Episodes In Rats Research Articles

Metabolic and perfusion responses to acute hypoglycemia in the rat cortex: A non-invasive magnetic resonance approach.

Hypoglycemia is critical condition during diabetic treatment that involves intensive insulin therapy, and it may impair brain function. We aimed to compare cortical responses of three hypoglycemic phases and the restoration of glycemia to control levels after a severe episode in rats using non-invasive perfusion magnetic resonance (MR) imaging and localized 1 H MR spectroscopy. Under light α-chloralose anesthesia, cortical blood flow (cCBF) was 42±3ml/100g/min at euglycemia (~5mM plasma glucose), was not altered at mild hypoglycemia I (42±4ml/100g/min, 2-3.5mM), increased to 60±8ml/100g/min under moderate hypoglycemia II (1-2mM) and amplified to 190±35ml/100g/min at severe hypoglycemia III (<1mM). 1 H MRS revealed metabolic changes at hypoglycemia I without any perfusion alteration. At hypoglycemia III, glutamine and glutamate decreased, whereas aspartate increased. When animals subsequently regained glycemic control, not all metabolites returned to their control levels, for example, glutamine. Meanwhile, ascorbate was increased with amplified hypoglycemic severity, whereas glutathione was reduced; these compounds did not return to normal levels upon the restoration of glycemia. Our study is the first to report cCBF and neurochemical changes in cortex upon five glycemic stages. The cortical responses of different hypoglycemic phases would explain variable neuronal damages after hypoglycemia and might help identify the degrees of hypoglycemic insults and further improve alternative therapies.

Rapid Atrial Pacing Promotes Atrial Fibrillation Substrate in Unanesthetized Instrumented Rats.

AimThe self-perpetuating nature of atrial fibrillation (AF) has been a subject of intense research in large mammalian models exposed to rapid atrial pacing (RAP). Recently, rodents are increasingly used to gain insight into the pathophysiology of AF. However, little is known regarding the effects of RAP on the atria of rats and mice. Using an implantable device for electrophysiological studies in rodents, we examined on a daily basis, the effects of continuous RAP on the developed AF substrate of unanesthetized rats and mice.Methods and ResultsAggressive burst pacing did not induce AF at baseline in the large majority of rodents, but repeatedly induced AF episodes in rats exposed to RAP for more than 2 days. A microarray study of left atrial tissue from rats exposed to RAP for 2 days vs. control pacing identified 304 differentially expressed genes. Enrichment analysis and comparison with a dataset of atrial tissue from AF patients revealed indications of increased carbohydrate metabolism and changes in pathways that are thought to play critical roles in human AF, including TGF-beta and IL-6 signaling. Among 19 commonly affected genes in comparison with human AF, downregulation of FOXP1 and upregulation of the KCNK2 gene encoding the Kir2.1 potassium channel were conspicuous findings, suggesting NFAT activation. Further results included reduced expression of MIR-26 and MIR-101, which is in line with NFAT activation.ConclusionOur results demonstrate electrophysiological evidence for AF promoting effects of RAP in rats and several molecular similarities between the effects of RAP in large and small mammalian models.

Consolidated bioprocessing in engineered B. subtilis lab strains: γ-PGA production from biomass

PEA is an endogenous mediator released together with the endocannabinoid anandamide from membrane phospholipids. It is a plant derived compound with analgesic and anti-inflammatory properties. We verified whether the pathophysiology of experimental cystitis involves changes in the levels of PEA and of some of its targets, ie CB1 and CB2 receptors, and PPARα. We also determined whether exogenously administered PEA could be proposed as a preventive measure for cystitis.Cystitis was induced by cyclophosphamide in female rats. Nociceptive responses, voiding episodes, gross damage, myeloperoxidase activity, bladder weight, bladder PEA and endocannabinoid levels (measured by liquid chromatography-mass spectrometry) and the expression of PEA targets (measured by quantitative reverse transcriptase-polymerase chain reaction) were recorded.Cyclophosphamide induced pain behavior, bladder inflammation and voiding dysfunction associated with increased bladder levels of PEA, up-regulation of CB1 receptor mRNA expression, down-regulation of PPARα mRNA and no change in CB2 receptor mRNA expression. Exogenously administered, ultramicronized PEA attenuated pain behavior, voids and bladder gross damage. The CB1 antagonist rimonabant and the PPARα antagonist GW6471 counteracted the beneficial effect of PEA on gross damage. Also, GW6471 further decreased voiding episodes in rats treated with PEA.The current study provides strong evidence for a protective role of PEA as well as an alteration in bladder levels of PEA and of some of its targets in cyclophosphamide induced cystitis.

