Theoretical proton affinity and fluoride affinity of nerve agent VX.

Proton affinity and fluoride affinity of nerve agent VX at all of its possible sites were calculated at the RI-MP2/cc-pVTZ//B3LYP/6-31G* and RI-MP2/aug-cc-pVTZ//B3LYP/6-31+G* levels, respectively. The protonation leads to various unique structures, with H(+) attached to oxygen, nitrogen, and sulfur atoms; among which the nitrogen site possesses the highest proton affinity of -ΔE ∼ 251 kcal/mol, suggesting that this is likely to be the major product. In addition some H(2), CH(4) dissociation as well as destruction channels have been found, among which the CH(4) + [Et-O-P(═O)(Me)-S-(CH(2))(2)-N(+)(iPr)═CHMe] product and the destruction product forming Et-O-P(═O)(Me)-SMe + CH(2)═N(+)(iPr)(2) are only 9 kcal/mol less stable than the most stable N-protonated product. For fluoridization, the S-P destruction channel to give Et-O-P(═O)(Me)(F) + [S-(CH(2))(2)-N-(iPr)(2)](-) is energetically the most favorable, with a fluoride affinity of -ΔE ∼ 44 kcal. Various F(-) ion-molecule complexes are also found, with the one having F(-) interacting with two hydrogen atoms in different alkyl groups to be only 9 kcal/mol higher than the above destruction product. These results suggest VX behaves quite differently from surrogate systems.

Inhibition of prostaglandin synthesis reduces the induction of MyoD expression in rat soleus muscle.

MyoD is a myogenic regulatory factor with a critical role in skeletal muscle development and regeneration. As muscle regeneration comes with an inflammatory process, it has been proposed that the inflammatory cells can play an important role in the induction of muscle fibres regeneration. The aim of the present work was to verify if a cyclooxygenase inhibitory drug (ketoprofen) would alter the normal expression of MyoD in a regenerating rat soleus muscle after an over-load lesion. Using immunohistochemical techniques, the numbers of m-cadherin-positive cells, a selective marker of satellite cells, and MyoD-positive cells were evaluated in functionally overloaded rat soleus muscles 4 days after a gastrocnemius tendon cut. The same study was conducted either with four rats injected with ketoprofen (100 mg/kg b.w./day) or with four rats injected with saline solution. The data obtained showed a very large decrease in the number of MyoD positive/m-cadherin positive cells in the ketoprofen injected group compared to the control group. Although further studies are needed to elucidate the sequence of biochemical events that induce a reduction of MyoD expression due to ketoprofen, the results demonstrate that prostaglandin synthesis is required for the induction of MyoD expression and that ketoprofen can affect this expression, with possible adverse effects on muscle regeneration.

Espresso coffee increases parasympathetic activity in young, healthy people.

Caffeine induces modifications of activity of the autonomic nervous system. This study analyzed the effect of a cup of espresso coffee on the heart rate variability (HRV) power spectral analysis, which is a method providing evaluation of the sympathetic and parasympathetic discharge. In young, healthy sedentary subjects (10 male, 10 female; aged 25-30 years), the HRV-power spectrum was evaluated over a period of 150 min after the administration of espresso coffee (caffeine, 75 mg) or decaffeinated coffee (caffeine, < 18 mg) in supine and seated position. Absolute values of the spectrum were summed in low (LF) and high frequencies (HF). The LF and HF spectra were used to estimate the sympathetic and parasympathetic activity, respectively. In the supine position, coffee increases HF, while decaffeinated coffee causes little modifications of HF. In the seated position, HF is not modified by coffee or decaffeinated coffee. Coffee and decaffeinated coffee do not induce any modification of LF in both positions. This experiment indicates that espresso coffee influences parasympathetic activity in the supine position.

Olanzapine blocks the sympathetic and hyperthermic reactions due to cerebral injection of orexin A.

