The effect of a selective 5-HT(1A) antagonist, 4-(2'-methoxy-)phenyl-1-[2'-(N-2"-pyridinyl)-p-iodobenzamino-]ethyl-piperazine (p-MPPI), on acute ethanol-induced hypothermia, sleep and suppression of acoustic startle reflex in C3H/He mice and Wistar rats was studied. Administration of p-MPPI at the doses of 0.4, 0.7 and 1.0 mg/kg reduced in a dose-dependent manner the ethanol-induced hypothermia and the sleep time and attenuated the ethanol-induced decrease of acoustic startle reflex magnitude in mice. Similar p-MPPI (0.4 mg/kg) effects on ethanol-induced sleep and hypothermia were obtained in rats. It was concluded that 5-HT(1A) receptors were involved in the mechanisms of the ethanol-induced hypothermia and sleep, and that 5-HT(1A) antagonist increased acute ethanol tolerance.
The administration of mercuric chloride (HgCl2), gold compounds, or D-penicillamine to Brown Norway (BN) rats causes a T helper (Th)2 cell-associated autoimmune syndrome characterized by the production of a number of autoantibodies, marked elevation of serum IgE concentration, and tissue injury in the form of a vasculitis and arthritis. We have recently shown that the same compounds in vitro sensitize BN rat peritoneal mast cells for IgE-triggered mediator release and interleukin-4 mRNA production. We wished to test the hypothesis that these agents influence mast cell function via an effect on intracellular reactive oxygen species (ROS) production/redox balance. Mast cells were obtained from BN rats by peritoneal washout. Incubation with HgCl2, gold compounds or D-penicillamine (the latter only in the presence of copper ions) led to the intracellular production of ROS as shown by the oxidative production of the fluorescent compound 2',7'-dichlorofluorescein. Mast cells were more sensitive than splenocytes to this effect. Direct oxidative stress (exposure to H2O2) produced a similar sensitization for mediator release to that caused by HgCl2. Inhibition of ROS formation by desferrioxamine or catalase diminished the enhancement of IgE-mediated serotonin release caused by HgCl2, as did replenishment of intracellular glutathione. 2-Mercaptoethanol exacerbated the toxicity of HgCl2, perhaps due to the formation of a lipophilic complex that enhanced HgCl2 uptake. Blocking of glutathione synthesis increased the toxicity of HgCl2, but also abolished any sensitizing effect on mediator release. These results support three main predictions of our hypothesis: (1) the compounds known to influence mast cell function all lead to the generation of ROS within the mast cell; (2) direct oxidative stress causes sensitization for mediator release by the mast cell; and (3) modulation of ROS production/redox balance within the mast cell modulates the effects of these compounds on mast cell function. The balance of oxidative/antioxidative influences may play an important role in the modulation of mast cell function, particularly in the context of chemically induced autoimmunity.
Insertion/deletion and VNTR polymorphisms of the serotonin transporter gene were tested for association with schizophrenia in patients varying in ethnicity. A difference in genetic predisposition was observed for continuous and shift-like schizophrenia forms, the former tending to be associated with genotype 12/12 in Tatars and L/L in Russians.
Biochemical serotonin and histamine determinations were applied to the reconstruction of three suspected homicide cases. To distinguish between ante-mortem and post-mortem wounds and to time the ante-mortem injuries the concentrations of free histamine and serotonin in the wound samples and in the control samples from neighbouring intact skin were examined. The results of these biochemical determinations allowed a reconstruction of the events and one of the three cases was shown to be suicide instead of homicide. The methods can be used at least during the first 4--5 days after death and sometimes even longer. This allows for international cooperation when investigating and reconstructing complicated cases of death.
BACKGROUND: Depressed mood is a major concern in the elderly, with consequences for morbidity and mortality. Previous studies have demonstrated that genetic factors in depression and subsyndromal depressive symptoms are no less important in the elderly than during other life stages. Variations in genes included in the serotonin system have been suggested as risk factors for various psychiatric disorders but may also serve as candidates for normal variations in mood. METHODS: This study included 684 elderly Danish twins to investigate the influence of 11 polymorphisms in 7 serotonin system genes on the mean level of depression symptomatology assessed over several years, reflecting individuals' underlying mood level. RESULTS: A suggestive association of sequence variations in genes responsible for the synthesis (TPH), recognition (5-HTR2A), and degradation (MAOA) of serotonin with depression symptomatology was found, although the effect was generally restricted to men. We also found that a specific haplotype in VMAT2, the gene encoding the vesicular monoamine transporter, was significantly associated with depression symptoms in men (p= .007). CONCLUSIONS: These results suggest that variations in genes encoding the components of serotonin metabolism may influence the basic mood level and that different genetic factors may apply in men and women.
