Naunyn Schmiedebergs Arch Pharmacol. 1982 Jul;320(1):14-9.
The effect of some antidepressants on prejunctional muscarinic receptors on the sympathetic nerves of the isolated rabbit ear artery.

Kwok YH, Mitchelson F.

The antimuscarinic activity of amitriptyline, desipramine, iprindole, mianserin and viloxazine on prejunctional sympathetic nerve endings were compared in the isolated rabbit ear artery. In the presence of cocaine (10 micro M) and yohimbine (1 micro M), amitriptyline (0.5-1 micro M), desipramine (1-3 micro M) and iprindole (5-10 micro M) produced parallel rightward shifts of the concentration-response curve for the inhibitory effect of carbachol (CCh) on responses to electrical stimulation of the preparation at 3 Hz. Mianserin (3 micro M) produced some inhibition but altered the slope of the concentration-responses curve to CCh while viloxazine (less than or equal to 10 micro M) produced no inhibition. The depression of tritium efflux by CCh from arteries preincubated in 3H-noradrenaline was inhibited significantly (P less than 0.05) by amitriptyline (0.1 micro M) and desipramine (1 micro M) and not by iprindole (17 micro M), mianserin (3 micro M) or viloxazine (10 micro M). Amitriptyline was 10-fold more active than desipramine and at least 30-fold more active than the other antidepressants as a muscarine receptor blocking drug in this preparation. Thus, mianserin, viloxazine and iprindole exhibit much weaker antimuscarinic activity relative to amitriptyline on prejunctional muscarine receptors on sympathetic nerve endings compared with that observed by others for excitatory muscarine receptors in sympathetic ganglia. The findings support an earlier suggest that these receptors differ.

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Neuropharmacology. 1989 May;28(5):477-80.
The effects of chronic treatment with amitriptyline and MDL 72394 on the control of 5-HT release in vivo.

Sleight AJ, Smith RJ, Marsden CA, Palfreyman MG.

Department of Physiology and Pharmacology, Medical School, Queen's Medical Centre, Nottingham, U.K.

The purpose of the experiments reported were to determine whether chronic treatment with either a monoamine oxidase (MAO) inhibitor or an uptake inhibitor would increase extracellular levels of 5-HT in vivo and whether such treatment resulted in a down-regulation of the 5-HT1B-mediated decrease in extracellular levels of 5-HT. Rats were given either saline, (E)-beta-fluoromethyline-m-tyrosine (MDL 72394 0.25 mg/kg p.o.) or amitriptyline (10 mg/kg p.o.) once a day for 21 days. Twenty-four hr after the final injection, dialysis loops were implanted into the frontal cortices of these rats and basal extracellular levels of 5-HT were measured. The effect of the 5-HT1 receptor agonist 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)1H indole succinate (RU 24969 10 mg/kg i.p.) on the extracellular level of 5-HT was then studied. Basal levels of 5-HT in saline-treated rats was found to be 27.9 +/- 3.9 fmol/20 microliters perfusate. Chronic treatment with amitriptyline had no effect on extracellular levels of 5-HT but chronic treatment with MDL 72394 significantly increased extracellular levels of 5-HT. Chronic treatment with either MDL 72394 or amitriptyline had no significant effect on the ability of RU 24969 to reduce extracellular levels of 5-HT. These results suggest that 5-HT1B receptors are not down-regulated in response to chronically raised extracellular levels of 5-HT.

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Eur J Pharmacol. 1983 Apr 22;89(1-2):69-76.
Effects of chronic antidepressant treatment on serotonin receptor activity in mice.

Friedman E, Cooper TB, Dallob A.

The effect of acute and chronic treatments with conventional and atypical antidepressant drugs on serotonin receptor activity was assessed by the responsiveness of mice to the serotonin receptor agonist 5-methoxy-N,N-dimethyltryptamine. Acute treatment with 10 mg/kg of amitriptyline, imipramine, trazodone, mianserin or viloxazine reduced the head twitch response measured 1 h following a challenged dose of the serotonin agonist. Acute iprindole and desmethylimipramine, however, had no effect on the serotonergic response. Chronic treatment with the clinically effective antidepressants amitriptyline, imipramine, desmethylimipramine, iprindole, and trazodone produced an enhanced responsiveness to 5-MeODMT. The enhanced responsiveness was first observed 24 h after cessation of treatment with most drugs. The effect lasted for at least 48 h. Chronic treatment with the neuroleptic haloperidol did not result in altered responsivity to the serotonin agonist. Brain accumulation of imipramine and amitriptyline and their deaminated metabolites were measured. Brain drug and metabolite levels peaked 1 h following both acute and chronic treatments. Brain accumulations of amitriptyline and its metabolite were much greater than those of imipramine and its metabolite. This pharmacokinetic data is consistent with an early (1 h) antagonism of the 5-MeODMT response and the emergence of hightened responsiveness to 5-MeODMT after chronic treatment, when brain drug levels are reduced. These findings are also consistent with the greater inhibitory effect found after treatment with amitriptyline than with imipramine. It is concluded that enhanced serotonin neurotransmission which develops during chronic treatment with antidepressant drugs may be related to the clinical action of these drugs.

