Differential effect of a single high dose of the tricyclic antidepressant imipramine on interleukin-1beta and tumor necrosis factor-alpha secretion following an in vivo lipopolysaccharide challenge in rats

Tricyclic antidepressants (TCAs) of which imipramine is one, are commonly used in the treatment of depressive disorders and other forms of psychiatric illness. There have been many reports regarding the suppressive effects of TCAs on immune function. However, information is still limited regarding the effects of TCAs on the immune system, as many of the studies conducted to date have concentrated on in vitro exposure to such drugs, or ex vivo measures of immunity following drug administration. Thus in the present investigation, an in vivo challenge with bacterial lipopolysaccharide (LPS) (100 microg/kg; i.p.) was used to assess immunocompetence following administration of a single high dose of the TCA, imipramine (100 mg/kg, p.o.). The results demonstrated that imipramine pretreatment inhibits LPS-induced increases in serum concentrations of the proinflammatory cytokine, tumor necrosis factor (TNF)-alpha both 3 and 6 h, following administration. However, LPS-induced interleukin (IL)-1beta secretion was not significantly altered following imipramine treatment at either of the timepoints examined. In addition, serum concentrations of corticosterone and the antiinflammatory cytokine IL-10 were measured, and imipramine treatment failed to alter either basal, or LPS-induced increases in these immunosuppressive agents. In conclusion, although IL-1beta and TNF-alpha are both macrophage-derived proinflammatory cytokines, the present study demonstrates a differential sensitivity of these cytokines to the suppressive effects of the TCA imipramine. Furthermore, the suppressive effects of imipramine on LPS-induced TNF-alpha secretion could not be attributed to either increased glucocorticoid levels, or increased secretion of the antiinflammatory cytokine IL-10. The relevance of these findings to antidepressant-induced immunotoxicity are discussed.     

Transferrin is required for normal distribution of 59Fe and 54Mn in mouse brain

Hypotransferrinemia (hpx/hpx) is a genetic defect in mice resulting in <1% of normal plasma transferrin (Tf) concentrations; heterozygotes for this mutation (+/hpx) have low circulating Tf concentrations. These mice provide a unique opportunity to examine the role of Tf in Fe and Mn transport in the brain. Twenty weanling wild-type BALB/cJ mice, 15 +/hpx mice, and 12 hpx/hpx mice of both sexes were injected i.v. with either 54MnCl(2) or 59FeCl(3) either 1 h or 1 week before killing at 12 weeks of age. Total brain counts of 54Mn and 59Fe were measured, and regional brain distributions were assessed by autoradiography. Hypotransferrinemia did not affect total brain Mn uptake. However, 1 week after i.v. injection, hpx/hpx mice had less 54Mn in forebrain structures including cerebral cortex, corpus callosum, striatum, and substantia nigra. The +/hpx mice had the highest total brain 59Fe accumulation 1 h after i.v. injection. A striking effect of regional distribution of 59Fe was noted 1 week after injection; in hpx/hpx mice, 59Fe was located primarily in choroid plexus, whereas in +/+ and +/hpx mice 59Fe was widely distributed, with relatively high amounts in cerebral cortex and cerebellum. We interpret these data to mean that Tf is necessary for the transport of Fe but not Mn across the blood-brain barrier, and that there is a Tf-independent uptake mechanism for iron in the choroid plexus. Additionally, these data suggest that endogenous synthesis of Tf is necessary for Fe transport from the choroid plexus.     

Changes in iron histochemistry after hypoxic-ischemic brain injury in the neonatal rat

Iron can contribute to hypoxic-ischemic brain damage by catalyzing the formation of free radicals. The immature brain has high iron levels and limited antioxidant defenses. The objective of this study was to describe the early alterations in nonheme iron histochemistry following a hypoxic-ischemic (HI) insult to the brain of neonatal rats. We induced a HI insult to the right cerebral hemisphere in groups of 7-day-old rats. Rats were anesthetized, then their brains were perfused and fixed at 0, 1, 4, 8, 24 hr, and 1, 2, and 3 weeks of recovery. Forty-micron-thick frozen sections were stained for iron using the intensified Perls stain. Increased iron staining was first detected within the cytoplasm of cells with pyknotic nuclei at 4 hr of recovery. Staining increased rapidly over the first 24 hr in regions of ischemic injury. By 7 days recovery, reactive glia and cortical blood vessels also stained. Increased staining in gray matter persisted at 3 weeks of recovery, whereas white matter tracts had fewer iron-positive cells compared to normal. The early increase in iron staining could be caused by an accumulation of iron posthypoxicischemic injury or a change in iron from nonstainable heme iron to stainable nonheme iron. Regardless of the source, our results indicate that there is an increase in iron available to promote oxidant stress in the neonatal rat brain following hypoxia-ischemia.     

Reboxetine attenuates forced swim test-induced behavioural and neurochemical alterations in the rat.

