Eur J Clin Pharmacol. 1987;32(3):317-20.
Lack of interaction of ranitidine with amitriptyline.

Curry SH, DeVane CL, Wolfe MM.

The possibility of an interaction of ranitidine with amitriptyline was assessed by means of amitriptyline and nortriptyline plasma concentration measurements, blood pressure and pulse rate, digit symbol substitution, and visual analogue scales. Ranitidine had no effect on amitriptyline or nortriptyline concentrations. Responses recorded by the digit symbol substitution and visual analogue scale tests correlated with changes in concentrations of amitriptyline and nortriptyline in plasma. No effects on blood pressure or pulse rate were observed. We concluded that there was no effect of ranitidine on amitriptyline kinetics or response in the conditions of our study.

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J Affect Disord. 1983 Feb;5(1):67-79.
Tryptophan and tyrosine ratios to neutral amino acids in endogenous depression. Relation to antidepressant response to amitriptyline and lithium + L-tryptophan.

Moller SE, Honore P, Larsen OB.

The plasma ratios of tryptophan and tyrosine to those amino acids that compete with them during transport across the blood-brain barrier have been determined in depressed patients before and after treatment for four weeks with amitriptyline or lithium + L-tryptophan. There was no relation between the absolute plasma concentrations of free or total tryptophan or tyrosine and the clinical response to amitriptyline. There was also no relation between pre-treatment ratio of plasma tyrosine to competing amino acids and response to amitriptyline, but depressives with subnormal tryptophan ratio improved significantly more than patients with supernormal tryptophan ratio with comparable serum drug levels. The therapeutic response to lithium + L-tryptophan was predicted neither by the absolute plasma concentrations of free or total tryptophan or tyrosine nor by the tyrosine ratio, but there was also a trend towards greater improvement in patients with subnormal compared with supernormal tryptophan ratio. The results suggest that the pre-treatment plasma ratio of tryptophan to competing amino acids is a useful predictor of clinical response to amitriptyline. The possible mode of action of amitriptyline and lithium + L-tryptophan is briefly discussed.

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Pharmacopsychiatry. 1985 Sep;18(5):314-9.
Amitriptylinoxide: receptor-binding profile compared with other antidepressant drugs.

Borbe HO, Zierenberg O.

The interactions of amitriptylinoxide and various antidepressant drugs with different neurotransmitter and drug receptors were investigated by receptor binding studies. Amitriptylinoxide had less affinity than amitriptyline for most of the receptors studied. Half maximal inhibition of acetylcholine receptor binding occurred for amitriptylinoxide at 18 mumol/l (amitriptyline: 0.32 mumol/l). Comparing all studied antidepressants for muscarinic acetylcholine receptor binding, amitriptylinoxide had the weakest affinity of all tested tricyclic compounds. Also the affinity of amitriptylinoxide for alpha-receptor binding was about 60 fold less than that of amitriptyline. For all antidepressants investigated, the lowest affinities were found for benzodiazepine, opiate and beta-receptor binding. The weak affinities of amitriptylinoxide for various receptors may be responsible for its reduced side-effects, while it still retains potent antidepressant properties by stabilising the amitriptyline-level in the brain.

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Neuropharmacology. 1983 Aug;22(8):983-92.
The effects of acute and repeated administration of various antidepressant drugs on clonidine-induced hypoactivity in mice and rats.

Heal DJ, Lister S, Smith SL, Davies CL, Molyneux SG, Green AR.

Small doses of clonidine produce hypoactivity in mice and rats, probably by stimulating pre-synaptic alpha 2-adrenoceptors in the brain. When mice were injected with desmethylimipramine (DMI, 5 mg/kg) before clonidine it attenuated the hypoactivity, while pretreatment with amitriptyline (5 mg/kg) or mianserin (5 mg/kg) potentiated this behaviour. In rats, desmethylimipramine (20 mg/kg) inhibited and mianserin (5 mg/kg) potentiated the clonidine-induced hypoactivity. Amitriptyline (20 mg/kg), however, had no effect on this behaviour in rats. Mice were also given repeated injections of these 3 antidepressant drugs (5 mg/kg twice daily for 14 days) and were tested with clonidine 12 and 60 hr after the final treatment. At 12 hr desmethylimipramine and amitriptyline both attenuated the hypoactivity responses while the reduction by mianserin was marginal (potency DMI greater than amitriptyline greater than mianserin). At 60 hr, however, amitriptyline and mianserin both decreased the clonidine-induced responses while the attenuation by desmethylimipramine was slight (potency amitriptyline congruent to mianserin greater than DMI). In rats, repeated injections of desmethylimipramine (20 mg/kg), administered twice daily for 14 days, attenuated the clonidine-induced hypoactivity 12 hr after the final treatment and this effect persisted for at least 72 hr. Furthermore, the degree of inhibition of the behavioural responses did not correlate with plasma concentrations of desmethylimipramine and persisted after disappearance of the drug from plasma. In conclusion, these data suggest that after repeated injection, desmethylimipramine, amitriptyline and mianserin all produce an adaptive decrease in the function of central alpha 2-adrenoceptors but the time course of this change differs with the individual antidepressant drug administered.