To investigate the effects on the central nervous system of severe cold stress with and without chlorpromazine, guinea pigs were treated with chlorpromazine or 0.9% NaCl and exposed to -20 degrees C or +23 degrees C for 1 h. Hypothalamic noradrenaline (NA), dopamine (DA), 5-hydroxy-tryptamine (5-HT), 3-methoxy-4-hydroxyphenyl ethylene glycol (MHPG), homovanillinic acid (HVA) and 5-hydroxy-indoleacetic acid (5-HIAA) were determined by high-performance liquid chromatography. Serum, urinary and vitreous fluid catecholamines, muscle and liver glycogen, and blood glucose were also measured. Chlorpromazine caused distinct hypothermia at -20 degrees C and slight hypothermia at +23 degrees C. The rise in hypothalamic MHPG, 5-HIAA and MHPG/NA and in 5-HIAA/5-HT ratios in the cold indicate increased noradrenergic and serotonergic activity. The latter was inhibited by chlorpromazine and a drug-induced inhibition of noradrenergic neurons could not be ruled out. Chlorpromazine increased the turnover of DA at room temperature and the same tendency was seen in the cold. The hypothermic animals had low serum catecholamines, indicating diminished sympathetic activity. The chlorpromazine-treated cold-exposed animals did not react to the environmental stress by sympathetic activation, as urinary NA and adrenaline were not elevated, but DA was excreted by all the drug-treated animals. Vitreous fluid NA and DA were elevated as an indicator of cold stress, and no drug effect was seen in this fluid.
Constitutive nitric oxide synthase inhibition combined with histamine and serotonin receptor blockade improves the initial ovalbumin-induced arterial hypotension but decreases the survival time in brown norway rats anaphylactic shock.
Anaphylactic shock accidents after allergen exposure are frequent. After immunization with ovalbumin (OVA), a common dietary constituent, we evaluated the efficacy of pretreatment with histamine-receptor or serotonin-receptor blockers administered alone or in combination with a nitric oxide synthase inhibitor (L-NAME) on OVA-induced anaphylactic shock in Brown Norway rats. Animals were allocated to the following groups (n = 6 each): control (0.9% saline); diphenydramine (15 mg kg(-1)); cimetidine (20 mg kg(-1)); diphenydramine + cimetidine; dihydroergotamine (50 microg kg(-1)); diphenydramine + cimetidine + dihydroergotamine; L-NAME (100 mg/kg) alone or associated with diphenydramine, cimetidine, diphenydramine + cimetidine, dihydroergotamine, or diphenydramine + cimetidine + dihydroergotamine. Mean arterial blood pressure (MABP), heart rate (HR), and survival time were monitored for 60 min following treatment. The shock was initiated with i.v. OVA. The MABP drop after i.v. OVA was worsened by diphenydramine and was modestly attenuated by cimetidine, dihydroergotamine, or both together. L-NAME potentiated slightly the effects of cimetidine and dihydroergotamine by lessening the initial MABP decrease, but this transient effect was not sufficient to prevent the final collapse or to improve survival time. Decreased vasodilatory (prostaglandins E2), increased vasoconstrictory (thromboxane B2) prostaglandins, and unchanged leukotriene C4 concentrations were contributory to the overall hemodynamic changes. Thus, the combined blockade of vasodilator mediators (histamine, serotonin, and nitric oxide) slowed the MABP drop in anaphylactic shock, but did not improve survival. More studies are needed to understand these discordant effects.
Correlative interconnections between frequency of impulse activity of aminergic neurons and neocortex electrical activity during action of bemitil (50 mg/kg) were investigated in 5 cats. It was shown that bemitil affects correlations between frequency of impulses of aminergic neurons and electrical activity of neocortex.
In the group of long-livers of the North-West of Russia, I/D polymorphism of angiotensin-converting enzyme (ACE) gene and C102T polymorphism of serotonin receptor (5-HT2A) gene were studied. No reliable differences in allele frequency of these genes between long-livers and young people were detected. Nevertheless, highly pronounced difference in the A1/A2 allele frequency of 5-HT2A gene between populations of the North-West of Russia, on the one hand, and of the USA, on the other hand, was discovered (i.e. 0.397(A1), 0.603(A2), and 0.615(A1), 0.385(A2), respectively). Differences of this kind between the two populations deserve special consideration, conditioning the necessity of further detailed analysis of other genes of the serotonin system in the populations of other regions of Russia.