J Toxicol Clin Toxicol. 1988;26(5-6):313-24.
Effects of naloxone and verapamil in experimental amitriptyline poisoning in rats.

Knudsen K, Ricksten SE, Heath A.

Department of Anesthesia and Intensive Care, University of Gothenburg, Sahlgren's Hospital, Sweden.

The effects of verapamil and naloxone as potential antidotes for amitriptyline-induced cardiotoxicity were investigated in an experimental rat model. Amitriptyline was infused continuously at a dose of 37.5 mg/kg/h. After 15 minutes, the animals were given either naloxone (2 mg/kg + 3 mg/kg/h), verapamil (0.08 mg/kg + 0.08 mg/kg/h), or physiological saline. In the group given naloxone, a significant decrease in heart rate was seen. Although MAP and max dP/dT increased, there was no significant difference from controls. Naloxone did not decrease mortality. When the bolus dose of verapamil was given, a significant decrease in MAP and max dP/dT was obtained. Although the mean blood pressure was significantly higher in those animals treated with verapamil who survived 60 minutes, verapamil did not change the course of the amitriptyline poisoning. In conclusion, our findings indicate that naloxone lacks significant positive effects and that verapamil has an additional negative inotropic effect. Neither drug can be recommended for the treatment of amitriptyline poisoning.

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Neuropharmacology. 1985 May;24(5):401-6.
Increase in levels and ex vivo release of thyrotrophin-releasing hormone (TRH) in specific regions of the CNS of the rat by chronic treatment with antidepressants.

Lighton C, Bennett GW, Marsden CA.

This study has investigated the effects of chronic treatment with amitriptyline, chlorimipramine, mianserin and metergoline on levels and ex vivo release of thyrotrophin-releasing hormone (TRH), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in specific regions of the brain and lumbar spinal cord of the rat. All four treatments caused a significant increase in levels of TRH in the lumbar spinal cord with amitriptyline producing the most marked effect. Amitriptyline alone caused a similar marked increase in levels of TRH in the nucleus accumbens and suprachiasmatic nucleus but none of the treatments had a significant effect on the TRH content of the median eminence or septal nuclei. Potassium-induced release of TRH and 5-HT ex vivo was measured from tissue slices of the nucleus accumbens, septal nuclei and lumbar spinal cord after treatment with amitriptyline and mianserin. An increase in release of TRH was observed only from tissue slices of areas where increased levels of the peptide had occurred; namely nucleus accumbens and lumbar spinal cord after administration of amitriptyline and lumbar spinal cord after mianserin. None of the drugs significantly altered the ex vivo release of 5-HT or 5-HIAA. The results are discussed in relation to a possible interaction between TRH and 5-HT receptors in the antidepressant action of these drugs.

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Eur J Pharmacol. 1985 Mar 26;110(1):137-41.
Why is amitriptyline much weaker than desipramine at decreasing beta-adrenoceptor numbers?

Wise H, Halliday CA.

Desipramine is consistently more effective than amitriptyline at causing beta-adrenoceptor down-regulation. Atropine, mepyramine, ketanserin, cyproheptadine and citalopram did not modify this action of desipramine in rats. Therefore inhibition of either muscarinic, histamine-H1, and 5-HT receptors or 5-HT uptake produced by amitriptyline is unlikely to account for its weaker effect on beta-adrenoceptors. A more likely explanation implicates noradrenaline uptake inhibition in vivo since amitriptyline was much weaker than desipramine and only effective after repeated dosing.

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J Neural Transm. 1982;54(1-2):65-73.
The effects of antidepressants on the autonomic nervous system--a current investigation.

Ikeda Y, Nomura S, Sawa Y, Nakazawa T.

