Effect of novel anxiolytic agent aphobazole on coherence of the brain biopotentials in MR and MNRA rats

Effect of the anxiolytic drugs afobazole, diazepam, and chlordiazepoxide on the cortical biopotential coherency was studied in MR and MNRA rats with increased and decreased level of emotionality, respectively. Afobazole increased a difference in the biopotential coherency between rats of the two lines in the range of EEG theta, alpha, and beta rhythms. In the subrange of dominating theta activity (6.00-7.25 Hz), this effect took place at the expense of reduced coherency in MNRA rats in the absence of changes in the MR line. Afobazole decreased the biopotential coherency in the alpha activity band (7.5-8.25 Hz) in the rats of both lines. This is indicative of the presence of a CNS-stimulating component in the pharmacological activity spectrum of afobazole. The expediency of using afobazole in patients with different levels of anxiety is discussed.     

Effect of a novel antimigraine preparation tropoxin on EEG of MR and MNRA rats

Effect of the new antimigraine drug tropoxin on the EEG profile was studied in MR and MNRA rats with genetically determined high and low levels of emotionality, respectively. In MR rats, tropoxin decreased the number of the bioelectric activity parameters changed by the stressor action (0.9% NaCl, i.p.). The drug reduced the spectral power in the EEG delta band, and increased that in the theta, beta-1, and beta-2 bands. This was evidence of the central stimulating action and the possible enhancement of the exploratory activity. In MNRA rats no changes in bioelectric activity were observed in the low-frequency delta and theta bands, while the spectral power in the beta-1, and beta-2 bands showed a decrease. It was concluded that a neural component is present in the mechanism of the tropoxin action, which may play an important part in the therapeutic effect of the new drug.     

Comparative analysis of the neurophysiological profile of group II metabotropic glutamate receptor activators and diazepam: effects on hippocampal and cortical EEG patterns in rats

Selective activation of the Group II metabotropic glutamate receptors 2/3 (mGlu2/3) by either full agonists or positive allosteric modulators (PAMs) show anxiolytic activity. In the present study the anxiolytic profile of mGlu2/3 receptor agonists LY-354740 and LY-404039 and the mGlu2 receptor PAM 1-methyl-2-((cis-3-methyl-4-(4-trifluoromethyl-2-methoxy)-phenyl)piperidin-1-yl)-1H-imidazo[4,5-b]pyridine (MTFIP) were evaluated using neurophysiology-based assays. Activation of mGlu2/3 receptors by these compounds, as well as the positive control diazepam, significantly decreased the frequency of hippocampal theta oscillation elicited by stimulation of the brainstem nucleus pontis oralis (nPO), a characteristic action of anxiolytic compounds. Since the nPO is a critical region involved in regulation of rapid eye movement sleep, mGlu2/3 receptor activators were also tested on sleep parameters, as well as on cortical and hippocampal encephalography (EEG) activity. Both mGlu2/3 agonists and the mGlu2 PAM significantly prolonged REM sleep latency and reduced total REM sleep duration while during the active awake state all compounds lowered hippocampal peak theta frequency. However, diazepam and mGlu2/3 agonists/PAM elicited opposite changes in cortical EEG delta and beta bands. Delta power significantly increased after any of the mGlu2/3 compounds but decreased after diazepam. In the beta band, mGlu2/3 receptor agonists dose-dependently decreased beta power in contrast to the well-known beta activation by diazepam. These effects lasted 3-4h and could not be explained by modest, transient changes (<1h) in waking and slow wave sleep. The current observations support the role of mGlu2/3 receptor activators as potential anxiolytic compounds, but indicate a distinct action on cortical EEG activity which is different from the effects of GABA(A) PAMs. This article is part of a Special Issue entitled 'Anxiety and Depression'.     

