Alcohol withdrawal changes cardiovascular responses to propranolol challenge

The cardiovascular effects and plasma concentrations of a single dose of propranolol (80 mg) were studied non-invasively in alcohol-dependent subjects during alcohol withdrawal (AW) on day 1 and after resolution of withdrawal symptoms on day 10. At the onset of AW, propranolol caused a bradycardic effect which was significantly weakened on day 10. This might result from an increased bioavailability of propranolol on day 1 and from marked sympathetic activity. Propranolol also produced a negative inotropic effect, relatively weaker on day 1 than on day 10, being associated with increased beta-receptor sensitivity towards the final phase of AW. These results suggest that peripheral and central beta-adrenergic systems modulate the cardiovascular system in AW.     

Nitric oxide mediates cardiovascular symptoms in alcohol withdrawal

We studied whether nitric oxide is involved in cardiovascular symptoms in alcohol withdrawal. Cardiovascular effects of isosorbide dinitrate (ISDN; 20 mg sublingually), a nitric oxide donor were compared in 21 alcohol-dependent subjects during alcohol withdrawal (n=11) on days 1, 2, 3, and 10 to those during remission (n=10; duration=60.7+/-10.5 days). Cardiovascular parameters were measured non-invasively. The levels of systolic and diastolic blood pressure, total peripheral resistance were significantly higher in patients with withdrawal than in remission. Same cardiovascular parameters showed different response to ISDN during withdrawal when compared to remission. The differences were largest during the initial phase (1-2 days) of withdrawal. Nitric oxide may mediate at least some cardiovascular symptoms in withdrawal.     

Mechanisms of cardiovascular dysregulation during alcohol withdrawal

Alcohol withdrawal (AW) is often accompanied by functional cardiovascular abnormalities which return to normal in few days. However, in some patients, they can predict future alterations in the cardiovascular system, even if they remain in abstinence. These changes are mediated by several central and peripheral mechanisms closely related to AW. The level of activation in the sympathetic nervous system is an important factor regulating the functioning of the cardiovascular system in AW directly and/or indirectly with L-type calcium channels and nitric oxide (NO). Other factors may contribute to cardiovascular alterations in AW including the renin-angiotensin-aldosterone system, vasopressin, cortisol and sodium sensitivity. Monitoring of the cardiovascular system is needed in patients undergoing treatment for AW. The patients with elevated systolic blood pressure (SBP) and diastolic blood pressure (DBP) after resolution of AW may require a fuller work-up of their cardiovascular system.     

Tapered progesterone withdrawal promotes long-term recovery following brain trauma

We previously demonstrated that after traumatic brain injury (TBI), acute progesterone withdrawal (AW) causes an increase in anxiety behaviors and cerebro-cellular inflammation compared to tapered progesterone withdrawal (TW). Our current study investigates the behavioral and cellular effects of AW two weeks after termination of treatments to determine the longer-term influence of withdrawal after injury. Adult, male Sprague-Dawley rats received either bilateral frontal cortex contusion (L) or sham (S) surgery. Rats were injected at 1 and 6 h post-injury, then every 24 h for six days. Vehicle (V)-treated rats were given 9 injections of 22.5% cyclodextrin, whereas AW rats received 9 injections of 16 mg/kg progesterone and TW rats received 7 injections of P at 16 mg/kg, followed by one at 8 mg/kg and one at 4 mg/kg. On day 8, sensory neglect and locomotor activity tests were initiated. Animals were killed 22 days post-TBI and the brains prepared for either molecular or histological analysis. Western blotting revealed increased brain-derived neurotrophic factor (BDNF) and heat shock protein 70 (HSP70) in TW vs. AW animals. P53 was increased in VL animals, whereas all progesterone-treated groups were equivalent to shams. TW animals had markedly decreased sensory neglect compared to AW animals and increased center time in locomotor activity assays. In addition, lesion reconstruction revealed a decreased lesion size for TWL over AWL over VL animals. Glial fibrillary acidic protein (GFAP) immunofluorescent staining followed this pattern as well. In conclusion, after TBI, AW affects select behaviors and molecular markers in the chronic recovery period.     