Since experiments regarding a possible relation between olanzapine and orexin A has been scarcely reported in international literature, this experiment tested the effect of olanzapine on the sympathetic and thermogenic effects induced by orexin A. The firing rates of the sympathetic nerves to interscapular brown adipose tissue (IBAT), along with IBAT, colonic temperatures and heart rate were monitored in urethane-anesthetized male Sprague-Dawley rats before an injection of orexin A (1.5 nmol) into the lateral cerebral ventricle and over a period of 150 min after the injection. The same variables were monitored in rats with an intraperitoneal administration of olanzapine (10mg/kg bw), injected 30 min before the orexin administration. The results show that orexin A increases the sympathetic firing rate, IBAT, colonic temperatures and heart rate. This increase is blocked by the injection of olanzapine. These findings indicate that olanzapine affects the complex reactions related to activation of orexinergic system.

Sympathetic and hyperthermic reactions by orexin A: role of cerebral catecholaminergic neurons.

This experiment tested the effect of a lesion of cerebral catecholaminergic neurons on the sympathetic and thermogenic effects induced by an intracerebroventicular (icv) injection of orexin A. The firing rates of the sympathetic nerves to the interscapular brown adipose tissue (IBAT), along with IBAT, colonic temperatures and heart rate were monitored in urethane-anesthetized male Sprague-Dawley rats before an injection of orexin A (1.5 nmol) into the lateral cerebral ventricle and over a period of 150 min after the injection. Three days before the experiment, the rats were pre-treated with an icv injection of 6-hydroxydopamine (6-OHDA) or 6-OHDA plus desipramine or saline. The results show that orexin A increases the sympathetic firing rate, IBAT, colonic temperatures and heart rate in the rats pre-treated with saline. This increase is blocked by the pre-treatment with 6-OHDA alone or 6-OHDA plus desipramine. These findings indicate that cerebral catecholaminergic neurons (particularly the dopaminergic pathway) play a fundamental role in the complex reactions related to activation of the orexinergic system.

Quetiapine lowers sympathetic and hyperthermic reactions due to cerebral injection of orexin A.

Since no experiment regarding a possible relation between quetiapine and orexin A has been reported in international literature, this experiment tested the effect of quetiapine on the sympathetic and thermogenic effects induced by orexin A. The firing rates of the sympathetic nerves to interscapular brown adipose tissue (IBAT), along with IBAT, colonic temperatures and heart rate were monitored in urethane-anesthetized male Sprague-Dawley rats before an injection of orexin A (1.5 nmol) into the lateral cerebral ventricle and over a period of 150 min after the injection. The same variables were monitored in rats with an intraperitoneal administration of quetiapine (5 or 10 mg/kg bw), injected 30 min before the orexin administration. The results show that orexin A increases the sympathetic firing rate, IBAT, colonic temperatures and heart rate. This increase is delayed or reduced by the injection of quetiapine. These findings indicate that quetiapine affects the complex reactions related to activation of orexinergic system. Possible influences on the control of body weight and temperature are discussed.

Risperidone potentiates the sympathetic and hyperthermic reactions induced by orexin A in the rat.

This experiment tested the effect of risperidone on the sympathetic and thermogenic effects induced by orexin A. The firing rates of sympathetic nerves to interscapular brown adipose tissue (IBAT), along with IBAT and colon temperatures and heart rate were monitored in urethane-anesthetized male Sprague-Dawley rats before an injection of orexin A (1.5 nmol) into the lateral cerebral ventricle and over a period of 2 hours after the injection. The same variables were monitored in rats with an intraperitoneal administration of risperidone (50 mg/kg bw), injected 30 min before the orexin administration. The results show that orexin A increases the sympathetic firing rate, IBAT, colonic temperatures and heart rate. This increase is enhanced by the injection of risperidone. These findings suggest that risperidone elevates the responses due to orexin, probably through an involvement of serotoninergic and dopaminergic pathways, which are affected by risperidone. Furthermore, we suggested the name "hyperthermine A" as additional denomination of "orexin A" by considering the strong influence of this neuropeptide on body temperature.

Hyperthermic reactions induced by orexin A: role of the ventromedial hypothalamus.