Quantitative electroencephalographic profile of 3-(4-hydroxy-1-piperidinyl)-6-(2,4-dichlorophenyl)-pyridazine (SR 41378) in the rat

Summary Quantitative electroencephalographic (QEEG) analysis was performed in rats following the oral administration of SR 41378 [3-(4-hydroxy-1-piperidinyl)-6-(2,4-dichlorophenyl)-pyridazine], a novel aminopyridazine derivative, which has been shown to possess anticonvulsant, antianxiety and hypnotic activities in mice and rats. The EEG effects of SR 41378 (10, 30 and 100 mg/kg) were compared to those of secobarbital (30 and 60 mg/kg) and diazepam (1, 3 and 10 mg/kg). SR 41378 and secobarbital increased the power of the middle-frequencies (8–16 Hz) of the EEG, reduced that of 4–8 Hz (theta) activities and did not affect 1–4 Hz (delta) activities. Diazepam also increased the power of middle-frequency activities and decreased that of both delta and theta activities. Quantitative EEG profiles were calculated from the mean integrated power (MIP) of selected frequency bands. The QEEG profile of SR 41378 was found to share common characteristics with those of secobarbital and diazepam: dose-dependent decrease of theta band MIP and increase of 8–20 Hz (middle beta bands) MIP. However, both SR 41378 and secobarbital induced a reduction of the 28–32 Hz (fast beta bands) MIP, whereas diazepam diminished the delta band. These results suggest that SR 41378, a novel chemical structure, shares common psychotropic properties with barbiturates and benzodiazepines.Part of this work has been presented at the 15th Annual Meeting of the Society for Neuroscience, October 20–25, 1985, Dallas, Texas, USA     

RELATIONSHIP BETWEEN THE DOSE-RESPONSE EFFECTS OF DIAZEPAM AND CLOBAZAM ON ELECTROENCEPHALOGRAPHIC PARAMETERS AND ON KINDLED AMYGDALOID SEIZURE ACTIVITY IN RATS

1. The possibility that the anticonvulsant activity of the benzodiazepines, diazepam and clobazam, is related to changes in EEG parameters, particularly beta activity, was investigated in amygdaloid kindled rats. 2. The effects of diazepam (1, 2, 4, 8 and 16 mumols/kg), administered intraperitoneally (i.p.), clobazam (1, 2, 4, 8, 16 and 32 mumols/kg, i.p.) or vehicle (dimethyl sulfoxide) on the cortical EEG of amygdaloid kindled rats were quantitated for 15 min using computerized period amplitude analysis. Immediately afterwards, the amygdala was stimulated and the after-discharge duration (AD) and the seizures stage (SS) were determined. 3. The equivalent percentage time (EPT) of the diazepam-treated group was decreased in the theta band (4-8 Hz) and increased in the alpha (8-12 Hz) and first six beta (12-36 Hz) bands. The mean peak amplitude (MPA) was increased in the alpha (8-12 Hz) and all seven beta bands (12-40 Hz). Clobazam increased the EPT and MPA in the alpha (8-12 Hz) and all seven beta (12-40 Hz) bands. The MPA was also increased by clobazam in the theta (4-8 Hz) band. 4. Diazepam reduced both the AD and SS of the kindled seizures at doses of 4, 8 and 16 mumols/kg, whereas clobazam was anticonvulsant at doses of 16 and 32 mumols/kg. The reduction in both AD and SS correlated with increases in the EPT and MPA in the first beta (12-16 Hz) band in the diazepam-treated group and in the first four beta (12-28 Hz) bands in the clobazam-treated group.     

Comparison of changes in the EEG of freely moving rats induced by enciprazine, buspirone and diazepam