Effects of electrical stimulation of dorsal raphe nucleus on neuronal response properties of barrel cortex layer IV neurons following long-term sensory deprivation

Objective

To evaluate the effect of electrical stimulation of dorsal raphe nucleus (DRN) on response properties of layer IV barrel cortex neurons following long-term sensory deprivation.

Methods

Male Wistar rats were divided into sensorydeprived (SD) and control (unplucked) groups. In SD group, all vibrissae except the D2 vibrissa were plucked on postnatal day one, and kept plucked for a period of 60 d. After that, whisker regrowth was allowed for 8–10 d. The D2 principal whisker (PW) and the D1 adjacent whisker (AW) were either deflected singly or both deflected in a serial order that the AW was deflected 20 ms before PW deflection for assessing lateral inhibition, and neuronal responses were recorded from layer IV of the D2 barrel cortex. DRN was electrically stimulated at inter-stimulus intervals (ISIs) ranging from 0 to 800 ms before whisker deflection.

Results

PW-evoked responses increased in the SD group with DRN electrical stimulation at ISIs of 50 ms and 100 ms, whereas AW-evoked responses increased at ISI of 800 ms in both groups. Whisker plucking before DRN stimulation could enhance the responsiveness of barrel cortex neurons to PW deflection and decrease the responsiveness to AW deflection. DRN electrical stimulation significantly reduced this difference only in PW-evoked responses between groups. Besides, no DRN stimulation-related changes in response latency were observed following PW or AW deflection in either group. Moreover, condition test (CT) ratio increased in SD rats, while DRN stimulation did not affect the CT ratio in either group. There was no obvious change in 5-HT_2A receptor protein density in barrel cortex between SD and control groups.

Conclusion

These results suggest that DRN electrical stimulation can modulate information processing in the SD barrel cortex.     

Catecholamine, indoleamine and corticosteroid responses in mice bearing tumors

The neurochemical and endocrine responses to inoculation of mice with the murine lymphoma cell line AW5E was studied. This cell line was chosen because it is NK cell lysis resistant and thus does not induce a normal immune response. Immune activation has long been known to be a potent stimulator of the hypothalamo-pituitary-adrenocortical (HPA) axis as well as brain catecholamine and indoleamine metabolism, involving increases in the brain concentrations of catabolites of norepinephrine (NE) and serotonin (5-HT), as well as free tryptophan. Mice injected intravenously with AW5E tumor cells exhibited small increases in plasma corticosterone and hypothalamic NE and 5-HT catabolites one day after injection. There were no significant changes after 6 or 8 days, but a sustained increase in hypothalamic NE and 5-HT metabolism appeared 10 days after injection. There were similar, but more limited changes in the brain stem and prefrontal cortex. On the last day tested (day 14), plasma corticosterone was slightly elevated, as were hypothalamic dopamine, NE and 5-HT catabolites and tryptophan. These results indicate that inoculation with AW5E tumor cells increases brain catecholamine and serotonin metabolism, the hypothalamus being the most sensitive region. The most marked increases occurred in the few days preceding death, and thus may be associated with the pathology of the tumor growth.     

Effects of selective dopamine D4 receptor antagonist, L-741,741, on sleep and wakefulness in the rat

The influence of the dopamine system upon sleep/wake states is not fully understood. To date, the role of dopamine D4 receptor has not been studied. The aim of this work is to study the influence of dopamine D4 receptor upon sleep/wake states in male rats. Male Wistar rats were implanted with electroencephalography and electromyography electrodes for sleep recording. Sleep/wake times were compared in rats first treated with control solution (vehicle) and the day after treated with a potent and highly selective D4 dopamine receptor antagonist. L-741,741 (1.5, 3, 6 mg/kg) or vehicle solution (10% DMSO in saline) was administered intraperitoneally at the beginning of the light period. Subsequently, 3 h of polysomnography were recorded and sleep-wake parameters evaluated. For statistical comparisons, Wilcoxon ranges test was performed. L-741,741 (1.5 mg/kg) only increased Light Slow Wave Sleep (SWS). 3 mg/kg enhanced Quiet Waking (QW) increasing number of episodes, whereas Active Waking (AW) was reduced decreasing mean episode duration. 6 mg/kg reduced number of episodes of Deep SWS and increased its latency. Light SWS was decreased reducing number of episodes and their duration. Total time spent asleep was reduced and time spent in AW was increased. REM latency was increased. These results suggest a role for D4 receptors in the regulation of wake and sleep.     

