1 An intracerebral perfusion method, brain microdialysis, was used to assess changes of 5-hydroxytryptamine (5-HT) release in the ventral hippocampus of the chloral hydrate-anaesthetized rat in response to systemic administration of a variety of 5-HT1 receptor agonists. 2 A stable output of reliably detectable endogenous 5-HT was measured in dialysates collected from ventral hippocampus with the 5-HT reuptake inhibitor, citalopram, present in the perfusion medium.3 Under these conditions the putative 5-HTlAagonist 8-hydroxy-24di-n-propylamino)tetralin (8-OH-DPAT) caused a dose-dependent (5-250 g kg 1, s.c.) reduction of 5-HT in hippocampal dialysates.4 Similarly, the putative 5-HT1A agonists gepirone (5 mgkg 1, s.c.), ipsapirone (5 mgkg 1, s.c.) and buspirone (5 mg kg -1, s.c.) markedly reduced levels of 5-HT in hippocampal perfusates whereas their common metabolite 1-(2-pyrimidinyl) piperazine (5mgkg-1, s.c.), which does not bind to central 5-HTlA recognition sites, had no effect. 6 These data are direct biochemical evidence that systemically administered putative 5-HTlA and 5-HTlB agonists markedly inhibit 5-HT release in rat ventral hippocampus in vivo.

The effect of manipulating the activity of central 5-hydroxytryptamine (5-HT) neurones on extracellular 5-HT in ventral hippocampus of the chloral hydrate-anaesthetized rat was studied using the brain perfusion method, microdialysis. Basal levels of 5-HT in the dialysates were close to the detection limits of our assay using HPLC with electrochemical detection. However, addition of the selective 5-HT reuptake inhibitor citalopram (10(-6) M) to the perfusion medium produced readily measurable amounts of dialysate 5-HT. Citalopram, therefore, was used throughout our experiments. Hippocampal dialysate levels of 5-HT sharply declined over the first hour after dialysis probe implantation, but then became constant. This stable output of 5-HT was reduced by 57% in rats treated 14 days previously with intracerebroventricular injections of the 5-HT neurotoxin 5,7-dihydroxytryptamine. Electrical stimulation (1-ms pulse width, 300 microA, 2-20 Hz) of the dorsal raphe nucleus for 20 min caused a rapid rise in hippocampal 5-HT output, which immediately declined on cessation of the stimulus and was frequency-dependent. Addition of tetrodotoxin (10(-6) M) to the perfusion medium reduced 5-HT levels to 75% of predrug values. Injection of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (0.5 and 2.5 micrograms) into the dorsal raphe nucleus caused a dose-related fall in hippocampal output of 5-HT compared to saline-injected controls. We conclude from these data that the spontaneous output of endogenous 5-HT into hippocampal dialysates, measured under our experimental conditions, predominantly originates from central 5-HT neurones and changes in accordance with their electrical activity.

14 Stroke Prevention in Atrial Fibrillation Investigators. Warfarin versus aspiAn for prevention of thromboembolism in atrial fibrillation: stroke prevention in atrial fibrillation II study. Lancet; 343:687-91.

SinmaryRelatively little is known about the epidemiology of carcinoid tumours in contrast to the extensive information available on their biochemical effects and natural history. Accordingly, we have used cancer regtstrations in England from 1979 to 1987, and in Scotland from 1980Scotland from to 1989 Carcinoid tumours were so named by Oberndorfer in 1907 because they resembled carcinomas but were thought to be of a more benign nature (Grahame-Smith, 1972). Since then the malignant potential of these tumours has been recognised. MacDonald (1956) has suggested that all extra-appendiceal carcinoids should be considered potentially malignant. Carcinoid tumours are the most common tumour of the appendix, the most common gastrointestinal neuroendocrine tumour and the most common form of bronchial adenoma. They may present with non-specific abdominal symptoms, with local symptoms such as haemorrhage or obstruction of the bowel or a bronchus, with evidence of metastasis or with the malignant carcinoid syndrome. This syndrome, first described in 1934, is characterised by facial flushing, bronchoconstriction, episodic diarrhoea and right-sided valvular heart disease (Cassidy, 1934;Grahame-Smith, 1972 England Cancer registration data were obtained from the OPCS on all carcinoid tumours first registered in 1979-87 in English residents. Although the OPCS also holds Welsh data, these could not be used in this study because they rarely include tumour morphology codes. Registrations of carcinoid tumours were identified using morphology codes 8240-8244 from the International Classification of Diseases for Oncology (ICD-O) (WHO, 1976). The tumours had been given either malignant site codes (ICD-9 140-208) (WHO, 1977) or site codes which indicated that their future behaviour was uncertain (ICD-9 235-238). Before 1979, when ICD-8 (WHO, 1%9) was used, tumours of uncertain behaviour were not coded separately from benign tumours and were not recorded by cancer-registries. The majority of carcinoid tumours are of uncertain malignancy. This study, therefore, was restricted to the period after 1979 when only tumours specifically reported as benign by the pathologist would not have been registered.Registrations were subdivided according to tumour site using the ICD-9 classification. Where necessary individual site codes were aggregated as follows: 'gastrointestinal tumours' ICD-9 150.0-154.8 and 235.2; 'thoracic tumours' ICD-9 162.0-165.9, 235.7 and 235.8. The uncertain codes are less specific with respect to site than the malignant codes (see Table I). The natural history of carcinoid tumours is such that the distinction between a malignant tumour and one of potential malignancy is not easily made. On examination of the data, there seemed to be inconsistency among registries in the proportion of cases assigned a malignant, as opposed to an uncertain, site code. Because of this evidence of crossover between the categories we did not analyse malignant tumours separately from those of uncertain behaviour.As the coding of carcinoid t...

We have investigated the effects of in vivo lithium treatment on cerebral inositol phospholipid metabolism. Twice-daily treatment of rats with LiCl (3 mEq/kg) for 3 or 16 days resulted in a 25-40% reduction in agonist-stimulated inositol phosphate production, compared with NaCl-treated controls, in cortical slices prelabelled with [3H]inositol. A small effect was also seen with 5-hydroxytryptamine (5-HT) 24 h after a single dose of LiCl (10 mEq/kg). Dose-response curves to carbachol and 5-HT showed that lithium treatment reduced the maximal agonist response without altering the EC50 value. This inhibition was not affected by the concentration of LiCl in the assay buffer. Stimulation of inositol phosphate formation by 10 mM NaF in membranes prepared from cortex of 3-day lithium-treated rats was also inhibited, by 35% compared with NaCl-treated controls. Lithium treatment did not alter the kinetic profile of inositol polyphosphate formation in cortical slices stimulated with carbachol. Muscarinic cholinergic and 5-HT2 bindings were unaltered by lithium, as was cortical phospholipase C activity and isoproterenol-stimulated cyclic AMP formation. [3H]Inositol labelling of phosphatidylinositol 4,5-bisphosphate was significantly enhanced by 3-day lithium treatment. The results, therefore, indicate that subacute or chronic in vivo lithium treatment reduces agonist-stimulated inositol phospholipid metabolism in cerebral cortex; this persistent inhibition appears to be at the level of G-protein-phospholipase C coupling.