The effect of enciprazine, buspirone and diazepam was investigated on the cortical electrical activity in freely-moving rats. Enciprazine (5 mg/kg, i.p.) and buspirone (5 mg/kg, i.p.) induced comparable changes, consisting in decreases of mean power values in delta and theta and increases in alpha and beta EEG frequency bands. Regarding only a particular area of the brain or particular frequency bands, these two compounds could not be clearly separated from each other. Changes in frequency bands induced by O-methoxy-phenyl-piperazine (5 mg/kg i.p.) (D 15157), the presumed main metabolite of enciprazine, were dose-related to that caused by the parent compound. The second metabolite (R,S)-1-4-(1-methoxy-4-hydroxy-phenyl)piperazin-1-yl-3-(3,4,5- trimethoxyphenoxy)propan-2-ol-dihydrochloride (D 20092) (5 mg/kg i.p.) evoked only minimal changes in the different frequency bands of the rats. The power spectra did not significantly differ from those seen in animals treated with saline. The action of diazepam (2 mg/kg i.p.) was characterized by decreases in alpha and delta frequency bands, accompanied by marked increases in fast beta waves. The marked frequency shifts caused by buspirone and enciprazine could clearly be differentiated from the EEG changes evoked by the minor tranquilizer, diazepam.     

Anxiolytic profile of pregabalin on elicited hippocampal theta oscillation

Previous published work with the novel anticonvulsant, analgesic and anti-anxiety medication, pregabalin (Lyrica^®), has shown that it has anxiolytic-like actions in several animal behavioral models. However, pregabalin is structurally and pharmacologically different from other classes of known anxiolytic drugs, and the mechanisms that alter brain activity to produce anxiolytic-like actions are not well understood. In an effort to determine more about the cellular mechanisms of pregabalin, we studied its effects on hippocampal theta activity of urethane-anesthetized rats that was elicited by electrical stimulation of the nucleus pontis oralis (nPO) in the brainstem. We found that systemic administration of pregabalin significantly reduced the frequency of stimulation-induced hippocampal theta activity similarly to the effects of diazepam. In addition, pregabalin (but not diazepam) significantly altered the stimulus intensity/frequency relationship, and increased slow delta oscillation (<3.0 Hz) in spontaneous hippocampal EEG in a dose-dependent manner. Our findings suggest that pregabalin may alter evoked theta frequency activity in the hippocampus by reducing neurotransmitter-mediated activation of either the septal nucleus or the hippocampus, and that its actions are unlikely to be mediated by direct activation of GABA neurotransmitter systems. These observations provide further insight to the action of pregabalin, and support the utilization of stimulation-induced theta model in discovery of novel anxiolytic drugs.     

Benzodiazepine anti-conflict effects in maudsley reactive (MR/Har) and non-reactive (MNRA/Har) rats

The Maudsley Reactive (MR/Har) and Non-Reactive (MNRA/Har) rat strains, bred originally by Broadhurst for differences in Open Field Defecation, also differ in their control (i.e., non-drug) behavior in the Conditioned Suppression of Drinking (CSD) conflict procedure, a second model behavior for the study of anxiety and/or emotionality in rats. The present studies compared the effects of diazepam and alprazolam on CSD behavior in these two strains of rats. In daily 10-min sessions, water-deprived rats were trained to drink from a tube that was occasionally electrified (0.2–0.5 mA), electrification being signaled by a tone. Both diazepam and alprazolam increased punished responding in a dose-related manner. The per cent increase in punished responding (for diazepam only) was comparable in the two strains; however, both statistical and empirical approaches indicated that the magnitude of the anti-conflict effect of benzodiazepines in MNRA/Har versus MR/Har rats was not related to differences in baseline (i.e., non-drug) punished responding. Based on the absolute change in shocks received, rats of the MNRA/Har strain exhibited a significantly greater anti-conflict effect following diazepam or alprazolam treatment than did rats of the MR/Har strain. These findings further the hypothesis that the behavioral differences exhibited by Maudsley MR/Har and MNRA/Har rat strains may constitute a genetically-based animal model for the study of emotionality and/or anxiety.     