Metabolism of omegas 3: Which is responsible for cardioprotective effects?

Cardioprotective effects of long-chain polyunsaturated fatty acids of the n-3 series (PUFAs) have been demonstrated and represent a novel approach to prevent myocardial infarctions or its consequences. Due to the abundance of double bonds, the main n-3 PUFAs; docosahexaenoic acid (C22: 6 n-3, DHA) are very sensitive to free radical oxidation and can undergo non-enzymatic spontaneous peroxidation under oxidative stress conditions as it occurs in ischemia/reperfusion. In this context, a lot of oxygenated metabolites of PUFAs-like neuroprostanes (NeuroPs) are produced and used as oxidative stress biomarkers but their activities were not determined. We investigated if the pericardial delivery of NeuroPs, protects the myocardium from ischemic damages during and following an ischemia/reperfusion (IR) episode in rats. Cardiac functions, infarct size and arrhythmias were studied and we observed that NeuroPs afford some cardioprotective effect during or after myocardial infarction. Indeed, compared with controls, NeuroPs-treated animals have significantly decreased infarct size (−28%) determined at the end of reperfusion and reduced ventricular arrhythmia score during reperfusion (−38%). Mechanistically, NeuroPs regulates calcium levels by stabilizing RyR2 activity (Roy et al., 2015), which can explain arrhythmias prevention during IR. Also, our results demonstrated an increase of membrane potential (ΔΨm) by the application of NeuroPs. This effect was not due to an augmentation of mitochondrial respiratory chain activity but by the effect leading to the diminution of protons leak. Swelling in response to Ca 2+ was prevented by NeuroP, indicating a decrease MPTP opening, which can be explain prevention of cell death during IR. These results suggest a novel pharmacological pathway of n-3 PUFAs and suggest that their well-known cardioprotective effects are mediated by their oxygenated metabolites such as NeuroPs.

0018 : Cardioprotection following injury heart failure afforded by a nonenzymatic oxygenated metabolite of omega 3 fatty acid involves ryanodine receptor mechanism and mitochondrial function

Cardioprotective effects of long-chain polyunsaturated fatty acids of the n-3 series (PUFAs) have been demonstrated and represent a novel approach to prevent myocardial infarctions or its consequences. Due to the abundance of double bonds, the main n-3 PUFAs; docosahexaenoic acid (C22: 6 n-3, DHA) are very sensitive to free radical oxidation and can undergo non-enzymatic spontaneous peroxidation under oxidative stress conditions as it occurs in ischemia/reperfusion. In this context, a lot of oxygenated metabolites of PUFAs like Neuroprostanes (NeuroPs) are produced and used as oxidative stress biomarkers but their activities were not determined. We investigated if the pericardial delivery of NeuroPs, protects the myocardium from ischemic damages during and following an ischemia/reperfusion (IR) episode in rats. Cardiac functions, infarct size and arrhythmias were studied and we observed that NeuroPs afford some cardioprotective effect during or after myocardial infarction. Indeed, compared with controls, NeuroPs-treated animals have significantly decreased infarct size (–28%) determined at the end of reperfusion and reduced ventricular arrhythmia score during reperfusion (–38%). Mechanistically, NeuroPs regulates calcium levels by stabilizing RyR2 activity (Roy et al., 2015), which can explain arrhythmias prevention during IR. Also, our results demonstrated an increase of membrane potential (⊗¬m) by the application of NeuroPs. This effect was not due to an augmentation of mitochondrial respiratory chain activity but by the effect leading to the diminution of protons leak. Swelling in response to Ca2+ was prevented by NeuroP, indicating a decrease MPTP opening, which can be explain prevention of cell death during IR. These results suggest a novel pharmacological pathway of n-3 PUFAs and suggest that their well-known cardioprotective effects are mediated by their oxygenated metabolites such as NeuroPs. The author hereby declares no conflict of interest

