Quantitative EEG analysis of a single dose of psychotropic drugs in healthy probands

In a series of 74 experiments in a double blind study, 25 healthy test persons were medicated with a single dose of Clomipramin, Desipramin, Imipramin, Diazepam, Carbamazepin, Haloperidol, and a placebo. At the end of one hour, and again at the end of three hours, an EEG was made whose frequency analysis revealed significant changes in about half the test persons. The antidepressives induced an increase in the theta waves, the slow alpha waves, and the slow beta waves, and a decrease in the fast alpha waves. The factors influencing the EEG are discussed.     

The pre-delirium syndrome in alcoholic patients in ambulatory care and its treatment

In an administrative district of roughly 70,000 inhabitants, two-thirds urban, one-third rural, 60 patients, 46 male, 14 female, received out-patient treatment for alcoholic predelirious syndromes during the period 1982-1986. The total number of predeliorious attacks was 91, age incidence lay between 18 and 65, peaking at 35 to 45. In 61.7% of the cases only one predelirious attack occurred, in 28.3% two, and in 10.0% three or more. Through the period there is a perceptible rising tendency. In eight cases there was an epileptic grand mal fit in the course of a predelirious attack. Out-patient treatment was successful in all but three cases, which definitely called for hospitalised treatment. Diazepam, Diazepam/Haloperiodol, and Distraneurin were administered orally as a regular part of the program of treatment. 30 times Diazepam and Haloperidol effected a cure, while in 61 attacks it appeared that treatment with Chlormethiazol was inevitable. Results are discussed and conclusions drawn.     

Effect of diazepam on visuomotor reaction time

20 male and 10 female adult, normal, healthy subjects, whose mean age was 26.34 yr., participated in a double-blind study of the effect of a single dose (0.2 mg./kg. of body weight) of diazepam on visuomotor reaction time. Reaction time was measured before drug administration, and 60 min., and 120 min. after administration. Separate reaction times for the dominant and nondominant hand were recorded. There were no significant differences between the diazepam and placebo group at each of the three time intervals. Diazepam in the single dose employed does not appear to affect adversely visuomotor reaction time of relatively young, normal, healthy adults. For both groups the difference in visuomotor reaction time between the dominant hand and the nondominant hand was statistically significant as expected.     

Diazepam-induced impairment of a go-no go successive discrimination

Diazepam (2.0 and 4.0 mg/kg, but not 1.0 mg/kg) administered in eight acquisition sessions significantly impaired the light-cued successive discrimination of male Sprague-Dawley rats. In two postdrug (vehicle) sessions, groups previously treated with the drug demonstrated good recovery in discrimination. An analysis of response components indicated that the impairment was due to the failure of drugged subjects to inhibit or withhold responses during the no go periods of the task. These findings are consistent with a "disinhibitory hypothesis" of drug impairment. The similarity of the present findings to those previously reported with chlordiazepoxide suggests that such effects are a generalized characteristic of the benzodiazepine class of drugs.     

Reversal of retrieval impairment caused by retroactive interference on a two-way active avoidance task in rats

Rats were exposed to an open field with flashing light (OFL; 60-W lamp, 30 Hz, for 7 min) 2 h after training and/or 2 h before testing in a two-way active avoidance task (30 trials, 0.5-mA footshock). Post-training OFL presentation caused retroactive interference, i.e., a retrieval impairment/amnesia for the avoidance task. Pretest OFL exposure reversed the post-training OFL-induced retrieval deficit. Diazepam (2.0 mg/kg), atropine (2.0 mg/kg), and methylatropine (0.1 mg/kg) administered before post-training OFL presentation blocked the OFL amnesic effect. However, these drugs did not counteract the pretest OFL-induced recovery of retrieval. Atropine and methylatropine administered 2 h before testing to rats receiving only post-training OFL presentation canceled the OFL-interfering effect. These results suggest: (1) that the amnesic effect of post-training OFL is due to failure of retrieval of the avoidance task, (2) that the reversal of this retrieval impairment by pretest OFL exposure may involve either priming or state-dependent mechanisms, and (3) that there are different modulatory mechanisms involved in post-training and pretest OFL effects.     

