Amitriptyline and nortriptyline as antagonists of central and peripheral cholinergic activation

Rathbun, Robert C.; Slater, Irwin H.

doi:10.1007/bf00413329

Cited by 64 publications

(10 citation statements)

References 14 publications

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“…Clinical findings have been replicated and extended to other antimuscarinics and treatment populations (Howland, 2009;Dagyt_ e et al, 2011;Janowsky, 2011;Drevets et al, 2013;Jaffe et al, 2013). It is noteworthy that amitriptyline, a tricyclic antidepressant with greater efficacy than SSRIs (Anderson, 1998;Deisenhammer et al, 2000), has one of the richest of antimuscarinic profiles (Rathbun and Slater, 1963). Given the reenergizing of both the cholinergic hypothesis of MDD and the pressing need for improved antidepressant agents, we undertook the present series of studies.…”

Section: Discussionmentioning

confidence: 94%

M₁and M₂Muscarinic Receptor Subtypes Regulate Antidepressant-Like Effects of the Rapidly Acting Antidepressant Scopolamine

Witkin

Overshiner

et al. 2014

J Pharmacol Exp Ther

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Scopolamine produces rapid and significant symptom improvement in patients with depression, and most notably in patients who do not respond to current antidepressant treatments. Scopolamine is a nonselective muscarinic acetylcholine receptor antagonist, and it is not known which one or more of the five receptor subtypes in the muscarinic family are mediating these therapeutic effects. We used the mouse forcedswim test, an antidepressant detecting assay, in wild-type and transgenic mice in which each muscarinic receptor subtype had been genetically deleted to define the relevant receptor subtypes. Only the M 1 and M 2 knockout (KO) mice had a blunted response to scopolamine in the forced-swim assay. In contrast, the effects of the tricyclic antidepressant imipramine were not significantly altered by gene deletion of any of the five muscarinic receptors. The muscarinic antagonists biperiden, pirenzepine, and 2/2 mice. Brain exposure and locomotor activity in the KO mice demonstrated that these behavioral effects of scopolamine are pharmacodynamic in nature. These data establish muscarinic M 1 and M 2 receptors as sufficient to generate behavioral effects consistent with an antidepressant phenotype and therefore as potential targets in the antidepressant effects of scopolamine.

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Section: Discussionmentioning

confidence: 94%

M₁and M₂Muscarinic Receptor Subtypes Regulate Antidepressant-Like Effects of the Rapidly Acting Antidepressant Scopolamine

Witkin

Overshiner

et al. 2014

J Pharmacol Exp Ther

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“…The tri-and tetra-cyclic antidepressants are not only capable of inhibiting noradrenaline uptake (Barth et al, 1975) but also possess cx-adrenoceptor blocking properties (Brodie, Dick, Kielholz, Poldinger & Main, 1974) and are able to inhibit the actions of acetylcholine at muscarinic receptors (Rathbun & Slater, 1963;Gupta, Gupta & Bhargava, 1967;Andrasi & Borsy, 1968). These drugs could therefore modify the concentration of noradrenaline in the Synaptic cleft not only through an action on noradrenaline re-uptake but also by modification of the functional state of the mechanisms controlling noradrenaline release.…”

Section: Introductionmentioning

confidence: 99%

The Effect of Amitriptyline on Presynaptic Mechanisms in Noradrenergic Nerves

Hughes

1978

British J Pharmacology

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Electrically evoked and resting overflow of tritium was measured from mouse vas deferens previously incubated with [3H]‐(—)‐noradrenaline. At low concentrations (1.6 × 10−7 to 4 × 10−6m) amitriptyline increased only the evoked tritium overflow while higher concentrations increased both evoked and resting overflow. In the presence of atropine (1 × 10−6m) amitriptyline still produced an increase in evoked tritium overflow. In the presence of a concentration of cocaine (1.1 × 10−5m) which produced a maximal blockade of the uptake of exogenous noradrenaline the application of amitriptyline still produced an increase in evoked tritium overflow. In the presence of a concentration of phentolamine (1 × 10−5m) that produced complete blockade of the presynaptic α‐adrenoceptors, amitriptyline still produced an increase in evoked tritium overflow. In the presence of cocaine and phentolamine together the effect of amitriptyline on evoked overflow was abolished. It is concluded that amitriptyline may raise synaptic levels of noradrenaline by blocking presynaptic α‐adrenoceptors controlling noradrenaline release and by blocking its uptake into sympathetic neurones.

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“…In the interpretation of the potentiation of adrenergic responses, the anticholinergic properties of these antidepressant drugs, re ported by several authors (8,29,23,17) should also be considered. Cyprolidol, in all animal systems, significantly, inhibited the de pressor response to acetylcholine.…”

Section: Discussionmentioning

confidence: 99%

Some Pharmacological Effects of a New Potential Antidepressant Cyprolidol (IN 1060) Compared with Imipramine

Brown¹,

Gershon²,

Korol³

1966

Pharmacology

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Amitriptyline and nortriptyline as antagonists of central and peripheral cholinergic activation

Cited by 64 publications

References 14 publications

M₁and M₂Muscarinic Receptor Subtypes Regulate Antidepressant-Like Effects of the Rapidly Acting Antidepressant Scopolamine

M₁and M₂Muscarinic Receptor Subtypes Regulate Antidepressant-Like Effects of the Rapidly Acting Antidepressant Scopolamine

The Effect of Amitriptyline on Presynaptic Mechanisms in Noradrenergic Nerves

Some Pharmacological Effects of a New Potential Antidepressant Cyprolidol (IN 1060) Compared with Imipramine

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Amitriptyline and nortriptyline as antagonists of central and peripheral cholinergic activation

Cited by 64 publications

References 14 publications

M1and M2Muscarinic Receptor Subtypes Regulate Antidepressant-Like Effects of the Rapidly Acting Antidepressant Scopolamine

M1and M2Muscarinic Receptor Subtypes Regulate Antidepressant-Like Effects of the Rapidly Acting Antidepressant Scopolamine

The Effect of Amitriptyline on Presynaptic Mechanisms in Noradrenergic Nerves

Some Pharmacological Effects of a New Potential Antidepressant Cyprolidol (IN 1060) Compared with Imipramine

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M₁and M₂Muscarinic Receptor Subtypes Regulate Antidepressant-Like Effects of the Rapidly Acting Antidepressant Scopolamine

M₁and M₂Muscarinic Receptor Subtypes Regulate Antidepressant-Like Effects of the Rapidly Acting Antidepressant Scopolamine