Mean power spectra from pharmaco-electrocorticographic studies: relative baseline correction and log transformation for a proper analysis of variance to assess drug effects.

The effects of drugs on electrocorticographic activity (ECoG) of the rat are studied in a routine screen. ECoG is recorded for 6-min periods before drug/vehicle administration and starting at 20 and 45 min thereafter. For each period, a mean power spectrum is calculated. Drugs are tested in 25 rats according to a 5 x 5 Latin square design and effects are assessed with analysis of variance. The validity of this assessment depends on assumptions on the chosen statistical model and the distribution of the data. In this study we consider the relative and absolute baseline corrected data. The assumptions appear to be better fulfilled if together with a relative baseline correction a logarithmic transformation is applied to the data.

Antidepressant and anxiolytic profiles of E-10-hydroxynortriptyline on electrocorticograms of rats.

Electrocorticograms of rats were recorded after administration of increasing doses of the major metabolite of nortriptyline (NT), E-10-hydroxynortriptyline (E-10-OH-NT). The results were compared with those of NT administration. In visual as well as computerized evaluations, E-10-OH-NT demonstrated clear antidepressant properties, thus confirming previous experiments in depressed patients. There is some evidence that E-10-OH-NT also has an anxiolytic profile. The results with the parent drug NT were not so pronounced. Since E-10-OH-NT has been shown to be devoid of side effects when previously administered to humans, this substance is clearly to be considered of interest for potential development into a new antidepressant. Whether or not the anxiolytic profile is of clinical interest needs to be investigated further.

Classification of psychotropic drugs based on pharmaco-electrocorticographic studies in vigilance-controlled rats.

The effects of a number of psycho-active drugs on electrocorticographic activity (ECoG) of the rat have been studied. Frontoparietal ECoG was recorded during 6-min periods immediately before drug/vehicle administration and starting at 20 and 45 min after administration. For each 6-min recording time, a mean power spectrum was calculated and smoothed. A quotient of the power at 20 and 45 min after and before drug, respectively, was then calculated. These quotients were used as input for an analysis of variance, followed by a t test and a normalization for the degrees of freedom, resulting in so-called n-profiles. Although each drug has its own characteristic n-profile, n-profiles of drugs belonging to the same clinical class have some characteristics in common. An automated classification system of psychotropic drugs, based on parameters extracted from n-profiles by discriminant analysis, is presented. For the antidepressant drug class the success rate of correct classification of antidepressant drugs is between 53 and 88%, for a neuroleptic drug in the neuroleptic drug class the success rate is 87%, for an anxiolytic drug in the anxiolytic drug class 100% and for a psychostimulant drug in the psychostimulant drug class between 86 and 100%. For a reliable classification of a drug about 10 n-profiles of active doses are needed. Using n-profiles, it appeared also possible to discriminate between antidepressant, neuroleptic, anxiolytic and psychostimulant drugs based on visual judgement. Moreover, visual evaluation of the n-profiles enables 4 subclasses to be recognized within the antidepressant class, 2 subclasses within the neuroleptic and 2 subclasses within the anxiolytic class.

Effects of depressant amino acids and antagonists on an in vitro spinal cord preparation from the adult rat.

A mature sacrococcygeal in vitro spinal preparation from the rat has been used to demonstrate effects of neutral amino acids and their antagonists. gamma-Aminobutanoate (GABA), glycine and taurine (0.5-5 mM) produced dose-dependent depression of spontaneous paroxysmal activity generated in Mg2+ -free medium. The depressant effect of GABA was antagonised selectively by picrotoxin (25-50 microM) and the depressant effects of glycine and taurine were antagonised selectively by strychnine (0.2 microM). Glycine (0.5-5 mM) had a dose-dependent depolarizing action which was present at the central ends of isolated ventral roots. gamma-Aminobutanoate and taurine, had only weak depolarizing actions on ventral root fibres. Depolarizing responses to glycine showed a marked fading. Reduction in the fading appeared to be responsible for a paradoxical potentiation of glycine-induced depolarizations, which occurred in the presence of strychnine (0.2-2 microM). Strychnine (2-10 microM), picrotoxin (10-50 microM) or bicuculline (10 microM) had little or no effect on the amplitude, duration or latency of the monosynaptic component of ventral root reflexes evoked by supramaximal stimulation of dorsal roots (DR-VRP). However all three antagonists introduced slow, NMDA receptor mediated, components to these ventral root potentials. Picrotoxin and bicuculline, but not strychnine, reversibly depressed the dorsal root potential evoked from an adjacent dorsal root (DR-DRP). The depressant actions of 2-amino-5-phosphonopentanoate (AP5), kynurenate and 3-((+/-)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) revealed both NMDA and non-NMDA receptor mediated components in the dorsal root potential.