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Eur J Pharmacol. 1982 Apr 8;79(1-2):17-22.
Withdrawal from chronic treatment with metergoline, dl-propranolol and amitriptyline enhances serotonin receptor mediated behaviour in the rat.

Stolz JF, Marsden CA.

Acute treatment of rats with metergoline (2 mg/kg), a serotonin antagonist, prevented the behavioural syndrome produced by the serotonin agonist 5-methoxy-N',N'-dimethyltryptamine (2.5 mg/kg, 5MEODMT). dl-Propranolol (15 mg/kg) and amitriptyline (15 mg/kg) also inhibited the behavioural syndrome. The 5MEODMT behavioural syndrome was attenuated when metergoline or amitriptyline were administered daily for 14 days and 5MEODMT administered 30 min after the injection on day 14. This attenuation was not seen with chronic dl-propranolol treatment. When 5MEODMT was administered 72 h after the last injection of metergoline, amitriptyline or dl-propranolol on day 14, the behavioural syndrome was enhanced. The results suggest that withdrawal from chronic treatment with serotonin antagonists results in functional supersensitivity of serotoninergic neurones.

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Ann Emerg Med. 1986 Aug;15(8):876-80.
Phenytoin: does it reverse tricyclic-antidepressant-induced cardiac conduction abnormalities?

Mayron R, Ruiz E.

Case reports have appeared describing a beneficial effect of phenytoin in reversing cardiac conduction abnormalities induced by tricyclic antidepressant (TCA) overdose. Controlled studies have not been published. The following questions were addressed using intravenous amitriptyline and phenytoin in a rabbit model: Can prophylaxis with phenytoin before amitriptyline poisoning forestall the onset of cardiac abnormalities? Would such prophylactic phenytoin administration allow a higher dose of amitriptyline before death occurs? Would phenytoin reverse the cardiotoxic effects of amitriptyline once in progress? Animals were used in repeated trials with one-week "washout" intervals and served as their own controls in all but the final trial. Prophylactic phenytoin did not change the potency of amitriptyline in inducing abnormal cardiac performance, nor did it allow the animals to be titrated to a higher dose of amitriptyline before death occurred. In 12 animals, phenytoin "rescue" at the point of a widened QRS or arrhythmia was attempted. Two showed improvement; the remainder did not. Because this portion of the experiment was neither blinded nor controlled, nor were respirations or blood pressure monitored, these results must be viewed cautiously. Although our results suggest that prophylactic phenytoin is not useful, its role in therapy of occasional cases requires further investigation.

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Neurobehav Toxicol Teratol. 1985 Mar-Apr;7(2):139-41.
Alcohol interactions with typical and atypical antidepressants.

Tartara A, Formigli L, Crema F, Maurelli M, Perucca E, Marchioni E, Manzo L, Savoldi F.

Selected parameters of central nervous system function have been examined in rabbits and mice given ethyl alcohol (ET) in combination with antidepressant drugs with different pharmacological profiles. A significant prolongation of the ET-induced loss of righting reflex was observed in mice treated with amitriptyline, 3 mg/kg, or trazodone, 8 mg/kg, injected intraperitoneally. The same drugs failed to cause narcosis when given alone to mice at doses up to 40 (amitriptyline) and 100 (trazodone) mg/kg. Rabbits given single 5 mg/kg IV doses of amitriptyline or trazodone exhibited a synchronous EEG pattern with an increase in spectrum total power that became more pronounced after IV injection of a low dose of ET (0.2 g/kg). The increase in the spectrum total power after ET was significantly greater in rabbits given trazodone than in those given amitriptyline. No significant interactive effects were observed in animals receiving combinations of ET with viloxazine, bupropion or fluvoxamine.

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Eur J Clin Pharmacol. 1979 Jun 12;15(5):335-40.
Inhibition of platelet uptake of serotonin in plasma from patients treated with clomipramine and amitriptyline.

Lingjaerde O.

The inhibition of serotonin uptake by platelets has been measured in blood from 20 patients on amitriptyline (50--225 mg daily), 14 patients on clomipramine (25--200 mg daily), and in an untreated group of 21 depressed patients. A complete kinetic analysis was carried out in each patient. Using the increase in the kinetic parameter Km as a measure of uptake inhibition, there was high correlation between the daily dose and inhibition within each drug group, clomipramine being about 10 times more potent than amitriptyline. The inhibition did not vary with age, sex, duration of treatment (up to 3 years), or concomitant use of moderate doses of benzodiazepines, neuroleptics or lithium. In the amitriptyline group the inhibition was significantly smaller in smokers than in non-smokers. The kinetic parameter Vmax was essentially unchanged in the amitriptyline group, and was markedly reduced in the clomipramine group, but without any correlation with dose. The mixed competitive-noncompetitive effect of clomipramine confirms previous in vitro findings.

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