Effects of Chronic Treatment of Methamphetamine and Imipramine on Amygdaloid Seizure's Generation

Abstract: We assessed the effects of chronic treatment of methamphetamine (1–2 mg/kg/day, i.p., 17 days) and imipramine (2–8 mg/kg/day, P.o., 17 days) on amygdala-generating seizures using the kindling method induced by low-frequency electrical stimulations. The number of stimulating pulses required for the triggering of epileptic after-discharge (pulse-number threshold: PNT) is the indicator of seizure generating threshold. A PNT elevation followed by its reduction occurred, compared to the pretreatment level, during a 2 mg/kg/day chronic methamphetamine treatment. A reduction in the PNT and triggered afterdischarge durations occurred during a chronic imipramine treatment. These results indicate that both methamphetamine and imipramine reduced the seizure generating threshold by repeated applications. It is suggested that this finding might be related to the psychoactive potency and associated neurochemical changes which are known to be caused by these drugs.     

Relapse prevention by means of paroxetine in ECT-treated patients with major depression: a comparison with imipramine and placebo in medium-term continuation therapy

In-patients with severe major depression were treated in the acute phase with electroconvulsive therapy (ECT) in combination with antidepressants. The drug treatment consisted of two randomized trials which were both extended into the post-ECT continuation phase. Patients with electrocardiological impairment were randomized to either 30 mg paroxetine daily or placebo under blind conditions. Patients without electrocardiological impairment were randomized to either 30 mg paroxetine daily or 150 mg imipramine daily. There was a high level of agreement between the Hamilton Depression Scale and the Melancholia Scale, demonstrating that the patients treated with ECT plus imipramine in the acute phase showed greater symptom reduction than those treated with ECT plus paroxetine. However, in the post-ECT phase paroxetine was superior to both imipramine and placebo in preventing relapse. Thus in the post-ECT phase 65% of the placebo-treated patients relapsed, compared to 30% of the imipramine-treated patients and 10% of the paroxetine-treated patients. The psychometric analysis of the Melancholia Scale in the continuation or post-ECT phase showed that relapsing patients displayed a pattern with lack of interests, impaired concentration, depressed mood and anxiety among the less severe symptoms (first-compartment symptoms). In other words, these symptoms represent the gate to full-blown depression (second-compartment symptoms). Serotonin-selective antidepressants such as paroxetine appear I to be more effective in controlling the first-compartment symptoms.     

Influence of olfactory bulbectomy and subsequent imipramine treatment on 5-hydroxytryptaminergic presynapses in the rat frontal cortex: behavioural correlates

1. Alterations of 5-hydroxytryptaminergic mechanisms are thought to play a special role in the pathogenesis of depression and antidepressant treatments are assumed to restore these changes.
2. We have used one of the most reliable models of depression, the olfactory bulbectomized rat to study the long term consequences of this manipulation and of subchronic imipramine treatment on two parameters of 5-hydroxytryptaminergic presynapses, 5-hydroxytryptamine (5-HT) transporter density and tryptophan hydroxylase apoenzyme concentration, in the frontal cortex as well as on active avoidance learning several weeks after bulbectomy.
3. The B_max value of [³H]-paroxetine binding and the concentration of the 5-HT synthesizing enzyme were both significantly elevated in the frontal cortex of bulbectomized rats compared to sham-operated controls.
4. Imipramine treatment, either by daily injections or by subcutaneous implantation of slow release imipramine-containing polymers reduced the elevated tryptophan hydroxylase apoenzyme levels in the frontal cortex of bulbectomized, but not of sham-operated control rats and restored the deficient learning performance of bulbectomized rats.
5. Both effects were more pronounced after continuous drug administration by imipramine-releasing polymers compared to daily i.p. injections.
6. These findings indicate that bulbectomy leads to a compensatory 5-hydroxytryptaminergic hyperinnervation of the frontal cortex. Chronic antidepressant treatment seems to attenuate the increased output of the 5-hydroxytryptaminergic projections in the frontal cortex through the destabilization of the rate limiting enzyme of 5-HT synthesis of the 5-hydroxytryptaminergic nerve endings in this brain region.

     

Imipramine decreases oesophageal pain perception in human male volunteers

Department of Medicine, Suite 501, Pepper Pavilion, Allegheny University Hospitals, Graduate, One Graduate Plaza, 1800 Lombard Street, Philadelphia, Pennsylvania 19146, USA

Correspondence to: Dr D O Castell.