A controlled trial of diazepam withdrawal in chronically anxious outpatients

Twenty-four middle-aged male chronically anxious outpatients who were taking diazepam at a mean dose of 17 mg/day for a mean duration of 5 years were assigned to maintenance (M), gradual withdrawal (GW) or abrupt withdrawal (AW) and followed weekly. No differences were seen in two self-report anxiety measures or in withdrawal symptoms between groups. Hamilton Anxiety Rating Scale scores were slightly elevated (F = 2.34, P < 0.05) in the AW patients at a mean duration of 4 weeks off diazepam. Thus, withdrawal from chronic diazepam (10–30 mg/day) use produced no prominent withdrawal syndrome, but the suggestion of graduai anxiety recurrence indicates the need for longer-term follow-up studies to adequately assess maintenance efficacy.     

急性期脑梗死患者血清MMP-9水平动态变化意义及与预后的关系

目的 通过对急性脑梗死患者不同时间点血清基质金属蛋白酶-9(Matrix Metalloproteinase,MMP-9)的测定和比较,探讨MMP-9水平与脑梗死TOAST分型及预后的关系.方法 收集急性脑梗死患者60例,对照组20例,分别测定急性脑梗死患者发病24h内、第5天和第10天的血清MMP-9含量,记录患者入院时的美国国立卫生研究所中风量表(NIHSS)评分;随访6个月,记录发病1个月时和发病6个月时的BI(Baahal Index)来评价预后.结果 (1)发病后24h内,脑梗死组TOAST各亚型血清MMP-9含量均升高,与对照组比较差异具有显著性(P<0.05),其中,CE组和LAA组MMP-9含量持续至第5天仍未下降,而SA组已逐渐降至正常水平;第10天各组MMP-9含量均降至正常水平.(2)发病后24h内血清MMP-9含量与相应时段NIHSS评分具有直线相关关系(r=0.883,P<0.01).(3)预后较好组其发病24h内血清MMP-9含量明显低于预后较差组(P<0.05).结论 (1)脑梗死后各组血清MMP-9的含量升高,但它们的变化趋势不尽相同.(2)发病后24h内MMP-9含量与与病情的严重程度有关.(3)脑梗死后24h内的血清MMP-9含量是预后的独立预测因素.

Abstract：

Objective To determine and compare the level of serum MMP-9 at acute stage of cerebral infarction and to approach the relationship among the level of serum MMP-9 and the classification of TOAST and the significance in prognosis. Methods 60 patients with cerebral infarction were included in our study,while 20 healthy people served as the control group. The serum specimens were gathered for MMP-9 determination with ELISA on admission, at the 5th and 10th day of onset. All patients were scored according to the American National Institutes of Health stroke scale ( NIHSS) on admission and recorded Barthal Index(BI) in the 1st and 6 month of onset. Results (1)The serum level of MMP-9 increased after cerebral infarction,and was significantly higher than those in the control group(P <0. 05). There was no significant difference between CE and LAA group ( P>0. 05). MMP-9 in CE and LAA group was significantly higher than those in SA group (P <0. 05) . MMP-9 in SA group decreased to normal level while was still higher in CE and LAA group on the 5th day of onset. On the 10th day MMP-9 in all groups decreased to normal. (2) There was a positive correlation between MMP-9 within 24 hours of onset and NIHSS( r = 0. 883 ,P < 0. 01) . (3) The serum level of MMP-9 in the cases with better prognosis was significantly lower than those with worse prognosis. Conclusions (1) The serum levels of MMP-9 in all groups increased, but the tendency of their variation was not similar;( 2 ) Serum level of MMP-9 was related to NIHSS, can reflect the severity of the state of cerebral the severity of the state of cerebral infarction;( 3 ) The level of serum MMP-9 within 24 hours of onset can predict prognosis of cerebral infarction independently.     

Firing of 'possibly' cholinergic neurons in the rat laterodorsal tegmental nucleus during sleep and wakefulness.