Relationship between electrocortical activity and beta-adrenergic receptor function in the rat after chronic desimipramine treatment.

The aim of this study was to investigate the effects of chronic administration of desimipramine (DMI) after 2, 7 or 20 mg/kg per day, administered by osmotic minipumps, on electrocortical activity and beta-adrenergic receptors in rat brain. Rats receiving DMI chronically show a dose- and time-dependent increase of electrocortical activity above 15 Hz as well as a dose- and time-dependent decrease below 15 Hz. Already after 3 days of treatment a clear effect on the electrocorticogram (ECoG) was seen. The maximal change in the ECoG was reached at the end of the study, after 24 days of treatment. After acute treatment (20 and 45 minutes after 2, 4 or 10 mg/kg i.p.) with DMI, a decrease of electrocortical activity is seen above 15 Hz. Thus the effect of acute DMI treatment on the ECoG is different from that of chronic treatment. In the same group of rats the effect of chronic DMI treatment on the beta-adrenergic receptor number was determined 24 hours after the last ECoG recording. The number of beta-adrenergic receptors was dose dependently reduced in the DMI-treated rats as determined by [3H]-dihydroalprenolol binding. There was no change in affinity (KD) of the ligand for the beta-receptor. This finding was corroborated by a decrease in the functional activity of the beta-adrenergic receptors, as determined by isoprenaline stimulated efflux of cyclic-AMP in cortex slices. These data indicate that chronic treatment with DMI, resulting in a down-regulation of the cortical beta-adrenergic system, is paralleled by pronounced effects on the ECoG of rats. The different ECoG profiles after chronic DMI treatment compared with acute treatment suggest that adaptive changes in the electrical brain activity continually develop during the chronic treatment with this antidepressant drug.

An in vitro mature spinal cord preparation from the rat.

The preparation of an isolated hemisected spinal cord preparation, maintained in vitro, from mature (180-300 g body weight) rats is described. Sacral and coccygeal segments (S2-Co1) gave consistent ventral root reflexes (DR-VRP) from electrical stimulation of dorsal roots. The mean latency and amplitude of the fastest component in the ventral root reflex, at 25 degrees C, were 1.6 msec +/- 0.4 SE mean and 8.2 mV +/- 0.9 SE mean, respectively (28 preparations). This component was resistant to the NMDA antagonist, 2-amino-5-phosphonopentanoate (AP5) but was depressed markedly by kynurenate. A slow component of the ventral root reflex, which was sensitive to AP5 was enhanced and spontaneous AP5-sensitive synaptic potentials sensitive to AP5 appeared in the absence of magnesium ions. The excitant amino acids L-aspartate, L-glutamate, N-methyl-D-aspartate (NMDA), kainate and quisqualate produced dose-dependent depolarizing responses in the ventral roots. The relative depolarizing potencies +/- SE mean (N) of NMDA, kainate and quisqualate, relative to L-glutamate = 1, were 96 +/- 30 (6), 234 +/- 57 (6) and 145 +/- 40 (5), respectively. These properties, apart from reduced latency of synaptic responses, are similar to those described previously for preparations from immature animals. However, it will be easier with the mature preparation to selective activate high and low threshold primary afferents.

