Chronic treatment with desipramine improves cognitive performance of rats in an attentional set-shifting test.

Alterations in central monoaminergic neurotransmission are important in the actions of many antidepressants. This study tested the hypothesis that tonic elevation of noradrenergic (NA) neurotransmission in medial prefrontal cortex (mPFC) by chronic treatment with the selective norepinephrine (NE) reuptake blocker desipramine (DMI) may contribute to the beneficial cognitive effects of this antidepressant drug (AD). Male Sprague-Dawley rats were treated with DMI acutely (15 mg/kg, i.p.) or chronically for 21 days (7.5 mg/kg/day via osmotic minipump) before assessing performance on an attentional set-shifting test. The extradimensional set-shifting component of this test reflects a process of cognitive flexibility that is dependent upon mPFC, and that we have shown previously to be facilitated by NA activity in mPFC. Microdialysis was performed to measure NE release in mPFC concurrently with behavioral testing. Acute DMI treatment produced an increase in extracellular NE levels in mPFC, and a modest improvement in overall performance across all task stages of the attentional set-shifting test, but failed to produce a significant improvement in any of the individual specific tasks comprising the test sequence. Chronic DMI treatment tonically elevated basal extracellular NE levels in mPFC, associated with a significant improvement in performance specifically on the extradimensional set-shifting component of the test. There was also a significant reduction in set loss errors in rats treated chronically with DMI. Hence, tonic elevation of NA transmission in mPFC by chronic DMI treatment was associated with a time-dependent facilitation of cognitive flexibility that may contribute to the mechanism whereby chronic treatment with ADs, specifically NE reuptake blockers, may exert a beneficial therapeutic effect on cognition in depressed patients.

Noradrenergic facilitation of shock-probe defensive burying in lateral septum of rats, and modulation by chronic treatment with desipramine.

We have previously shown that acute stress-induced release of norepinephrine (NE) facilitates anxiety-like behavioral responses to stress, such as reduction in open-arm exploration on the elevated-plus maze and in social behavior on the social interaction test. Since these responses represent inhibition of ongoing behavior, it is important to also address whether NE facilitates a response that represents an activation of behavior. Correspondingly, it is unknown how a chronic elevation in tonic steady-state noradrenergic (NA) neurotransmission induced by NE reuptake blockade might alter this acute modulatory function, a regulatory process that may be pertinent to the anxiolytic effects of NE reuptake blockers such as desipramine (DMI). Therefore, in this study, we investigated noradrenergic modulation of the shock-probe defensive burying response in the lateral septum (LS). In experiment 1, shock-probe exposure induced an acute 3-fold increase in NE levels measured in LS of male Sprague-Dawley rats by microdialysis. Shock-probe exposure also induced a modest rise in plasma ACTH, taken as an indicator of perceived stress, that returned to baseline more rapidly in rats that were allowed to bury the probe compared to rats prevented from burying by providing them with minimal bedding, indicating that the active defensive burying behavior is an effective coping strategy that reduces the impact of acute shock probe-induced stress. In experiment 2, blockade of either alpha(1)- or beta-adrenergic receptors in LS by local antagonist microinjection immediately before testing reduced defensive burying and increased immobility. In the next experiment, chronic DMI treatment increased basal extracellular NE levels in LS, and attenuated the acute shock probe-induced increase in NE release in LS relative to baseline. Chronic DMI treatment decreased shock-probe defensive burying behavior in a time-dependent manner, apparent only after 2 weeks or more of drug treatment. Moreover, rats treated chronically with DMI showed no significant rise of plasma ACTH in response to shock-probe exposure. Thus, acute stress-induced release of NE in LS facilitated defensive burying, an active, adaptive behavioral coping response. Chronic treatment with the NE reuptake blocker and antidepressant drug DMI attenuated acute noradrenergic facilitation of the active burying response, and also attenuated the level of perceived stress driving that response. These results suggest that long-term regulation of the acute modulatory function of NE by chronic treatment with reuptake blockers may contribute to the mechanisms by which such drugs exert their anxiolytic effects in the treatment of stress-related psychiatric conditions, including depression and anxiety.