Electroencephalographic study with buspirone, a novel nonbenzodiazepine anxiolytic, and its major metabolite, 1-(2-pyrimidinyl)piperazine (1-PP), in rabbits

The electroencephalographic (EEG) effects of buspirone and its major metabolite, 1-(2-pyrimidinyl)piperazine (1-PP), were investigated in rabbits with chronic electrode implants, and the effects were compared with those of diazepam. Intravenous administration of buspirone at 0.1 to 1.0 mg/kg evoked an increase in the arousal EEG pattern period (low amplitude fast waves) in the cortical EEG and synchronization of the hippocampal theta waves with decreased voltages, whereas both 1-PP (0.5 to 2.0 mg/kg, i.v.) and diazepam (1.0 and 2.0 mg/kg) evoked an increase in the drowsy EEG pattern periods: high voltage slow waves and spindle bursts in the cortical EEG and desynchronization of the hippocampal theta waves. Buspirone at higher doses caused behavioral excitation in rabbits, whereas both 1-PP and diazepam produced sedation. Buspirone did not affect EEG arousal responses to both auditory stimulation (2,000 Hz, monotone) and electrical stimulation (100 Hz, 0.1 msec, 3-6 V) of the midbrain reticular formation or the posterior hypothalamus. However, 1-PP tended to inhibit the EEG arousal response to auditory stimulation but not brain stimulation, and diazepam markedly suppressed the responses induced by both stimulations. The recruiting response induced by centromedian thalamic stimulation at a low frequency (7 Hz, 0.1 msec, 4-8 V) was not affected by buspirone, 1-PP and diazepam. Neither buspirone nor 1-PP had an effect on the photic driving response to a flash light (2 Hz) in the occipital cortex of the rabbit, whereas the response was suppressed by diazepam. Both buspirone and 1-PP enhanced the duration of after discharges induced by electrical stimulation (50 Hz, 0.5 msec, 4-15 V) of the dorsal hippocampus, whereas diazepam markedly inhibited the afterdischarges. These results suggest that the EEG effect of buspirone is quite different to those of 1-PP and diazepam in qualitative aspects. It is also suggested that buspirone, unlike diazepam, is an effective anxiolytic drug without a sedative effect.     

EEG spectral power density profiles during NREM sleep for gaboxadol and zolpidem in patients with primary insomnia

There is significant interest in the functional significance and the therapeutic value of slow-wave sleep (SWS)-enhancing drugs. A prerequisite for studies of the functional differences is characterization of the electroencephalography (EEG) spectra following treatment in relevant patients. We evaluate for the first time gaboxadol and zolpidem treatments in insomniac patients using power spectra analysis. We carried out two randomized, double-blind, crossover studies. Study 1, 38 patients received gaboxadol 10 mg and 20 mg and zolpidem 10 mg; study 2, 23 patients received gaboxadol 5 mg and 15 mg. Treatments were administered during two nights and compared with placebo. Gaboxadol 10, 15 and 20 mg enhanced slow-wave activity (SWA) and theta power. In 1 Hz bins gaboxadol 10 and 20 mg enhanced power up to 9 Hz. In study 2, 15 mg gaboxadol showed a similar effect pattern. Zolpidem suppressed theta and alpha power, and increased sigma power, with no effect on SWA. In the 1 Hz bins zolpidem suppressed power between 5-10 Hz. Gaboxadol dose-dependently increased SWA and theta power in insomniac patients. In contrast, zolpidem did not affect SWA, reduced theta and alpha activity and enhanced sigma power. EEG spectral power differences may be consequences of the different mechanisms of action for zolpidem and the SWS-enhancing agent, gaboxadol.     

Studying the mechanisms of ladasten action

The effect of N-(2-adamantyl)-N-(p-bromophenyl)amine (ladasten) on the behavior of MR and MNRA inbred rats with different emotional-stress reaction (ESR) phenotypes was studied in the conventional open-field test. Ladasten (30 mg/kg, i.p.) produced anxiolytic effect in MR rates, while not influencing MNRA animals. At the same time, a model stress induced disorder in the regulation of 3 H-diazepam binding to the benzodiazepine site of GABA(A) receptor in MR (but not in MNRA) rats. Ladasten administered in the anxiolytic dose prevented stress-induced changes in reception at this site.     

