Animal experiment:

Rats[2]Male Wistar rats weighing 220-250 g at the beginning of the experiment are used. The animals, housed in groups of 6-8 have free access to food and water and are kept on a 12 hr light/dark cycle (light on at 6a.m.) at a temperature. The rats are anaesthetized with pentobarbital (50 mg/kg i.p.) and an osmotic minipump is implanted subcutaneously in the dorsal thoracic interscapular region. Each pump delivers 5 mg/kg/day of Trimipramine or amitriptyline. Control rats are implanted with pumps filled with 0.9%, saline. The total volume of solution in the pump is sufficient for at least 14 days delivery of drugs. After implantation, the incision is cleaned and sutured and the animals kept warm until they recovered from anaesthesia[2].

Trimipramine (maleate) is a potent antagonist of histamine H1 receptor, serotonin 5-HT2A, and α1-adrenergic receptors [1].

The histamine H1 receptor is widely expressed tissues, such as smooth muscles, vascular endothelial cells, heart, and the central nervous system. Histamine H1 receptor (H1R) antagonists are very effective drugs alleviating the symptoms of allergic reactions [2]. 5-HT2A receptor shows constitutive activity. Variations in5-HT2A receptor can produce profound alterations in cognitive states [3]. The adrenergic receptors play an important role in modulating sympathetic nervous system activity as well as a site of action for many therapeutic agents. The α1-adrenergic receptor is the prime mediators of smooth muscle contraction and hypertrophic growth. The α1-adrenergic receptor plays an essential role in smooth muscle, growth, neurological, and cardiovascular function [4].

Trimipramine (maleate) is a tricyclic antidepressant compound that antagonizes several types of neurotransmitter receptors. Trimipramine potently antagonized the activity of histamine H1 serotonin 5-HT2A, and α1-adrenergic receptors with the Kd value of 0.27 nM, 24 nM, and 24 nM, respectively. Trimipramine moderately antagonized the activity of dopamine D2 with the Kd of 180 nM. Trimipramine inhibited the activity of muscarinic acetylcholine with the Kd of 58 nM. Trimipramine weakly inhibited the activity of 5-HT2C, D1, α2-adrenergic receptors (Kd = 680 nM) [1]. Trimipramine (maleate) was a weak to moderate reuptake inhibitor of serotonin (Ki = 149 nM for SERT), and an extremely weak inhibitor of norepinephrine (Ki = 2.5 μM for NET) and dopamine (Ki = 3.8 μM for DAT) reuptake in slices of rat cerebral cortex [5,6].

References:
[1] Richelson E, Nelson A.  Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro[J]. Journal of Pharmacology and Experimental Therapeutics, 1984, 230(1): 94-102.
[2] Shimamura T, Shiroishi M, Weyand S, et al.  Structure of the human histamine H1 receptor complex with doxepin[J]. Nature, 2011, 475(7354): 65-70.
[3] Harvey J A.  Role of the serotonin 5-HT2A receptor in learning[J]. Learning & Memory, 2003, 10(5): 355-362.
[4] Piascik M T, Perez D M.  α1-Adrenergic receptors: new insights and directions[J]. Journal of Pharmacology and Experimental Therapeutics, 2001, 298(2): 403-410.
[5] Gross G, Xie X, Gastpar M.  Trimipramine: pharmacological reevaluation and comparison with clozapine[J]. Neuropharmacology, 1991, 30(11): 1159-1166.
[6] Tatsumi M, Groshan K, Blakely R D, et al.  Pharmacological profile of antidepressants and related compounds at human monoamine transporters[J]. European journal of pharmacology, 1997, 340(2): 249-258.