Classification of psychotropic drugs by rat EEG analysis: the anxiolytic profile in comparison to the antidepressant and neuroleptic profile.

Electroencephalograms were recorded from the parietal and frontal cortex of freely moving rats held in constant vigilance by placing them in a slowly turning drum. The effects of 5 clinically effective anxiolytics, buspirone, meprobamate, phenobarbital, chlordiazepoxide and diazepam, were studied after intraperitoneal injection of different doses. After on-line fast Fourier transformation of the EEG signal, the drug effects were quantified by an Analysis of Variance. This resulted in a t profile for each drug dosage. Averaging the t profiles of all dosages of a drug results in a 'drug profile'. Averaging the drug profiles of the 5 anxiolytic drugs tested results in an 'anxiolytic profile'. This profile is characterized by a power decrease from 8 to 11 Hz and above 70 Hz and a power increase from 20 to 60 Hz. The anxiolytic profile is compared with the formerly defined antidepressant and neuroleptic profiles and can be clearly distinguished from the latter two.

Classification of psychotropic drugs by rat EEG analysis: learning set development.

EEG recordings from 5 different brain areas of freely moving rats were performed under controlled vigilance stage conditions. Effects of antidepressant and neuroleptic drugs were assessed following their intraperitoneal injection. Quantification of the drug effects was achieved by analysis of variance following on-line fast-Fourier transformation of the EEG signal. This resulted in so-called drug profiles. From the individual antidepressant and neuroleptic drug profiles, an antidepressant and neuroleptic drug class profile was calculated. Using the absolute power for the calculation of the antidepressant and neuroleptic drug class profiles gave a better discrimination between the two drug class profiles than using the relative power. The antidepressant and neuroleptic drug class profiles derived from the n. amygdala and hippocampus did not show significant differences. The antidepressant and neuroleptic drug class profiles showed significant differences (p less than 0.05) in rather small frequency bands from the n. caudatus (16-14 Hz), n. accumbens septum (19-24 and 27-31 Hz) and cortex (10-20 Hz).

Comparison of the (pro)convulsive properties of fluvoxamine and clovoxamine with eight other antidepressants in an animal model.

Freely moving rats were implanted with cortical, caudal, thalamic, and reticular electrodes. Drugs were infused intravenously at a constant rate up to a final cumulative dose of 40, 50, or 60 mg/kg. Doses of 10 mg/kg imipramine, viloxazine, desmethylimipramine, mianserin, and maprotiline produced spike-wave complexes, spikes, and increased spindling. General sustained discharges occurred after 20 mg/kg of mianserin, viloxazine, imipramine, desmethylimipramine and amitriptyline, and after 30 mg/kg of maprotiline. An abnormal high-amplitude pattern was evident after mianserin, amitriptyline, imipramine, and desmethylimipramine. On the average, seizures were observed at 40 mg/kg and were seen after desmethylimipramine (50 mg/kg), mianserin (30 mg/kg), amitriptyline (20 mg/kg), imipramine (40 mg/kg), maprotiline (40 mg/kg), and zimelidine (50 mg/kg). Ranking the tested antidepressants in decreasing order in accordance with their relative (pro)convulsive properties gives: amitriptyline greater than mianserin much greater than imipramine greater than desmethylimipramine greater than viloxazine much greater than maprotiline much greater than zimelidine greater than clovoxamine greater than nomifensine = fluvoxamine.

Effects of antidepressants on the EEG of the rat.

The aim of the study was to detect whether antidepressants cause specific EEG effects in rats. The results presented are based on quantitative evaluation of a series of 6-min vigilance-controlled EEG recordings in rats under standardized conditions. Standard conditions comprised: a vigilance control, a rigid test procedure in which drugs and rats are divided according to a Greek-Latin square, and the same electrode placement. Computer analyses are based on an analysis of variance for which the averaged power spectral values are used as input. The use of a moving window technique in this type of EEG studies is introduced in comparison to the well-known use of fixed frequency bands. A number of antidepressants have been tested and several common characteristics are found.