Accepted for publication 19 January 1998

Background—Visceral hyperalgesia is a hallmark of functional gastrointestinal disorders. Antidepressants improve symptoms in these patients, although their mode of action is unclear. Antidepressant, anticholinergic, and analgesic mechanisms have been proposed.
Aims—To investigate whether imipramine, which has a visceral analgesic effect, increases pain thresholds to experimental visceral pain.
Methods—Visceral perception for first sensation and pain was measured with intraoesophageal balloon distension in 15 male volunteers. The effect of imipramine was studied in a double blind, placebo controlled, crossover study. Imipramine was given in ascending doses for 12 days (25 mg days 1-3, 50 mg days 4-6, 75 mg days 7-12), with oesophageal perception studied on day 13. 
Results—Inflation volumes and intraballoon pressures at first sensation were not different between placebo and imipramine. Balloon inflation volume at pain threshold was higher on imipramine (p=0.015). Median intraballoon pressures were not different at pain threshold for placebo and imipramine. Oesophageal wall compliance was not affected by imipramine.
Conclusion—Increased pain thresholds on imipramine in this group of normal male volunteers in the absence of changes in oesophageal tone imply the presence of a visceral analgesic effect.
(GUT 1998;:807-813)

Keywords: antidepressants;  imipramine;  visceral hyperalgesia;  oesophageal balloon;  distension;  functional bowel syndromes

     

Chronic Administration of Imipramine Normalizes Decreased Sexual Motivation and Increased Predisposition to Catalepsy Induced by Propylthiouracil in Rats

Thyroxine synthesis inhibitors increase the predisposition to catalepsy and decrease sexual motivation and the amplitude of the acoustic startle reflex in rats. The sensitivity of these behavioral changes to antidepressants remains uncertain. Chronic administration of the classical tricyclic antidepressant imipramine (15 mg/kg, 21 days) prevented the appearance of high sensitivity to catalepsy and the decrease in sexual motivation in Wistar rats given propylthiouracil (50 mg/liter, 28 days), without altering the amplitude of the startle reflex. Normalization of behavior in response to imipramine was not associated with changes in movement activity in the open field test or the animals’ body weight. There was also no change in the expression of the 5-HT_2A serotonin receptor gene in the frontal cortex. The model of propylthiouracilinduced catalepsy with reduced sexual motivation in rats has potential for studying the role of thyroid abnormalities in the development of depression and the mechanisms of action of antidepressants. Translated from Zhurnal Vysshei Nervnoi Deyatel’nosti imeni I. P. Pavlova, Vol. 58, No. 2, pp. 217–225, March–April, 2008.     

Influence of antidepressant drugs on chlorpromazine metabolism in human liver--an in vitro study

The aim of the present study was to investigate the possible effects of antidepressant drugs (fluvoxamine, imipramine) on the metabolism of the aliphatic-type phenothiazine neuroleptic chlorpromazine in the human liver. The experiment was performed in vitro using human liver microsomes. The kinetic analysis of chlorpromazine metabolism carried out in the absence or presence of antidepressants showed that fluvoxamine potently inhibited chlorpromazine 5-sulfoxidation (K(i) = 2.8 μM), mono-N-demethylation (K(i) = 1.4 μM) and di-N-demethylation (K(i) = 1.1 μM) via a competitive mechanism at therapeutic antidepressant concentrations. Imipramine moderately diminished the rate of chlorpromazine 5-sulfoxidation (K(i) = 8.7 μM, competitive inhibition), mono-N-demethylation (K(i) = 16.0 μM, non-competitive inhibition) and di-N-demethylation (K(i) = 13.5 μM mixed inhibition). Considering the serious side-effects of chlorpromazine and some of its metabolites, metabolic interactions between this neuroleptic and antidepressant drugs (especially the chlorpromazine-fluvoxamine interaction) may be of pharmacological and clinical importance.     

Effect of tricyclic antidepressants on sphingomyelinase and other sphingolipid hydrolases in C6 cultured glioma cells

Cationic amphiphilic drugs, which include tricyclic antidepressants, have been shown to give rise to lipidoses under experimental conditions, with a general increase of lipids especially phospholipids. We report here an early and important decrease in sphingomyelinase activity in C6 glioma cells cultured in the presence of imipramine or desipramine at final concentrations of 0.01 and 0.05 mM. The effect was both dose-dependent and time-dependent and was observed before any lipid accumulation. Cerebroside beta-glucosidase and cerebroside beta-galactosidase had normal activities under the same experimental conditions and thus there was no general effect on membrane-bound sphingolipid hydrolases. A decrease of sphingomyelinase activity has been previously reported for two amphiphilic compounds, perhexiline maleate and AY 9944. These results suggest a potential function of sphingomyelinase in the mode of action of these drugs.