Tricyclic antidepressants influence the autonomic nervous system, as is well known; and endogenous depression shows autonomic nervous symptoms besides the readily observable emotional changes. This is a report on a current investigation of the effects of antidepressants on the function of the autonomic nervous system. In a preliminary study 2 kinds of antidepressants, amitriptyline (tricyclic) and nomifensine (non-tricyclic) were administered to 20 healthy volunteers. The palmar skin potential reflex (SPR), heart rate and respiratory rate were recorded and serum dopamine-beta-hydroxylase (DBH) activity was assayed both before and after the administration of antidepressant. The results were as follows: 1. In the amitriptyline group, the spontaneous SPR and serum DBH activity decreased, and heart rate increased; and the degree of change before and after administration of the drug was statistically significant. Thus amitriptyline seems to suppress the activity of sympathetic nervous system, in addition to suppressing the functioning of the parasympathetic nervous system. 2. In the nomifensine group, spontaneous SPR and serum DBH activity tended to increase. This seems to indicate that nomifensine suppresses neither the parasympathetic nor the sympathetic nervous functions. 3. Amitriptyline and nomifensine has different effects on the sympathetic nervous system, suggesting correspondingly divergent pharmacological mechanisms for the depressive modality.

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Arch Immunol Ther Exp (Warsz). 1975;23(6):787-94.
Influence of some antidepressant drugs on the circulatory system: II. Action of amitriptyline and nortriptyline on basic circulatory parameters.

Banaszkiewicz W, Grzymislawska I, Mrozikiewica A.

Amitriptyline and nortriptyline in doses higher than 0.5 mg/kg exert a hypotensive action, and doses of less than 0-5 mg/kg have no characteristic effect on blood pressure. Both drugs diminished amplitude of cardiac contractions in situ in experimental animals. Low doses increased frequency and amplitude of respirations, and higher doses paralyzed respiratory function. Animals died as a result of paralysis of the respiratory center. In decapitated animals both drugs exhibited activity similar to that in animals with intact central nervous system, but their hypotensive effect was less pronounced. Blockade of the sympathetic and parasympathetic systems and of vegetative ganglia had no influence on the action of amitriptyline and nortriptyline on blood pressure. In low doses both amitriptyline and nortriptyline potentiated, and in high doses weakened the hypertensive effect of noradrenaline.

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Pharmacol Biochem Behav. 1987 Feb;26(2):313-9.
Effects of age on antidepressant kinetics and memory in Fischer 344 rats.

McMahon TF, Weiner M, Lesko L, Emm T.

Experiments were conducted in young (3-4 months) and old (24-25 months) male Fischer 344 rats to assess the effects of amitriptyline, scopolamine, and zimelidine on short term memory using an eight arm radial maze paradigm. Kinetic analyses employing serial blood sampling were also conducted for amitriptyline and zimelidine in an attempt to determine if age-related deficits in performance could be related to changes in pharmacokinetics. In the maze, acquisition of performance was significantly decreased in old rats compared to young. Amitriptyline (5 mg/kg) produced a significant decrement in maze performance on day four of a five day testing period in both young and old rats, while scopolamine (1 mg/kg) produced an initial decrement on day one, followed by a return towards pre-treatment levels in these two age groups. Zimelidine (5 mg/kg) produced no performance decrement in either young or old rats. Kinetic analyses revealed an increased half-life, slower plasma clearance, and a larger volume of distribution of amitriptyline and zimelidine in old rats. Although the kinetic parameters in aged rats exhibited a change in the direction of a decreased ability to metabolize both drugs, this change was not of sufficient magnitude to produce an additive detrimental effect on maze performance.

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Clin Pharmacol Ther. 1980 May;27(5):602-6.
Effect of amitriptyline antidotes on repetitive extrasystole threshold.

Tobis JM, Aronow WS.

The effect of amitriptyline that leads to ventricular tachycardia was evaluated by the repetitive extrasystole threshold (RET) technique in 18 dogs. The RET was 28.8 +/- 7.9 mamp before and 8.2 +/- 5.3 mamp after amitriptyline, p less than 0.001. Physostigmine, propranolol, sodium bicarbonate, and left stellate ganglionectomy reversed the effect of amitriptyline on RET. We conclude that amitriptyline overdose predisposes to sudden death by lowering the ventricular fibrillation threshold. This cardiotoxic effect is mediated partly through the central nervous system and can be inhibited by increased plasma binding (bicarbonate), cholinergic stimulation (physostigmine), beta adrenergic blockade (propranolol), and sympathetic denervation (left stellate ganglionectomy).

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