Role of 5-HT1A autoreceptors in the mechanism of action of serotoninergic antidepressant drugs: recent findings from in vivo microdialysis studies

Summary— Although a new generation of selective serotonin reuptake inhibitors (SSRIs) has been introduced in therapeutics as antidepressant drugs, a two to four week lag period still occurs between starting treatment with SSRIs and the onset of therapeutic effects in man. In vivo cerebral microdialysis can be used to measure extracellular concentrations of serotonin (5-hydroxytryptamine, 5-HT), which reflect intrasynaptic events. With the coupling of this new experimental method to very sensitive analytical assays such as liquid chromatography with electrochemical detection, it has recently been possible to obtain two major arguments supporting the hypothesis that somatodendritic 5-HT_1A autoreceptors situated in the raphe nuclei play an important role in the mechanism of action of SSRIs. First, in the rat, single administration of SSRIs at low doses comparable to those used therapeutically increases extracellular 5-HT concentrations in the vicinity of the cell body and the dendrites of serotoninergic neurones of the raphe nuclei. This effect is more marked than that observed in regions rich in nerve endings (frontal cortex). The magnitude of the activation of the serotoninergic neurotransmission depends on the brain area studied and the dose of the SSRIs administered to rats. This could be explained by simultaneous activation of somatodendritic 5-HT_1A autoreceptors by endogenous 5-HT in the raphe nuclei, thereby limiting the corticofrontal effects of the antidepressant. Second, SSRIs cause a larger increase in extracellular 5-HT concentrations in the nerve endings when administered chronically: 5-HT autoreceptors may have gradually desensitized during the 2–4 weeks of treatment with SSRIs. Preliminary studies of patients with depression appear to confirm these experimental results, as co-administration of a 5-HT_1A autoreceptor antagonist and a SSRI accelerated the onset of the antidepressant effect (< 1 week).     

SCREENING AND TREATMENT FOR HYPERUPIDAEMIA IN NON-INSULIN-DEPENDENT DIABETES: A PROSPECTIVE ASSESSMENT OF 350 PATIENTS

SUMMARY This report presents experiences in screening 350 non-insulin-dependent diabetics for hypercholesterolemia and results of 1 year's treatment. Mean serum total cholesterol was 6.4 mmol/l at screening; 46 patients whose initial total serum cholesterol was above 7.0 mmol/l attended for detailed assessment and treatment. Mean total cholesterol concentrations fell between screening and review (7.8 vs 7.1 mmol/l, P<0.01). Levels fell below 7.0 mmol/l in 13 patients with diet alone. After excluding patients with secondary dyslipidaemia (including poor diabetic control), 10 patients received lipid-lowering drug treatment. Total cholesterol and triglyceride concentrations fell significantly and the HDL/non- HDL cholesterol ratio improved on treatment. Screening diabetic patients identifies a small group of hyperlipidaemic patients, whose lipoprotein profiles improve with drug treatment. Many of those screened, however, do not ultimately require drug treatment using a cut-off of 7.0 mmol/l.     

BLOOD PRESSURE CONTROL AND CARDIOVASCULAR RISK IN PATIENTS OF INDO-ASIAN AND AFRICAN-CARIBBEAN DESCENT

SUMMARY Hypertension is a major risk factor for premature death. Large outcome studies have demonstrated reduced morbidity and mortality associated with antihypertensive therapy in mixed patient populations, but data on morbidity and mortality in defined ethnic groups are lacking. Management of cardiovascular risk factors, which frequently coexist with hypertension, presents a logical management strategy in these patients. Indo-Asian patients are particularly prone to insulin resistance and non-insulin-dependent diabetes mellitus (NIDDM), which are associated in turn with potentially atherogenic lipid profiles and poor cardiovascular outcomes. Diuretics and β-adrenoceptor blockers exert theoretically adverse effects on lipid profiles and should be used with caution in Indo-Asian patients at risk of developing NIDDM. Hypertensive African-Caribbean patients are at increased risk of stroke and tend to suffer greater target organ damage, including renal dysfunction and cardiac hypertrophy. Hypertension in African-Caribbean patients is less sensitive to β-adrenoceptor blockade or ACE inhibition than in white patients. Selective α₁-adrenoceptor antagonists and calcium channel blockers are equally effective antihypertensive agents in all races. While calcium channel blockers are metabolically neutral, α₁-adrenoceptor blockers promote a potentially less atherogenic lipid profile. Further study of the effects of antihypertensive treatment on morbidity and mortality in ethnic groups is required, particularly in Indo-Asian patients.     