The forced swim test is a behavioural paradigm that is predicative of antidepressant activity in rodents. Until recently, research has focused on the ability of antidepressant drugs to decrease immobility in the forced swim test paradigm, but the neurochemical sequelae induced by swim stress, or the neurochemical basis of antidepressant-induced behavioural changes have received little attention. In this regard, we have recently demonstrated that forced swim test exposure increases serotonergic activity in the amygdala, frontal cortex and hippocampus and dopamine turnover in the striatum. In addition, forced swim test-exposure activates the hypothalamic pituitary adrenal axis. The purpose of the present study was to examine the effect of treatment with the selective noradrenaline reuptake inhibitor reboxetine (3, 10 and 30 mg/kg; i.p.) on immobility and defaecation scores in the forced swim test, and on forced swim test-induced neurochemical and hypothalamic pituitary adrenal axis changes in the rat. Reboxetine treatment (10 and 30 mg/kg) significantly decreased immobility and defaecation in the forced swim test in dose dependent manner. Furthermore, reboxetine produced a dose dependent attenuation of forced swim test-induced increases in serotonin turnover in the amygdala and frontal cortex and dopamine turnover in the striatum. Reboxetine (30 mg/kg) produced a modest, but non-significant, attenuation of forced swim test-induced increases in serum corticosterone concentrations. These data demonstrate that, in addition to the behavioural activity of reboxetine in the rat forced swim test paradigm, a dose-dependent attenuation of swim stress-induced increases in serotonergic and dopaminergic activity occurred in a region specific manner. These are the first data to demonstrate that treatment with the selective noradrenaline reuptake inhibitor, reboxetine can impact on the activity of other neurotransmitter systems in response to stress. Moreover, these data further demonstrate that this paradigm is a valuable tool in studying the effect of antidepressants, on both behaviour and swim stress-related alterations in central neurotransmitter function and hypothalamic pituitary adrenal axis activity in the rat.     

Gender differences in drinking restraint.

OBJECTIVE: This study examines the factor structure and the predictive power of drinking restraint for men and women as measured by the Temptation and Restraint Inventory (TRI). The TRI assesses two factors: Cognitive-Emotional Preoccupation (CEP) and Cognitive-Behavioral Control (CBC). METHOD: A group of 418 drinkers was drawn from a university sample and divided by gender into two groups. Men (n = 122) were of a mean age (+/-SD) of 23 +/- 7 years; women (n = 296) were of a mean age of 22.5 +/- 8 years. Subjects completed the TRI and the Alcohol Dependence Scale (ADS) and validated quantity and frequency of drinking indices. RESULTS: Drinking restraint for the men was found to better predict alcohol dependence, quantity of drinking and frequency of drinking. Moreover, two factors confirming the TRI's CEP and CBC model were extracted for the men, but only one factor was extracted for the women. CONCLUSIONS: It was proposed that, as men tend to drink greater amounts of alcohol more often, they have learned to distinguish more clearly the conflicts in their personal control over drinking. If the TRI is to be used as a diagnostic and treatment tool, it is recommended that clinicians be cognizant of possible gender differences in restrained drinking behavior.     

A pilot study of mirtazapine in post-traumatic stress disorder

Recently, studies of pharmacotherapy for post-traumatic stress disorder (PTSD) have been focused on serotonin-selective reuptake inhibitors (SSRI), despite a number of treatment-limiting side-effects. Mirtazapine, a novel drug with both noradrenergic and serotonergic properties, may be effective in individuals who demonstrate intolerance to side-effects of and a limited response to SSRIs. Six outpatients with severe, chronic PTSD were treated with mirtazapine, up to 45 mg/day for 8 weeks. Efficacy assessments and side-effect monitoring were performed at baseline and weeks 2, 4, 6 and 8. Fifty percent of the sample demonstrated improvement of 50% or more from baseline using a global rating. In addition, improvements were noted on both interviewer-administered and self-rated scales of PTSD and of depression. The drug was well tolerated with few significant side-effects. Mirtazapine was associated with clinical improvement in 50% of subjects with severe, chronic PTSD, suggesting a need for further investigation in double-blind, placebo-controlled trials.     

Acetabular fractures before and after the introduction of seatbelt legislation

Objectives

To compare the incidence and severity of acetabular fractures and associated injuries before and after seatbelt legislation.

Design

A retrospective study.

Setting

Two major trauma centres, which are teaching hospitals.

Patients

Three hundred and ninety-three patients who sustained acetabular fractures during the 5 years before and 5 years after seatbelt legislation was enacted. Of these, the fractures in 198 patients (50.4%) resulted from a motor vehicle accident.

Main Outcome Measures

The number and severity of acetabular fractures and associated injuries.

Results

There has been a significant reduction in the number of acetabular fractures (p = 0.005) since seatbelt use became mandatory, and the complexity of the fractures has decreased. There has also been a marked reduction in associated injuries, such as fractures of other bones, and head, chest and abdominal injuries (p < 0.001).

Conclusion

The seatbelt law has been a useful preventive measure, resulting in a reduction in the incidence of acetabular fractures and associated injuries.