Effect of S-adenosyl-L-methionine sulfate tosylate (FO-1561) on functional recovery after transient cerebral ischemia in rats

The present investigation was undertaken to examine the recovery of functions, spontaneous EEG activity and cerebral ATP content during blood recirculation following cerebral ischemia in rats. The ischemia was induced by bilateral carotid artery 30 min-occlusion 24 hr after the permanent electrocauterization of bilateral vertebral arteries. EEG spectral analysis was performed by the Berg transform. The recovery of EEG activity was assessed by the time elapsing from the onset of blood recirculation until the delta (0.5-4 Hz), theta (4-8 Hz), alpha (8-13 Hz) or beta (13-32 32 Hz) band reappeared and the relative proportion of the four bands at 45 and 60 min after recirculation. Following the 20 min recirculation, the brains were frozen in situ with liquid nitrogen and then stored at -80 degrees C for later extraction for analysis. Concentrations of ATP in the cerebral cortex were determined with enzymatic methods. In animals administered FO-1561 (10 approximately 100 mg/kg, i.v.) simultaneously with blood recirculation, the reduction of time elapsing until reappearance of the theta, alpha and beta bands, the decrease in proportion of the delta band and the increase in that of the theta, alpha and beta bands which indicated the facilitation of transition to the normal state were observed. In animals administered FO-1561 (100 mg/kg), the improvement of ATP content was detected. These results demonstrate that FO-1561 may have a beneficial effect on the recovery from dysfunctions due to cerebrovascular disorder.     

Electroencephalographic (EEG), EEG power spectra, and behavioral correlates in rats given phencyclidine

The electroencephalogram (EEG), electromyogram (EMG) and behavior were monitored in rats with chronic cerebrocortical and temporalis muscle electrodes. They were injected acutely with 0, 2, 4 and 8 mg/kg of phencyclidine (i.p.). The EEG power spectra correlated in a dose-related manner, with the direct EEG and behavioral effects of phencyclidine. At 2 mg/kg, the EEG consisted primarily of low amplitude theta activity from 6 to 8 Hz, accompanied by behavioral arousal and hyperactivity. At 4 mg/kg, the EEG theta activity persisted and was superimposed on a background of high amplitude slow waves which were associated with the emergence of ataxia. Locomotion and stereotypy intensified at this dose. The power spectra of these changes in the EEG were characterized by two distinct spectral peaks lying between 0-5 and 5-10 Hz. After 8 mg/kg, EEG activity shifted predominantly to lower frequencies between 2 and 3 Hz. This shift produced a large increase in spectral power in the 0-5 Hz band which was accompanied behaviorally by severe ataxia, limited locomotion, and stereotypy of head and forepaw movements. Similarities and differences between these EEG changes induced by phencyclidine and the EEG effects of ketamine and SKF 10047 were obtained.     

Alcohol consumption and anti-alcohol effect of afobazol in MR and NMRA rats

Dynamics of the alcohol intake variation in MR and MNRA inbred rats with different emotional-stress reaction (ESR) phenotypes was studied in the course of a 7-month voluntary alcoholization. Initially, the MNRA rats with an active ESR phenotype showed a higher level of a 15% aqueous ethanol consumption than did the MR rats. After 3 months, the consumption of ethanol in the highly emotional MR rats sharply increased and was retained on a high level during subsequent alcoholization. The new anxiolytic agent afobazol [5-ethoxy-2(morpholinoethylthio)-benzimidazole hydrochliride] did not potentiate the CNS depressant action of alcohol. A 2-week administration of afobazol (1 mg/kg, i.p.) after a 6-month alcoholization markedly reduced the alcohol consumption and reduced the craving to alcohol in the rats of both lines studied.     