Poikiloderma of Civatte: a clinical and epidemiological study

BACKGROUND: Although a common dermatosis, idiopathic poikiloderma of the face and neck has not been studied in depth for decades. OBJECTIVES: To reassess the clinical and epidemiological characteristics of poikiloderma of Civatte (PC). MATERIAL AND METHODS: Fifty consecutive patients with PC. Evaluation included history taking and physical examination. Epidemiological and clinical parameters were recorded and analysed. The literature from 1923 until today, was reviewed thoroughly. RESULTS: The frequency of PC among dermatologic patients was estimated to be 1.4%. There were 34 females (68%) and 16 males in the present study. The mean age at diagnosis was 47.8 years for females and 61.7 years for males. The majority (88%) had skin phototype II or III. Among females, 26 were at their peri-menopausal stage, including three cases of iatrogenic menopause. Four patients reported that other blood-related family members also had PC. The v and the sides of the neck and the upper chest were most often affected in a symmetric distribution. The face (preauricular and parotid region) was involved in 19 patients (38%). The erythemato-telangiectatic clinical type predominated (58%), followed by the mixed (22%) and the pigmented type (20%). Almost half of the patients (46%) were symptomatic (itching, burning and 'flushing'). The mean duration from onset to diagnosis was 6.2 years according to the patients' report. The course was usually slowly progressive (82%) and irreversible. CONCLUSIONS: PC shows characteristic features, supporting the theory that it represents a distinct entity. It is rather common in Greece. Although menopausal women predominated in our cohort, men were not uncommonly affected and were diagnosed at an older age. Based on the predominating clinical feature, PC can be classified into three clinical forms. Symmetry and sparing of the anatomically shaded areas of the neck are highly characteristic for PC. Face involvement was not as common and as severe as it had been considered in the past. Recognition of clinical type is important for the selection of the most appropriate treatment, which, despite the advent of novel modalities, remains problematic.     

VALIDATION OF A SUBENDOCARDIAL ISCHAEMIC SHEEP MODEL BY INTRACORONARY FLUORESCENT MICROSPHERES

1. We evaluated the use of non-radioactive fluorescent-labelled microspheres (FM) for the measurement of regional myocardial blood flow (RMBF) in an ischaemic sheep model. 2. Injection of FM directly into the coronary artery was compared with left atrial injection. There was a good correlation in the measurement of RMBF between these two injection methods (r = 0.92; n= 107 data points). Injection into the coronary artery requires less FM (one twentieth of that required by atrial injection) and is more economical. 3. The use of a fluorescent technique without filtering myocardial tissue was investigated. Calibration curves from the fluorescence plus myocardial tissue samples were similar to those of the pure fluorescence samples and both showed a linear relationship between fluorescent intensity and the number of microspheres (r > 0.97). These results indicate that the extraction of six fluorescent dyes (blue-green, yellow-green, green, orange, red and crimson) directly from the aqueous solution using ethyl acetate is effective. 4. A subendocardial ischaemic model was produced by partially occluding the circumflex artery (CxA) with concomitant left atrium (LA) pacing. During ischaemia, the endocardium/epicardium (Endo/Epi) flow ratios in the ischaemic area changed from 1.04 ± 0.12 to 0.47 ± 0.17 (P < 0.05; CxA injection) and from 1.08 ± 0.12 to 0.51 ± 0.05 (P < 0.05; LA injection). The ratio in the non-ischaemic area remained unchanged (1.12 ± 0.26 to 1.01 ± 0.22; not significant). 5. RMBF calculation using coronary inflow as the reference flow was also compared with that using the traditional method. We found that, in this study in which a non-filtering technique was applied, using coronary inflow as the reference flow was superior to the conventional distal sampling method.