To clarify functional roles of mesopontine cholinergic neurons as a component of an activating system, single neuronal activity in the laterodorsal tegmental nucleus (LDT) of undrugged rats, whose head was fixed painlessly, was recorded along with cortical EEG and neck EMG. Activity of some dorsal raphe (DR) neurons was also recorded for comparison. Most of the animals had been sleep-deprived for 24 h. Observation was made only on neurons generating broad spikes, presumed from previous studies to be cholinergic or monoaminergic. The position of recorded neurons was marked by Pontamine sky blue ejected from the glass pipette microelectrode, and was identified on sections processed for NADPH diaphorase histochemistry which specifically stained cholinergic neurons. According to their firing rates during wakefulness (AW), slow-wave sleep (SWS) and paradoxical sleep (PS), 46 broad-spike neurons in the LDT were classified into 4 groups: (1) neurons most active during AW and silent during PS (some of these neurons might be serotonergic rather than cholinergic, as all the 9 neurons in the DR); (2) neurons most active during PS and silent during AW; (3) neurons equally more active during AW and PS than SWS; and (4) others mainly characterized by transiently facilitated activity at awakening and/or onset of PS. Neurons of groups 2 and 3 were the major constituents of the LDT. In most neurons change in firing preceded EEG change, except at awakening from PS. These results suggest that: (1) the LDT is composed of cholinergic neurons with heterogenous characteristics in relation to sleep/wakefulness; and (2) some tegmental cholinergic neurons play a privotal role in induction and maintenance of PS.     

Firing of ‘possibly’ cholinergic neurons in the rat laterodorsal tegmental nucleus during sleep and wakefulness

To clarify functional roles of mesopontine cholinergic neurons as a component of an activating system, single neuronal activity in the laterodorsal tegmental nucleus (LDT) of undrugged rats, whose head was fixed painlessly, was recorded along with cortical EEG and neck EMG. Activity of some dorsal raphe (DR) neurons was also recorded for comparison. Most of the animals had been sleep-deprived for 24 h. Observation was made only on neurons generating broad spikes, presumed from previous studies to be cholinergic or monoaminergic. The position of recorded neurons was marked by Pontamine sky blue ejected from the glass pipette microelectrode, and was identified on sections processed for NADPH diaphorase histochemistry which specifically stained cholinergic neurons. According to their firing rates during wakefulness (AW), slow-wave sleep (SWS) and paradoxical sleep (PS), 46 broad-spike neurons in the LDT were classified into 4 groups: (1) neurons most active during AW and silent during PS (some of these neurons might be serotonergic rather than cholinergic, as all the 9 neurons in the DR); (2) neurons most active during PS and silent during AW; (3) neurons equally more active during AW and PS than SWS; and (4) others mainly characterized by transiently facilitated activity at awakening and/or onset of PS. Neurons of groups 2 and 3 were the major constituents of the LDT. In most neurons change in firing preceded EEG change, except at awakening from PS. These results suggest that: (1) the LDT is composed of cholinergic neurons with heterogenous characteristics in relation to sleep/wakefulness; and (2) some tegmental cholinergic neurons play a pivotal role in induction and maintenance of PS.     

Neonatal capsaicin treatment modulates experience‐dependent plasticity in the rat barrel cortex

Previous studies have reported that capsaicin‐induced C‐fiber depletion results in expansion of low threshold somatosensory mechanoreceptive fields. Here we used this paradigm to investigate its effect on experience‐dependent plasticity in the barrel cortex of rats. All but the D2 vibrissa were first plucked on postnatal day 0 (P0), P5, or P8, and kept plucked for a period of 30 days before being allowed to regrow for 7–9 days prior to the recording session. To assess receptive field characteristics the spared D2 principal whisker (PW) and the deprived D1 adjacent whisker (AW) were moved either singly or in concert, neuronal responses being recorded in layers IV and V of the D2 barrel. In vehicle‐treated rats, PW‐evoked ON responses (layer IV) were increased only in those animals that first had their vibrissae plucked on P0, whereas AW‐evoked ON responses (layers IV and V) were decreased in the P0, P5, and P8 groups. In the capsaicin‐treated animals, PW‐evoked ON responses (layer IV) were increased in all three groups, but no decrease was recorded in the AW‐evoked ON (layers IV and V) responses. In the vehicle‐ and capsaicin‐treated animals, the greatest decrease in inhibitory interactions was observed in the P5 and P0 groups, respectively. These findings indicate that, following the induction of experience‐dependent plasticity, the resultant changes in excitatory and integrative circuits can be further influenced by C‐fiber depletion. J. Comp. Neurol. 518:3427–3438, 2010. © 2010 Wiley‐Liss, Inc.     