Progressive, Seizure-Like, Spike-Wave Discharges Are Common in Both Injured and Uninjured Sprague-Dawley Rats: Implications for the Fluid Percussion Injury Model of Post-Traumatic Epilepsy.

Variable-duration oscillations and repetitive, high-voltage spikes have been recorded in the electrocorticogram (ECoG) of rats weeks and months after fluid percussion injury (FPI), a model of traumatic brain injury. These ECoG events, which have many similarities to spike-wave-discharges (SWDs) and absence seizures, have been proposed to represent nonconvulsive seizures characteristic of post-traumatic epilepsy (PTE). The present study quantified features of SWD episodes in rats at different time points after moderate to severe FPI, and compared them with age-matched control rats. Control and FPI-injured rats at 1 year of age displayed large-amplitude and frequent SWD events at frontal and parietal recording sites. At 3-6 months, SWDs were shorter in duration and less frequent; extremely brief SWDs (i.e., "larval") were detected as early as 1 month. The onset of the SWDs was nearly always synchronous across electrodes and of larger amplitude in frontal regions. A sensory stimulus, such as a click, immediately and consistently stopped the occurrence of the SWDs. SWDs were consistently accompanied by behavioral arrest. All features of SWDs in control and experimental (FPI) rats were indistinguishable. None of the FPI-treated rats developed nonconvulsive or convulsive seizures that could be distinguished electrographically or behaviorally from SWDs. Because SWDs have features similar to genetic absence seizures, these results challenge the hypothesis that SWDs after FPI reflect PTE.

Anti-apoptotic, anti-oxidant, and anti-inflammatory effects of thalidomide on cerebral ischemia/reperfusion injury in rats

Thalidomide has shown protective effects in different models of ischemia/reperfusion damage. To elucidate the mechanisms of such protection, this study assessed the effects of thalidomide on the oxidative stress and inflammatory response induced by ischemia/reperfusion episodes in rats. Rats underwent middle cerebral artery occlusion (MCAO) for 2hours. All animals were sacrificed after different reperfusion times. Rats were administered either DMSO or thalidomide (20mg/kg (i.p.)) at different times before or during reperfusion: 1) 1h before reperfusion; the infarct area was measured 2h after reperfusion. 2) 10min before reperfusion and 80min after reperfusion; the infarct area was measured 24h after reperfusion; and 3) 10min before reperfusion and 1h, 24h, 48h, and 68h after reperfusion; the infarct area was measured 72h after reperfusion. Thalidomide reduced the infarct area 24h and 72h after MCAO, and decreased the neurological deficit in all groups with respect to controls. Thalidomide also lowered significantly the number of TUNEL-positive cells, levels of Bax, caspase-3, lipoperoxidation, and pro-inflammatory cytokines, and increased the levels of SOD1, Bcl-2 and pAkt. These results show that thalidomide has neuroprotective effects, apparently due to its anti-apoptotic, anti-oxidant, and anti-inflammatory effects.