This experiment tested the involvement of the ventromedial hypothalamus (VMH) in the sympathetic and hyperthermic reactions induced by an intracerebroventricular (i.c.v.) injection of orexin A (1.5 nmol). In the first part of the experiment, the firing rate and cytochrome oxidase activity of the VMH neurons, and the colonic temperature were monitored in 12 urethane-anaesthetized rats before an i.c.v. injection of orexin and over a period of 2 h after the injection. Orexin induced an increase in the firing rate, colonic temperature and cytochrome oxidase activity. A group of 12 rats was used as a control: saline, but not orexin, was injected. No modifications in the firing rate, cytochrome oxidase reactivity and colonic temperature were noted. In the second part of the experiment, 12 rats were anaesthetized and lesioned bilaterally in the VMH with an injection of ibotenic acid. Sham lesions were carried out in 12 control rats. After 48 h, all animals were anaesthetized with ethyl-urethane. The firing rates of the sympathetic nerves to interscapular brown adipose tissue (IBAT), along with IBAT and colonic temperatures and heart rate were monitored before and over a period of 2 h after an i.c.v. injection of orexin or saline in the lesioned and sham-lesioned rats. Orexin increased the sympathetic firing rate, IBAT and colonic temperatures and heart rate in the sham-lesioned rats. These increases were reduced by lesion of VMH. Saline did not induce any modification. These findings indicate that the VMH is involved in the control of the orexin-induced hyperthermia.

Clozapine blocks sympathetic and thermogenic reactions induced by orexin A in rat.

This experiment tested the effect of clozapine on the sympathetic and thermogenic effects induced by orexin A. The firing rates of the sympathetic nerves to interscapular brown adipose tissue (IBAT), along with IBAT and colonic temperatures were monitored in urethane-anesthetized male Sprague-Dawley rats before and for 5 h after an injection of orexin A (1.5 nmol) into the lateral cerebral ventricle. The same procedure was carried out in rats treated with orexin A plus an intraperitoneal administration of clozapine (8 mg/kg bw), an atypical antipsychotic that is largely used in the therapy of schizophrenia. The same variables were monitored in rats with clozapine alone. A group of rats with saline injection served as control. The results show that orexin A increases the sympathetic firing rate, IBAT and colonic temperatures. Clozapine blocks completely the reactions due to orexin A. These findings suggest that clozapine influences strongly the thermogenic role of orexin A. Furthermore, the remarkable hyperthermic role played by orexin A is confirmed.

Extracellular GABA in the medial hypothalamus is increased following hypocretin-1 administration.

AIM: Hypocretin 1 is an hypothalamic neuropeptide that induces an increase in food intake when administered into the cerebral lateral ventricle. As it is well known that the medial hypothalamus (MH) is involved in the feeding behaviour also through GABAergic circuits, the aim of this experiment was to investigate the effect of an hypocretin 1 intracerebroventricular (icv) injection on the extracellular levels of GABA in the MH. METHODS: GABA levels in the MH were evaluated in six rats by microdialysis and high performance liquid chromatography-electrochemical detection 30 min before and every 30 min for an over all period of 6 h after an icv injection of hypocretin 1. The same procedure was used in another group of six rats but saline was injected into the lateral ventricle as control. RESULTS: The results show that extracellular GABA increases in the MH after the injection of hypocretin 1 at 60 min and at 3 h after the injection. CONCLUSION: This finding suggests a possible mechanism by which hypocretin 1 should induce hyperphagia in the first hour after injection. As it is already known that the inhibition of the MH by injection of GABA causes an increase of food intake, it is possible that hypocretin 1 causes an increase in food intake by increasing the GABA release in the MH. The lack of an increase in the GABA level after the fourth hour is consistent with the lack of an increase in food intake at this time, as we observed in previous experiments. The finding of a biphasic increase in the GABA level, at 60 min and at 3 h, was unexpected and should be further investigated.

Injection of orexin A into the diagonal band of Broca induces sympathetic and hyperthermic reactions.

This experiment tested the effect of an injection of orexin A into the diagonal band of Broca on the sympathetic activity and body temperature. Concentration of glycerol into white fat of lumbar region, firing rates of sympathetic nerves to interscapular brown adipose tissue (IBAT), IBAT and colonic temperatures, and heart rate were monitored in urethane-anesthetized male Sprague-Dawley rats for 30 min before and 150 min after injections of orexin A (0.4 and 0.7 nmol) into the diagonal band of Broca. The same variables were monitored in control rats with an injection of saline. The results show that orexin A increases glycerol concentration, sympathetic firing rate, IBAT and colonic temperatures, and heart rate. The saline injection did not induce any modification. These findings suggest that the diagonal band of Broca is a cerebral structure involved in the induction of the hyperthermia due to orexin A.