Human tumor necrosis factor-alpha augments experimental allergic encephalomyelitis in rats

The effect of human recombinant tumor necrosis factor-alpha (TNF) on experimental allergic encephalomyelitis (EAE) was studied in Lewis rats. TNF was injected intraperitoneally at a daily dose of 1 x 10(3) or 2 x 10(4) U for 8 consecutive days from one day after sensitization with guinea-pig spinal cord in complete Freund's adjuvant. All rats in the control group developed clinical signs of EAE but recovered within 8 days after the onset. Injections of 2 x 10(4) U/day of TNF resulted in a significant prolongation of clinical EAE: clinical signs were sustained for up to 15 days after onset. Histologically, rats receiving 2 x 10(4) U/day of TNF had more severe cellular infiltrations in the spinal cord than controls. The augmentation of EAE was not found in rats receiving 1 x 10(3) U/day of TNF or TNF that had been neutralized with anti-TNF monoclonal antibody.     

Abnormal expression of tyrosine hydroxylase immunoreactivity in Purkinje cells precedes the onset of ataxia in dilute-lethal mice.

Expression of tyrosine hydroxylase (TH) immunostaining in the cerebellum was examined in dilute-lethal mice (DL) prior to and following the onset of ataxia. DL walked normally on postnatal days 7 and 8. Falling over when walking was exhibited by about 20% of DL on day 9 and by all DL by day 10. TH-positive Purkinje cells in lobules IX and X of the vermis of either ataxic or non-ataxic DL were clearly observed on day 9 when compared to control mice, and had drastically increased by day 10. These results revealed that abnormal TH expression occurred in some Purkinje cells of DL cerebella, preceding the onset of ataxia.     

The prognostic significance of changes in lesion size of established cerebral infarcts on computed tomography of the brain

BACKGROUND: As a second part of our prospective study, we assessed the size of the infarct lesion on computed tomography (CT) of the brain at two fixed time points after stroke in order to investigate its influence on the clinical outcome. METHODS: From 220 consecutive stroke patients, admitted within 24 h after onset with symptoms lasting more than 24 h, we selected 150 displaying an anterior circulation infarct or syndrome. All included patients had CT scans without contrast enhancement on day 3 (+/- 8 h) and on day 10 (+/- 8 h) after stroke onset. The size of the X-ray hypoattenuation zone was determined by superimposing the CT slices on digital cerebral vascular maps, on which the contours of the infarct area were delineated. The lesion size was expressed as the fraction of the total surface area of these digital cerebral maps. The patients were divided into four groups according to their degree of disability at 3 months on the modified Rankin (R) scale as follows : R 0-1, R 2-3, R 4-5, R 6. RESULTS: There was a clear association between lesion size on CT, on day 3 and on day 10, and the clinical outcome. Lesion size decreased between day 3 and day 10 in the groups R 0-1 and R 2-3, remained unchanged in the group R 4-5 and further increased in group R 6. CONCLUSION: Lesion size on CT is a significant predictor of stroke outcome. It decreases from day 3 to day 10 in patients with no or low disability at 3 months, but increases in those who do not survive their stroke.     