Protective Effect of Palmitoylethanolamide in a Rat Model of Cystitis

PEA is an endogenous mediator released together with the endocannabinoid anandamide from membrane phospholipids. It is a plant derived compound with analgesic and anti-inflammatory properties. We verified whether the pathophysiology of experimental cystitis involves changes in the levels of PEA and of some of its targets, ie CB1 and CB2 receptors, and PPARα. We also determined whether exogenously administered PEA could be proposed as a preventive measure for cystitis. Cystitis was induced by cyclophosphamide in female rats. Nociceptive responses, voiding episodes, gross damage, myeloperoxidase activity, bladder weight, bladder PEA and endocannabinoid levels (measured by liquid chromatography-mass spectrometry) and the expression of PEA targets (measured by quantitative reverse transcriptase-polymerase chain reaction) were recorded. Cyclophosphamide induced pain behavior, bladder inflammation and voiding dysfunction associated with increased bladder levels of PEA, up-regulation of CB1 receptor mRNA expression, down-regulation of PPARα mRNA and no change in CB2 receptor mRNA expression. Exogenously administered, ultramicronized PEA attenuated pain behavior, voids and bladder gross damage. The CB1 antagonist rimonabant and the PPARα antagonist GW6471 counteracted the beneficial effect of PEA on gross damage. Also, GW6471 further decreased voiding episodes in rats treated with PEA. The current study provides strong evidence for a protective role of PEA as well as an alteration in bladder levels of PEA and of some of its targets in cyclophosphamide induced cystitis.

Sustained Liver Glucose Release in Response to Adrenaline Can Improve Hypoglycaemic Episodes in Rats under Food Restriction Subjected to Acute Exercise

Background. As the liver is important for blood glucose regulation, this study aimed at relating liver glucose release stimulated by glucagon and adrenaline to in vivo episodes of hypoglycaemia. Methods. The blood glucose profile during an episode of insulin-induced hypoglycaemia in exercised and nonexercised male Wistar control (GC) and food-restricted (GR, 50%) rats and liver glucose release stimulated by glucagon and adrenaline were investigated. Results. In the GR, the hypoglycaemic episodes showed severe decreases in blood glucose, persistent hypoglycaemia, and less complete glycaemic recovery. An exercise session prior to the episode of hypoglycaemia raised the basal blood glucose, reduced the magnitude of the hypoglycaemia, and improved the recovery of blood glucose. In fed animals of both groups, liver glucose release was activated by glucagon and adrenaline. In fasted GR rats, liver glycogenolysis activated by glucagon was impaired, despite a significant basal glycogenolysis, while an adrenaline-stimulated liver glucose release was recorded. Conclusions. The lack of liver response to glucagon in the GR rats could be partially responsible for the more severe episodes of hypoglycaemia observed in vivo in nonexercised animals. The preserved liver response to adrenaline can partially account for the less severe hypoglycaemia in the food-restricted animals after acute exercise.

Behavioral characteristics and pharmacological manipulations of a nicotine-entrainable circadian oscillator

Chronic daily administration of nicotine and other drugs of abuse has been found to entrain pre- and post-drug circadian locomotor activity episodes that oscillate on a 24-h schedule and persist for several days after administration ceases. This drug-entrainable oscillator system could conceivably lead to circadian rhythms of drug seeking and drug use in human drug addicts. The present study (1) characterizes the ability of daily nicotine administration to entrain circadian wheel-running activity episodes in rats across a range of doses, lighting schedules, and food access; and (2) tests whether pre- and post-nicotine episodes can be altered through pharmacological manipulations. Adult female rats were housed in wheel boxes for 35–60 d, and both wheel-running and feeding-related behaviors were measured continuously. Following acclimation, nicotine or saline was administered for 16–24 d, and the rats were left undisturbed for several test days to observe the persistence of nicotine-entrained activity. The results showed that nicotine dose-dependently entrains wheel-running activity, and the highest dose of 1.0 mg/kg produces robust pre- and post-nicotine circadian activity episodes under constant, fixed, and variable light/dark schedules. In the pharmacological manipulation experiment, nicotine-entrained rats were administered one of seven pharmacological treatments (varenicline, mecamylamine, acamprosate, topiramate, naltrexone, SB-334867, or bupropion) in place of the nicotine injection for 2 d, and the rats were not disturbed for four subsequent days. Most of the treatment drugs significantly reduced post-nicotine activity episodes, but only three treatments affected pre-nicotine episodes: the μ- and κ-opioid receptor antagonist naltrexone, the orexin-1 receptor antagonist SB-334867, and the AMPA (2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid)/kainate antagonist topiramate. These results show that chronic daily nicotine administration is a robust zeitgeber that dose-dependently entrains a nonphotic oscillator system that includes opioid, orexin, and glutamate pathways.