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Br J Pharmacol. 1986 May;88(1):129-39.
Changes in the behavioural response to a TRH analogue following chronic amitriptyline treatment and repeated electroconvulsive shock in the rat.

Bennett GW, Green AR, Lighton C, Marsden CA.

The arousal elicited in rats by injection into the nucleus accumbens of the thyrotrophin-releasing hormone analogue CG 3509 (orotyl-histidyl-prolineamide) was used to assess the responsiveness to thyrotrophin-releasing hormone following repeated treatment with amitriptyline or electroconvulsive shock. Fourteen day administration of amitriptyline (15 mg kg-1 i.p. twice daily) reduced the behavioural response to bilateral intra-accumbens injection of CG 3509 (2 X 2.5 micrograms). CG 3509-induced hyperactivity, recovery from pentobarbitone-induced anaesthesia and the reversal of both pentobarbitone-induced hypothermia and decreased respiration, were all significantly reduced compared to either the response of the animals prior to amitriptyline administration or that observed in rats following chronic saline administration. Repeated administration of electroconvulsive shock (5 shocks over 10 days) significantly increased CG 3509-induced hyperactivity and the degree of reversal of pentobarbitone-induced hypothermia and respiratory depression following CG 3509 administration. The results demonstrate that chronic antidepressant treatments alter the central functional responsiveness to thyrotrophin-releasing hormone. These changes are discussed with respect to the effects of antidepressant treatments on 5-hydroxytryptamine receptors and possible thyrotrophin-releasing hormone--aminergic interactions.

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Acta Pharmacol Toxicol (Copenh). 1986 Aug;59(2):103-12.
Chronic treatment with antidepressant drugs and the analgesia induced by 5-methoxy-N,N-dimethyltryptamine: attenuation by desipramine.

Danysz W, Minor BG, Post C, Archer T.

The effect of chronic and acute oral or intraperitoneal treatment with the antidepressant drugs, desipramine, amitriptyline, alaproclate and iprindole, upon pain thresholds in the tail flick, hot plate and shock titration tests of nociception in saline- and 5-MeODMT-treated rats was studied. Chronic desipramine treatment increased the pre-test tail flick latencies. In the saline-treated rats, chronic oral desipramine treatment increased tail flick latencies, whereas chronic oral amitriptyline treatment decreased tail flick latencies. In 5-MeODMT-treated rats, chronic oral desipramine treatment attenuated the effects of 5-MeODMT (1 mg/kg) in all three tests of nociception, whereas chronic amitriptyline caused a potentiation in the tail flick and hot plate tests. Chronic oral iprindole treatment attenuated 5-MeODMT-induced analgesia in the hot plate test. Chronic intraperitoneal desipramine treatment attenuated 5-MeODMT analgesia in the tail flick and shock titration tests. In a different chronic treatment experiment, oral desipramine treatment attenuated 5-MeODMT analgesia in the tail flick test and zimeldine did for both the tail flick and hot plate tests, whereas mianserin potentiated 5-MeODMT-induced analgesia in both the tail flick and hot plate tests. In the saline-treated rats, acute treatment with all four drugs, desipramine, amitriptyline, iprindole and alaproclate, elevated the shock thresholds, whereas in 5-MeODMT-treated rats, desipramine and amitriptyline elevated shock thresholds. Two main conclusions can be drawn: chronic desipramine caused a quite consistent attenuation of 5-MeODMT-induced analgesia and the effects of acute treatment differed strongly from that of the chronic treatment. The effects of chronic administration with these antidepressants were compared with other findings using different measures of behavioural and receptor function.

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Psychopharmacology (Berl). 1986;88(3):279-84.
Inhibition of head twitch response to quipazine in rats by chronic amitriptyline but not fluvoxamine or citalopram.

Pawlowski L, Melzacka M.

Chronic (twice daily/14 days), but not acute, treatment with 10 mg/kg PO amitriptyline reduced the number of quipazine (5 mg/kg)-induced head twitches in rats, measured 2 h (but not 72 h) after the last administration of the drug. Similar treatment with fluvoxamine or citalopram, which are more potent and much more specific serotonin uptake inhibitors than amitriptyline, did not affect the quipazine-induced response. In acute experiments, fluvoxamine (10 mg/kg PO) and citalopram (10 mg/kg PO) potentiated the head twitch reaction induced by L-5-hydroxytryptophan (50 mg/kg IP) given together with Ro 4-4602 (25 mg/kg IP), a peripheral decarboxylase inhibitor. Amitriptyline (10 mg/kg PO) slightly decreased the number of L-5-hydroxytryptophan (5-HTP)-induced head twitches. Higher doses of amitriptyline (20-40 mg/kg PO) also inhibited the quipazine-induced head twitch reaction. The brain level of amitriptyline measured 0.5-24 h after the last oral administration of the chronic dose of 10 mg/kg was always much higher than that observed at the same time intervals after an acute oral dose of 20 or 40 mg/kg. The results obtained indicate that a postsynaptic rather then presynaptic mechanism is responsible for the development of subsensitivity of the central serotonin receptors in the course of chronic treatment with amitriptyline.

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