Cognitive and locomotor/exploratory behavior after chronic exercise in the olfactory bulbectomy animal model of depression

Despite the evidence that exercise improves cognitive behavior in animal models, little is known about these beneficial effects in animal models of pathology. We examined the effects of activity wheel (AW) running on contextual fear conditioning (CFC) and locomotor/exploratory behavior in the olfactory bulbectomy (OBX) model of depression, which is characterized by hyperactivity and changes in cognitive function. Twenty-four hours after the conditioning session of the CFC protocol, the animals were tested for the conditioned response in a conditioned and a novel context to test for the effects of both AW and OBX on CFC, but also the context specificity of the effect. OBX reduced overall AW running behavior throughout the experiment, but increased locomotor/exploratory behavior during CFC, thus demonstrating a context-dependent effect. OBX animals, however, displayed normal CFC behavior that was context-specific, indicating that aversively conditioned memory is preserved in this model. AW running increased freezing behavior during the testing session of the CFC protocol in the control animals but only in the conditioned context, supporting the hypothesis that AW running improves cognitive function in a context-specific manner that does not generalize to an animal model of pathology. Blood corticosterone levels were increased in all animals at the conclusion of the testing sessions, but levels were higher in AW compared to sedentary groups indicating an effect of exercise on neuroendocrine function. Given the differential results of AW running on behavior and neuroendocrine function after OBX, further exploration of the beneficial effects of exercise in animal models of neuropathology is warranted.     

Abrupt or precipitated withdrawal from morphine induces immunosuppression

The present studies tested the effect of withdrawal from morphine by two different paradigms, abrupt withdrawal (AW) or precipitated withdrawal (PW), on the capacity of murine spleen cells to mount an in vitro antibody response. Mice were made dependent by chronic treatment using s.c. implanted morphine slow-release pellets. Splenocytes were harvested at various time points after withdrawal and the number of antibody-forming cells determined using a plaque-forming cell (PFC) assay. The results indicate that induction of abstinence from morphine in dependent mice by either paradigm caused marked immunosuppression between 24 and 48 h post-withdrawal. However, the kinetics of onset and recovery from immunosuppression were different in AW and PW.     

Effects of isosorbide dinitrate on regional cerebral blood flow and intracranial pressure in cats]

The effects of isosorbide dinitrate (ISDN) on regional cerebral blood flow (rCBF) and intracranial pressure (ICP) were examined in cats. A low dose of ISDN (2.5 micrograms/kg/min) infusion did not show any changes in cerebral hemodynamics. During high dose of ISDN (5.0 micrograms/kg/min) or NTP (5.0 micrograms/kg/min) infusion, mean blood pressure (mBP) decreased by 10 to 20% accompanied by decreased cerebral perfusion pressure (CPP: mBP-ICP), however, rCBF or ICP did not change. It is concluded that intravenous administrations of ISDN in a dose of 2.5-5.0 micrograms/kg/min that produce slight decrease in blood pressure did not influence on cerebral hemodynamics.     

Activation of 5-HT3 receptors leads to altered responses 6 months after MDMA treatment

The recreational drug “Ecstasy” [3,4-methylenedioxymethamphetamine (MDMA)] has a well-characterised neurotoxic effect on the 5-hydroxytryptamine (5-HT) neurons in animals. Despite intensive studies, the long-term functional consequencies of the 5-HT neurodegeneration remains elusive. The aim of this study was to investigate whether any alteration of 5-hydroxytryptamine-3 (5-HT₃) receptor functions on the sleep–wake cycle, motor activity, and quantitative EEG could be detected 6 months after a single dose of 15 mg/kg of MDMA. The selective 5-HT₃ receptor agonist m-chlorophenylbiguanide (mCPBG; 1 mg/kg, i.p.) or vehicle was administered to freely moving rats pre-treated with MDMA (15 mg/kg, i.p.) or vehicle 6 months earlier. Polysomnographic and motor activity recordings were performed. Active wake (AW), passive wake (PW), light slow wave sleep (SWS-1), deep slow wave sleep (SWS-2), and paradoxical sleep were classified. In addition, EEG power spectra were calculated for the second hour after mCPBG treatment for each stage. AW increased and SWS-1 decreased in the second hour after mCPBG treatment in control animals. mCPBG caused significant changes in the EEG power in states with cortical activation (AW, PW, paradoxical sleep). In addition, mCPBG had a biphasic effect on hippocampal theta power in AW with a decrease in 7 Hz and a stage-selective increase in the upper range (8–9 Hz). Effects of mCPBG on the time spent in AW and SWS-1 were eliminated or reduced in MDMA-treated animals. In addition, mCPBG did not increase the upper theta power of AW in rats pre-treated with MDMA. These data suggest long-term changes in 5-HT₃ receptor function after MDMA.