Effects of multiple daily nicotine administrations on pre- and post-nicotine circadian activity episodes in rats.

Administration of a single daily dose of nicotine has been shown to entrain circadian activity episodes both preceding and following the administration time that persist for several days after drug administration ceases. The present study tested the effects of multiple daily nicotine administrations on circadian activity episodes in adult female rats kept under constant light and rate-limited food access. Eight rats received 7 separate 7-day nicotine injection series, each followed by a 3-day test phase without injections. Subcutaneous nicotine was administered once a day during the 1st and 7th series, twice daily during the 2nd and 6th series, three times daily during the 3rd and 5th series, and four times daily during the 4th series. To control the cumulative daily dose throughout the study, 1.0 mg/kg nicotine was evenly divided among the injections within a single day. Pre- and post-administration effects of nicotine declined across the day, and significant entrainment of both pre- and post-nicotine episodes occurred for only one daily injection in each series. Additionally, post-nicotine episodes showed a different dose-response curve than the pre-nicotine episodes: post-nicotine wheel turns increased as the dose decreased, whereas pre-nicotine wheel turns remained relatively constant as the dose changed. These results provide evidence that nicotine-induced circadian entrainment to a single administration time does occur when the drug is administered multiple times a day, and pre- and post-nicotine circadian episodes are mediated at least partially by separate mechanisms.

Brain Injury and Recovery Following Binge Ethanol: Evidence from In Vivo Magnetic Resonance Spectroscopy

The binge-drinking model in rodents using intragastric injections of ethanol (EtOH) for 4 days results in argyrophilic corticolimbic tissue classically interpreted as indicating irreversible neuronal degeneration. However, recent findings suggest that acquired argyrophilia can also identify injured neurons that have the potential to recover. The current in vivo magnetic resonance (MR) imaging and spectroscopy study was conducted to test the hypothesis that binge EtOH exposure would injure but not cause the death of neurons as previously ascertained postmortem. After baseline MR scanning, 11 of 19 rats received a loading dose of 5 g/kg EtOH via oral gavage, then a maximum of 3 g/kg every 8 hours for 4 days, for a total average cumulative EtOH dose of 43 +/- 1.2 g/kg and average blood alcohol levels of 258 +/- 12 mg/dL. All animals were scanned after 4 days of gavage (post-gavage scan) with EtOH (EtOH group) or dextrose (control [Con] group) and again after 7 days of abstinence from EtOH (recovery scan). Tissue shrinkage at the post-gavage scan was reflected by significantly increased lateral ventricular volume in the EtOH group compared with the Con group. At the post-gavage scan, the EtOH group had lower dorsal hippocampal N-acetylaspartate and total creatine and higher choline-containing compounds than the Con group. At the recovery scan, neither ventricular volume nor metabolite levels differentiated the groups. Rapid recovery of ventricular volume and metabolite levels with removal of the causative agent argues for transient rather than permanent effects of a single EtOH binge episode in rats.

A single application of MK801 causes symptoms of acute psychosis, deficits in spatial memory, and impairment of synaptic plasticity in rats

