Changes in the levels of biogenic amines in different brain regions and the cerebrospinal fluid in rats were measured after acute or chronic treatment with tricyclic antidepressants. After single or 3 weeks' treatment with imipramine or desipramine, blocks of tissues were obtained from seven regions of the brain (frontal cortex, corpus striatum, hippocampus, thalamus, hypothalamus, substantia nigra and cerebellum) immediately after collection of the cerebrospinal fluid (CSF) from the cisterna magna. The concentrations of biogenic amines and their metabolites (norepinephrine, epinephrine, dopamine, 5-hydroxytryptamine (5-HT), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA)) in brain tissues and the CSF were measured using the high performance liquid chromatography-electrochemical detection system (HPLC-ECD). Treatment with desipramine or imipramine caused major alterations in the concentrations of central norepinephrine or 5-HT and its metabolite, respectively. Brain regional responses were variable according to the kind of tricyclic antidepressants and the duration of treatment. It is noteworthy that chronic treatment with both desipramine and imipramine caused altered hippocampal concentrations of norepinephrine and/or 5-HT and its metabolites. Striatal DOPAC concentrations were also changed after acute or chronic treatment with both drugs. These results suggest that tricyclic antidepressants altered neurotransmission according to the brain region, and the hippocampal norepinephrine and 5-HT and/or the striatal dopamine may have a significant role for the expression of antidepressant action of tricyclic antidepressants.
Animal ; Antidepressive Agents, Tricyclic/*pharmacology ; Biogenic Monoamines/*metabolism ; Brain/*drug effects/metabolism ; Desipramine/pharmacology ; Imipramine/pharmacology ; Male ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo study the derivatives of 1,2,4-triazino[5,6-b]indole-3-thione for antidepressant activity in olfactory bulbectomized (OBX) rats. Out of various derivatives tested for acute tail suspension test, the two derivatives showing prominent action were selected for bilateral olfactory bulbectomy model of chronic depression in rats.

METHODSThe sub acute effects of 14-day oral pretreatment of two derivatives labeled as 3a (70 mg/kg) and 3r (70 mg/kg), imipramine (20 mg/kg), fluoxetine (30 mg/kg) and moclobemide (15 mg/kg) were evaluated on bilateral bulbectomy induced rise in body weight, hyperphagia, hyperactivity, and on sexual dysfunction. The serum sodium concentration, body temperature, and heart rate were also recorded.

RESULTSThe derivatives 3a and 3r showed reversal of drop in body weight, reversed OBX induced hyperactivity, normalized body temperature, heart rate, and serum sodium concentration. In elevated maze test, moclobemide, 3a, 3r treatment significantly reduced time spent in open arm as compared to OBX rats. 3a and 3r also improved sexual behavior parameters.

CONCLUSIONSThe present study shows promising antidepressant action and provides a proof of concept for the chronic treatment of 3a, 3r to treat depression.

Acetamides ; pharmacology ; Acetanilides ; pharmacology ; Animals ; Antidepressive Agents ; pharmacology ; Behavior, Animal ; drug effects ; Depression ; drug therapy ; etiology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Female ; Fluoxetine ; pharmacology ; Imipramine ; pharmacology ; Male ; Moclobemide ; pharmacology ; Olfaction Disorders ; complications ; pathology ; Olfactory Bulb ; surgery ; Rats ; Rats, Sprague-Dawley ; Triazines ; pharmacology