MR/Har and MNRA/Har Maudsley rat strains: differential response to chlordiazepoxide in a conflict task

The Maudsley Reactive (MR/Har) and Non-Reactive (MNRA/Har) rat strains, selectively bred for differences in open field defecation, have also been shown to differ in their baseline behavior in the Conditioned Suppression of Drinking (CSD) procedure, a second "model" behavior for the study of anxiety and/or emotionality in rats. The present studies were designed to compare the responsiveness of these two strains to the typical antianxiety agent chlordiazepoxide in the CSD paradigm. In daily 10-minute sessions, water-deprived rats were trained to drink from a tube that was occasionally electrified (0.5 mA), electrification being signaled by a tone. Consistent with previous reports, after several weeks of CSD testing, MNRA/Har rats accepted significantly more shocks than did MR/Har rats during control (nondrug) sessions. In both strains, the number of shocks accepted was inversely related to the intensity of the shock used (0.25-1.0 mA), with MNRA/Har rats accepting significantly more shocks than MR/Har rats at all intensities examined. The effects of various doses (1.25-28.4 mg/kg, IP) of chlordiazepoxide were determined in subjects of the MNRA/Har strain at the original training intensity (0.5 mA), while a lower intensity (0.25 mA) was utilized in MR/Har rats. Although punished responding in control (i.e., nondrug) CSD sessions did not differ under these conditions, MNRA/Har rats were found to be more responsive to the anticonflict effects of chlordiazepoxide than rats of the MR/Har strain. This strain difference in anticonflict efficacy of chlordiazepoxide was quite dramatic, with MNRA/Har rats accepting twice as many shocks as MR/Har rats following maximally effective doses of chlordiazepoxide. Low doses of chlordiazepoxide increased water intake slightly, while higher doses decreased water intake. Surprisingly, the chlordiazepoxide-induced depression of water intake was greater in rats of the MR/Har strain. Thus, these Maudsley Reactive and Non-Reactive rat strains, bred originally for their differences in open field behavior, also differ markedly in their responsiveness to chlordiazepoxide in the CSD paradigm. These findings further support the hypothesis that the MR/Har and MNRAHar rat strains may represent a genetically-based "animal model" for the study of emotionality and/or anxiety.     

Effects of antidepressants and related drugs on the quantitatively analyzed EEGs of beagles

Power spectral analysis was applied to beagles' EEGs to determine if clinically effective antidepressants produce changes different from those produced by related drugs. Bipolar EEGs were recorded from screws chronically implanted in the skull 5 mm anterior and 10 mm posterior to bregma, 4 mm left of midline. The normalized spectral estimates obtained after intravenous drug injection (minus the temporally corresponding spectral estimates after saline) were averaged across dogs. Drug effects were related to dose and time. Reliable effects of imipramine, amitriptyline, desipramine, and mianserin were an increase in the percent of power in the 4.5–7.5 Hz (theta) band, an increased percent of power in the alpha band at low doses, a decreased percent of power above 22 Hz (beta-2), and an increased total spectral absolute power, at doses that produced no symptoms. Chlorpromazine's EEG effects were similar to the antidepressants'. Atropine increased percent theta and decreased percent beta-1 and beta-2, but was distinguished from the above drugs since it also increased percent delta and produced symptoms at the lowest effective dose. The other drugs either had no effect on percent theta (physostigmine) or decreased it (chlordiazepoxide, dextroamphetamine, and cocaine); cocaine increased only percent delta. Chlordiazepoxide, dextroamphetamine, and physostigmine increased percent beta-1 and/or beta-2, and they either decreased total power (dextroamphetamine) or produced no change in this parameter, and thus were distinguished from antidepressants. The results support the conclusion that antidepressants have distinct acute effects on brain electrical activity, and suggest that novel antidepressants can be detected by EEG spectral analysis in dogs.     