Schizophrenia is mostly a progressive psychiatric illness. Although cognitive changes in chronic schizophrenia have been investigated, little is known about the consequences of a single psychotic episode on memory mechanisms and formation. We investigated changes in hippocampal long-term potentiation (LTP) and spatial memory in a rat model of an acute psychotic episode. Application of NMDA receptor antagonists, such as MK801 (dizolcilpine) in rats, have been shown to give rise to an acute and short-lasting behavioral state, which mirrors many symptoms of schizophrenia. Furthermore, NMDA antagonist-intake in humans elicits symptoms of schizophrenia such as hallucinations, delusions, and affective blunting. We therefore treated animals with a single systemic injection of MK801 (5 mg/kg). Increased stereotypy, locomotion, and ataxia were evident immediately after MK801-treatment, with effects disappearing within 24 h. MK801-treatment caused a disruption of prepulse inhibition of the acoustic startle reflex, 1 day but not 7 or 28 days after treatment. These effects were consistent with the occurrence of an acute psychotic episode. LTP was profoundly impaired in freely moving rats 7 days after MK801 application. Four weeks after treatment, a slight recovery of LTP was seen, however marked deficits in long-term spatial memory were evident. These data suggest that treatment with MK801 to generate an acute psychotic episode in rats, gives rise to grave disturbances in synaptic plasticity and is associated with lasting impairments with the ability to form spatial memory.

Disinhibition of perifornical hypothalamic neurones activates noradrenergic neurones and blocks pontine carbachol-induced REM sleep-like episodes in rats.

Studies in behaving animals suggest that neurones located in the perifornical (PF) region of the posterior hypothalamus promote wakefulness and suppress sleep. Among such cells are those that synthesize the excitatory peptides, orexins (ORX). Lack of ORX, or their receptors, is associated with narcolepsy/cataplexy, a disorder characterized by an increased pressure for rapid eye movement (REM) sleep. We used anaesthetized rats in which pontine microinjections of a cholinergic agonist, carbachol, can repeatedly elicit REM sleep-like episodes to test whether activation of PF cells induced by antagonism of endogenous, GABA(A) receptor-mediated, inhibition suppresses the ability of the brainstem to generate REM sleep-like state. Microinjections of the GABA(A) receptor antagonist, bicuculline (20 nl, 1 mm), into the PF region elicited cortical and hippocampal activation, increased the respiratory rate and hypoglossal nerve activity, induced c-fos expression in ORX and other PF neurones, and increased c-fos expression in pontine A7 and other noradrenergic neurones. The ability of pontine carbachol to elicit any cortical, hippocampal or brainstem component of the REM sleep-like response was abolished during the period of bicuculline-induced activation. The activating and REM sleep-suppressing effect of PF bicuculline was not attenuated by systemic administration of the ORX type 1 receptor antagonist, SB334867. Thus, activation of PF neurones that are endogenously inhibited by GABA(A) receptors is sufficient to turn off the brainstem REM sleep-generating network; the effect is, at least in part, due to activation of pontine noradrenergic neurones, but is not mediated by ORX type 1 receptors. A malfunction of the pathway that originates in GABA(A) receptor-expressing PF neurones may cause narcolepsy/cataplexy.

Effects of AP5 infusion into the lateral ventricle on the activities and hippocampal electrical patterns of sleep episodes in rats

Although N-methyl- d-aspartate (NMDA) receptors of the hippocampus are mainly associated with learning and memory that might occur “on-line” during sharp waves (SPWs) and theta-rhythm, the participation of hippocampal NMDA receptors in sleep-related processes has not been well studied. In this study, the activity of sleep episodes, hippocampal SPWs and theta-rhythm were recorded in rats received a repeated infusion of NMDA receptor antagonist, d, l-2-amino-5-phosphonopentanoic acid (AP5), into the lateral ventricle in a 5-h daytime sleep. The first trial AP5 infusion (30 mM/2 μl) did not change measures of the activity of slow wave sleep (SWS), paradoxical sleep (PS) and awake episodes, but induced a delay in the latency of the first onset of PS; in the hippocampal EEG, it increased the amplitude of SPWs within SWS and shifted the amplitude/spectral power of theta-rhythm from high to low frequency within PS. The repeated AP5 infusion augmented the activity of SWS, and impaired PS and awake episodes; in the EEG-sleep picture, it maintained high scores of SPWs with the complete blockade of theta-rhythm generation. When AP5 rat was woken, the theta-rhythm was seen during exploratory behavior. These findings provide evidence that hippocampal NMDA receptors via SPWs or directly associated with the synaptic events of theta-rhythm generation are critical for the PS activities.

