peripheral arc transfer characteristics

“…However, the vagal efferent fibers should play a critical role in the dynamic baroreflex control of HR, because the vagal control is much faster than the sympathetic control (4,18). Although desipramine is the least potent antimuscarinic compound among the tricyclic antidepressants (10), it could affect the vagal control of HR via the interaction between the vagal and sympathetic systems (18,23). Further studies are required to elucidate the effects of desipramine on the dynamic vagal control of HR.…”

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

“…Chronic treatment with TCAs produces supersensitivity of a central muscarinic mechanism Dilsaver and Davidson, 1987;Dilsaver and Snider, 1988). Hyperfunction of central muscarinic mechanisms may be involved in the biology of depression (Janowsky et al, 1972;Dilsaver, 1986a-6).…”

Antidepressant withdrawal syndromes: phenomenology and pathophysiology

“…Antidepressant withdrawal symptoms respond to centrally active antimuscarinic agents (28,29). Finally, my associates and I have demonstrated that amitriptyline (30,31), amoxapine and desipramine (32) all enhance sensitivity of a central muscarinic mechanism to the hypothermic effects of oxotremorine.…”