Unhealthy effects of atmospheric temperature and pressure on the occurrence of myocardial infarction and coronary deaths. A 10-year survey: the Lille-World Health Organization MONICA project (Monitoring trends and determinants in cardiovascular disease).

BACKGROUND: Associations between an increase in coronary heart disease occurrence and low atmospheric temperatures have been reported from mortality data and hospital admission registries. However, concomitant increases in noncardiovascular case fatality rates and selection bias of hospital cases may weaken this observation. In this study, we addressed the question of the relationships between fatal and nonfatal coronary diseases and meteorological variables in 10-year data (1985 to 1994) collected in a morbidity registry (Lille-WHO MONICA Project) monitoring 257 000 men from 25 to 64 years of age. METHODS AND RESULTS: The impacts of atmospheric temperature (in Celsius) and pressure (in millibars) on daily rates of myocardial infarction (MI) and coronary deaths were studied. Percentages of variation of event rates according to meteorological variations were derived from the relative risks estimated with a Poisson regression model. During the 10-year longitudinal survey, 3616 events occurred. Rates of events decreased linearly with increasing atmospheric temperature. For atmospheric pressure, we detected a V-shaped relationship, with a minimum of daily event rates at 1016 mbar. A 10 degrees C decrease was associated with a 13% increase in event rates (P<0.0001); a 10-mbar decrease <1016 mbar and a 10-mbar increase >1016 mbar were associated with a 12% increase (P=0.001) and an 11% increase (P=0. 01) in event rates, respectively. These effects were independent and influenced both coronary morbidity and mortality rates, with stronger effects in older age groups and for recurrent events. CONCLUSIONS: This longitudinal study is the first to estimate the attributable effect of meteorological variables on MI morbidity in population and strongly argues for a systematic fight against cold in cardiovascular disease prevention, particularly in older ages and after a first MI.

Risk of dementia in parents of probands with and without the apolipoprotein E4 allele. The EVA study.

STUDY OBJECTIVE: Age, family history of dementia and the epsilon 4 allele of the apolipoprotein E gene have been associated with Alzheimer's disease (AD). Considering the strength of APOE-epsilon 4 as a genetic risk factor for AD, this factor might explain a large part of the association between AD and a family history of dementia. Therefore, in the general population, a higher frequency of dementia should be observed among parents of probands with at least one epsilon 4 allele than in parents of probands without this allele. DESIGN, SETTING, AND PARTICIPANTS: The study investigated a sample of 1153 volunteers between 59 and 71 years old, genotyped for the APOE gene, all participating in the EVA study. Dementia in their parents was determined using a self reported questionnaire. MAIN RESULTS: The frequency of dementia in 2164 parents was examined and it was found that 245 were demented. The percentage of demented parents was 13.0% in the subgroup of parents of subjects having one or two epsilon 4 alleles and 10.8% in the other subgroup. The relative risk of dementia among parents according to the APOE-epsilon 4 status of probands, was calculated using a Cox model adjusted for the educational level of parents and their history of stroke: RR = 1.21 (95% CI 0.90, 1.63). CONCLUSION: This lack of association supports the observation that in the general population, APOE-epsilon 4 cannot explain a large part of family history of dementia.

[Secondary prevention of coronary disease in France. Result of the EUROASPIRE study: the Lille register of ischemic cardiopathies]. / Prévention secondaire de la maladie coronaire en France. Résultats de l'étude EUROASPIRE, registre des cardiopathies ischémiques de Lille.