Ca3 neuronal activities of dorsal and ventral hippocampus are differentially altered in rats after prolonged post-ischemic survival

The aim of the present study is to explore the potential hyper-excitability of hippocampal CA3 neurons in rats after prolonged post-ischemic survival. We conducted 15-min four-vessel-occlusion ischemic episodes in rats, allowed these animals to survive for approximately 8 months and then examined the basic morphological features and population synaptic activities of CA3 neurons. In fixed tissue sections obtained from dorsal hippocampi of post-ischemic rats, we observed a complete loss of the CA1 neurons together with a shrunken CA1 sector. Extracellular recordings in slices revealed that the overall synaptic activities of dorsal hippocampal CA3 neurons were decreased in post-ischemic rats compared with sham-operated controls. Both sham control and post-ischemic ventral hippocampal neurons were capable of exhibiting intermittent spontaneous field potentials in slices. These spontaneous field potentials spread from the CA3 to the CA1 area and their generation relied on the activity of glutamate alpha-amino-3-hydroxy-5-methyl-4 isoxazole proprionic acid (AMPA) receptors. The propensity for displaying these spontaneous field potentials appeared to be greater in post-ischemic slices than sham control slices. Our data suggest that the hyper-excitability of the post-ischemic hippocampus, if it occurs, may preferentially take place in the ventral CA3 circuitry.

Accumbal dopamine and serotonin in anticipation of the next aggressive episode in rats.

Autonomic and limbic neural activities are linked to aggressive behavior, and it is hypothesized that activities in the cardiovascular and monoaminergic systems play a role in preparing for an aggressive challenge. The objective was to learn about the emergence of monoamine activity in nucleus accumbens before an aggressive confrontation that was omitted at the regular time of occurrence, dissociating the motoric from the aminergic activity. Dopamine, serotonin, heart rate and behavioral activity were monitored before, during and after a single 10-min confrontation in resident male Long-Evans rats fitted with a microdialysis probe in the n. accumbens and with a telemetry sender (experiment 1). DA, but not 5-HT efflux, was confirmed to increase in n. accumbens during and after a single aggressive episode. In aggressive males that confronted an opponent daily for 10 days (experiment 2) heart rate rose 1 h before the regularly scheduled encounter relative to control rats, as measured on day 11 in the absence of any aggression. Concurrently, DA levels increased by 60-70% over baseline levels and 5-HT levels decreased by 30-35% compared to baseline levels. These changes were sustained over 1 h, and contrasted with no significant changes in DA, 5-HT, heart rate or behavioral activity in control rats. The rise in mesolimbic DA appears to be significant in anticipating the physiological and behavioral demands of an aggressive episode, and the fall in 5-HT in its termination, dissociated from the actual execution of the behavior.

Effect of the GABAA agonist gaboxadol on nocturnal sleep and hormone secretion in healthy elderly subjects.

Aging is associated with a dramatic decrease in sleep intensity and continuity. The selective GABA(A) receptor agonist gaboxadol has been shown to increase non-REM sleep and the duration of the non-REM episodes in rats and sleep efficiency in young subjects and to enhance low-frequency activity in the electroencephalogram (EEG) within non-REM sleep in both rats and humans. In this double-blind, placebo-controlled study, we investigated the influence of an oral dose of 15 mg of gaboxadol on nocturnal sleep and hormone secretion (ACTH, cortisol, prolactin, growth hormone) in 10 healthy elderly subjects (6 women). Compared with placebo, gaboxadol did not affect endocrine activity but significantly reduced perceived sleep latency, elevated self-estimated total sleep time, and increased sleep efficiency by decreasing intermittent wakefulness and powerfully augmented low-frequency activity in the EEG within non-REM sleep. These findings indicate that gaboxadol is able to increase sleep consolidation and non-REM sleep intensity, without disrupting REM sleep, in elderly individuals and that these effects are not mediated by a modulation of hormone secretion.