Multiparametric analysis of the effect of ethanol in various doses on EEG in rats

Multiparametric EEG analysis (840 parameters) was performed for 24 points over the entire dorsal cerebral cortex in outbred rats intraperitoneally injected with ethanol in low (0.75 g/kg), medium (2.0 g/kg), and high subnarcotic (4.5 g/kg) doses. Acute intoxication with low ethanol doses led to an increase in the spectral power and coherence in the frequency band of the dominating theta-rhythm peak (5.75-7.25 Hz), which was indicative of activation of the septo-hippocampal system (with improvement of the related functions such as attention, memory, and exploratory activity). The coherence was also increased in several high-frequency bands of the EEG alpha- and beta-rhythm. Ethanol administered in medium and high doses produced a shift of the dominating theta-rhythm peak to lower frequencies (4.50-5.75 Hz), which was evidence of reduced activity of the septo-hippocampal system and the related CNS functions. These doses of ethanol significantly decreased the spectral power and coherence in most of the high-frequency bands of the EEG alpha- and beta-rhythm, which can be explained by reduced energy and synaptic activity of the cortex leading to impaired high brain functions and the development of somnolent and narcotic effects. Using special sets of reliably modified parameters and a special algorithm, it is possible to solve the inverse problem of identifying experiments (EEG fragments) corresponding to low, medium, and high doses of ethanol.     

Power and coherence analysis of the EEG in hospitalized alcoholics and nonalcoholic controls

EEG recordings from 56 alcoholics (20 women) and 9 nonalcoholic controls (15 women) were compared using power spectral density and coherence techniques. Alcoholics had more power in the delta frequency bands (1-4 Hz) and less power in alpha (9-13 Hz) from all regions of the skull. Interhemispheric coherence scores from homologous brain sites were greater for alcoholics in the delta band (1-4 Hz) but greater for nonalcoholics in the higher frequencies. Among alcoholics, power in the alpha bandwidth was positively correlated with Brain Age Quotient (BAQ) scores, whereas delta power was inversely related to BAQ scores. Increased power in the beta frequencies (14 + Hz) among alcoholics was a function of the time elapsed since the last drink and the use of chlordiazepoxide during detoxication. Issues relating to transient brain dysfunction in recently abstaining alcoholics are also discussed.     

EEG power spectra and auditory P300 during free smoking and enforced smoking abstinence

We investigated resting EEG and auditory P300 during free smoking and 36 h of enforced smoking abstinence in 12 healthy volunteers. Resting EEG was recorded on 19 scalp leads and auditory P300 was obtained by an oddball paradigm task. Spectral analysis of EEG (absolute and relative power, mean frequency), latency and amplitude of auditory P300 were considered for statistical analysis. EEG changes were not significant during free smoking but were significant during smoking abstinence. Theta absolute power increased by +57% (P<.001), whereas alpha and delta absolute power increased by +26% (P<.01) and +19% (P<.01), respectively; theta absolute power change was delayed and prolonged. Alpha mean frequency reduced by -0.31 Hz (P<.001), whereas delta, theta and beta1 mean frequency increased by +0.13 Hz (P<.05), +0.09 Hz (P<.05) and +0.23 Hz (P<.01), respectively. Auditory P300 amplitude and latency were unaffected by smoking abstinence. Resting EEG, but not auditory P300, was sufficiently sensitive to detect changes during enforced smoking abstinence, and EEG bands had different temporal changes.     

Neuropharmacological profile of clobazam,a new 1′, 5′-benzodiazepine

The effect of the new 1,5-benzodiazepine clobazam on visual evoked potentials (VEP) and spontaneous EEG in the conscious rabbit and on spinal polysynaptic reflexes in the decerebrated cat was studied in comparison to the 1,4-benzodiazepine diazepam. Clobazam was half as potent as diazepam in depressing the amplitude of visual evoked potentials in the nonanaesthetized rabbit, whereas the depressing effect on spinal polysynaptic reflexes in the decerebrated cat was only 1/7–1/30 of the diazepam effect. The action of clobazam and diazepam on VEP also showed differences in time course, i.e., the peak effect of clobazam lasted from 1 to 6 h after application, whereas the effect of diazepam appeared after 10min and declined already after 1 h. Both compounds had similar effects on computer-analyzed spontaneous EEG in the rabbit (power spectrum analysis), with an increase of power in the beta-band (13–39 Hz) and a decrease in the alpha (8–13 Hz) and theta (4–8 Hz) bands.Clobazam (Frisium^®) is a new psychotropic drug of Hoechst AG, Frankfurt/Main