The EUROASPIRE study was initiated to assess the impact of recommendations concerning secondary prevention of coronary artery disease in Europe published in 1994 by the European Societies of Cardiology, Hypertension and Atherosclerosis. France and eight other countries are involved in this project. The authors report the French data. A total of 546 men and women, aged less than 71, divided into 4 diagnostic groups (coronary bypass, angioplasty, myocardial infarction, acute ischaemia) were selected in different departments of cardiology. Data concerning their main risk factors and management were noted from the hospital files. At least 6 months after their hospital admission, 396 patients were systematically interrogated and examined. The availability of information on the risk factors in the hospital files varied according to the risk factor and diagnostic group from 61 to 97%. At the time of hospital admission, 42% of patients were considered to be smokers and 23% to be obese. Six months after hospital admission, 28% of patients were still smoking, 34% were obese, 49% had total cholesterol levels greater than 5.5 mmol/L (2.10 g/L) and 48% had blood pressure readings of over 140/90 mmHg. In France, as in other European countries, the prevalence of modulable risk factors of coronary artery disease is high at least 6 months after hospital admission. Systematic application of the recommendations of scientific societies should result in a significant decrease in recurrences and in mortality after an initial coronary event.

Chronic intermittent cold stress and serotonin depletion induce deficits of reversal learning in an attentional set-shifting test in rats.

RATIONALE: Chronic stress perturbs modulatory brain neurotransmitter systems, including serotonin (5-HT), and is a risk factor for psychiatric disorders such as depression. Deficits in cognitive flexibility, reflecting prefrontal cortical dysfunction, are prominent in such disorders. Orbitofrontal cortex (OFC) has been implicated specifically in reversal learning, a form of cognitive flexibility modulated by 5-HT. OBJECTIVES: The objectives of the study were (1) to assess the effects of chronic intermittent cold (CIC) stress, a potent metabolic stressor, on performance of rats in an attentional set-shifting test (AST), and (2) to assess a possible role for serotonin in CIC-induced deficits and test the effects of acute serotonin reuptake blockade. MATERIALS AND METHODS: Male Sprague-Dawley rats were exposed to CIC stress (14 days x 6 h/day at 4 degrees C) before testing on the AST. In subsequent experiments, brain 5-HT was depleted in naïve rats with para-chlorophenylalanine or 5-HT release was increased acutely in CIC-stressed rats with citalopram (5 mg/kg, s.c.) given 30 min prior to the first reversal task. Microdialysis was used to assess CIC-induced changes in 5-HT release in OFC during testing. RESULTS: CIC-stressed rats exhibited a selective impairment on the first reversal task in the AST. 5-HT depletion induced a similarly selective deficit in reversal learning. The CIC-induced impairment in reversal learning was attenuated by acute 5-HT reuptake blockade. 5-HT release was reduced in OFC of CIC-stressed rats during behavioral testing. CONCLUSIONS: The CIC stress-induced impairment of cognitive flexibility may involve dysregulation of 5-HT modulatory function in OFC. Such deficits may thus model relevant symptoms of neuropsychiatric disorders that respond positively to SSRI treatment.

Norepinephrine transporter regulation mediates the long-term behavioral effects of the antidepressant desipramine.

The relationship between the ability of repeated desipramine treatment to cause downregulation of the norepinephrine transporter (NET) and produce antidepressant-like effects on behavior was determined. Treatment of rats with 15 mg/kg per day desipramine reduced NET expression, measured by (3)H-nisoxetine binding and SDS-PAGE/immunoblotting, in cerebral cortex and hippocampus and reduced the time of immobility in the forced-swim test. The antidepressant-like effect on forced-swim behavior was evident 2 days following discontinuation of desipramine treatment when plasma and brain levels of desipramine and its major metabolite desmethyldesipramine were not detectable. Reduced NET expression resulted in reduced norepinephrine uptake, measured in vitro, and increased noradrenergic neurotransmission, measured in vivo using microdialysis. Overall, the dose-response and time-of-recovery relationships for altered NET expression matched those for production of antidepressant-like effects on behavior. The importance of increased noradrenergic neurotransmission in the persistent antidepressant-like effect on behavior was confirmed by demonstrating that it was blocked by inhibition of catecholamine synthesis with alpha-methyl-p-tyrosine. The present results suggest an important role for NET regulation in the long-term behavioral effects of desipramine and are consistent with clinical data suggesting that enhanced noradrenergic neurotransmission is necessary, but not sufficient, for its antidepressant actions. Understanding the mechanisms underlying NET regulation in vivo may suggest novel targets for therapeutic intervention in the treatment of depression.