Carbachol models of REM sleep: recent developments and new directions.

Since the early '60s, injections of a broad-spectrum muscarinic cholinergic agonist, carbachol, into the medial pontine reticular formation (mPRF) of cats have been extensively used as a tool with which to study the neural mechanisms of rapid eye movement (REM) sleep. During the last decade, new carbachol models of REM sleep were introduced, including chronically instrumented/behaving rats and "reduced" preparations such as decerebrate or anesthetized cats and rats. The combined results from these distinct models show interspecies similarities and differences. The dual nature, both REM sleep-promoting and wakefulness (or arousal)-promoting, of the cholinergic effects exerted within the mPRF is more strongly expressed in rats than in cats. This strengthens the possibility suggested by earlier central neuronal recordings that active wakefulness and REM sleep have extensive common neuronal substrates, and may have evolved from a common behavioral state. Carbachol studies using different intact and reduced models also suggest that powerful REM sleep episode-terminating effects originate in suprapontine structures. In contrast, the timing of REM sleep-like episodes in decerebrate models is determined by a pontomedullary neuronal network responsible for the generation of an ultradian cycle similar to the basic rest-activity cycle of N. Kleitman. Other presumed species differences, such as the more widespread distribution of carbachol-sensitive sites or the relative failure of carbachol to increase the duration of REM sleep episodes in rats when compared to cats, may be of a quantitative or technical nature. While carbachol and many other neurotransmitters and peptides microinjected into the mPRF evoke, enhance or suppress REM sleep, the most sensitive site(s) of their actions have not been fully mapped, and the nature of the cellular and neurochemical interactions taking place at the sites where carbachol triggers the REM sleep-like state remain largely unknown. Similarly, little is known about the pathways between the mPRF and medial medullary reticular formation, but the existing evidence suggests that they are reciprocal and essential for the generation of both natural and carbachol-induced REM sleep. Studies of the mesopontine cholinergic neurons, which are hypothesized to be the main source of endogenous acetylcholine for the mPRF, need to be extended to neurons of the mPRF and cells located functionally downstream from this important site for REM sleep, or both REM sleep and active wakefulness.

Antagonism of methomyl-induced toxicosis by diphenhydramine in rats

The efficacy of diphenhydramine in the prevention and treatment of methomyl-induced toxicosis was evaluated in female rats. Diphenhydramine at 10 and 20 mg/kg subcutaneously (s.c.) given immediately after methomyl increased the LD 50 of methomyl (6.29 mg/kg intraperitoneally (i.p.)) in the rats by 71 and 75% respectively. Diphenhydramine at 20 mg/kg s.c. given immediately after methomyl (6 mg/kg i.p.) decreased the occurrence of cholinergic signs of toxicosis, and prevented convulsions, gasping and death by 100% in comparison with the control (methomyl-saline) group. Diphenhydramine administration at 2.5, 5 and 10 mg/kg s.c. 20 min before methomyl (8 mg/kg i.p.) significantly and dose-dependently decreased the number of convulsion episodes in rats in comparison with the control group. This effect was similar to those of atropine and diazepam pretreatments at 20 mg/kg s.c. Diphenhydramine and atropine at 20 mg/kg i.p. given 5 min after the methomyl administration (8 mg/kg i.p.) were close to each other in reducing the signs of cholinergic toxicity as well as the severity of toxicosis induced by methomyl in rats. Methomyl at 4 and 8 mg/kg i.p. significantly decreased erythrocyte (40 and 43%) and plasma (23 and 31%) cholinesterase activities in comparison with the control group. Diphenhydramine (10 mg/kg s.c.) injected 15 min before methomyl significantly decreased the inhibitory effect of methomyl (4 and 8 mg/kg i.p.) on erythrocyte cholinesterase to 17 and 27%, respectively. The inhibitory effect on plasma cholinesterase was not affected by the diphenhydramine pretreatment. The data suggest that diphenhydramine could be of therapeutic value in reducing the toxic effects of methomyl.