Cholinergic-dopaminergic interactions in radial-arm maze performance

Although acetylcholine and dopamine are believed to play complementary roles in motor function, a comparable neurochemical interaction has not been established for cognitive function. The muscarinic receptor blocker scopolamine and the dopaminergic antagonist haloperidol have been found to impair choice accuracy of rats in the radial-arm maze. In the present study, low doses of these two drugs were administered intraperitoneally either alone or in combination to rats trained on a working memory task (food reward) in an eight-arm radial maze. Scopolamine, 0.125 mg/kg, produced a significant decrease in choice accuracy (i.e., arm entries until an error). Haloperidol, 0.0625 mg/kg, did not cause a significant decrease in accuracy, but there was a trend in that direction. The combination of haloperidol with scopolamine attenuated significantly the amnestic effect of scopolamine. These results suggest that, like motor behavior, cognitive function may be influenced by the balance between acetylcholine and dopamine.     

Behavioral performance effects of verapamil in normotensive and renovascular hypertensive baboons

Behavioral performances of normotensive and hypertensive adult male baboons were tested before, during, and following chronic oral dosing with verapamil. Performances during a five-color simultaneous match-to-sample task were measured for two doses (2.0, and 3.2 mg/kg/day) and vehicle. Each dose was administered for 21 consecutive days preceded and followed by 14-day baseline and recovery periods, respectively. Choice reaction times increased by 9% during the lower dose of verapamil, compared to vehicle; choice reaction times were unchanged at the higher dose. At baseline and during vehicle administration, the yellow and white stimuli were the most difficult to discriminate correctly; discrimination of these colors was slightly impaired by the lower, but not the higher dose of verapamil. Verapamil’s behavioral effects were not modulated by blood pressure changes since both baboon groups showed equivalent changes in behavioral performance, but only renovascular hypertensive baboons showed blood pressure decreases. Verapamil appears to be an effective hypotensive and does not produce profound psychomotor impairment at clinically used doses during the first weeks of treatment.     

Behavioral performance effects of verapamil in normotensive and renovascular hypertensive baboons.

Behavioral performances of normotensive and hypertensive adult male baboons were tested before, during, and following chronic oral dosing with verapamil. Performances during a five-color simultaneous match-to-sample task were measured for two doses (2.0, and 3.2 mg/kg/day) and vehicle. Each dose was administered for 21 consecutive days preceded and followed by 14-day baseline and recovery periods, respectively. Choice reaction times increased by 9% during the lower dose of verapamil, compared to vehicle; choice reaction times were unchanged at the higher dose. At baseline and during vehicle administration, the yellow and white stimuli were the most difficult to discriminate correctly; discrimination of these colors was slightly impaired by the lower, but not the higher dose of verapamil. Verapamil's behavioral effects were not modulated by blood pressure changes since both baboon groups showed equivalent changes in behavioral performance, but only renovascular hypertensive baboons showed blood pressure decreases. Verapamil appears to be an effective hypotensive and does not produce profound psychomotor impairment at clinically used doses during the first weeks of treatment.     

Effects of cocaine on simple reaction times and sensory thresholds in baboons.

The effects of chronic, daily administration of cocaine on auditory and visual reaction times and thresholds were studied in baboons. Single intramuscular injections of cocaine hydrochloride (0.1 to 5.6 mg/kg) were given once daily for periods of 10 to 25 days, and were followed immediately by psychophysical tests designed to assess cocaine's effects on simple reaction times as on auditory and visual threshold functions. Consistent reductions in reaction times were frequently observed over the cocaine dose range of 0.32 to 1.0 mg/kg; at higher doses, either decreases or increases in reaction times were observed, depending upon the animal. Lowered reaction times generally occurred immediately following the 1st day's cocaine injection, and continued through all subsequent days during the dose administration period, suggesting little development of tolerance or sensitivity to these reaction-time effects. Reaction-time decreases showed a U-shaped dose-effect function. The greatest decreases in reaction times occurred from 0.32 to 1.0 mg/kg, and produced an average reaction-time decrease of 10 to 12%. Concurrently measured auditory and visual thresholds showed no systematic changes as a function of cocaine dose. Pausing was observed during performance of the psychophysical tasks, with the length of total session pause times being directly related to cocaine dose.     

Well‐being and the accessibility of pleasant and unpleasant concepts

The trait–congruency hypothesis predicts that persons high in positive or negative trait affect more readily process pleasant or unpleasant stimuli, respectively. In two studies, participants were administered measures of personality and affect. Moreover, a yes/no lexical decision task with pleasant, unpleasant and neutral words was administered in Study 1, whereas a go/no‐go task was used in Study 2. Several methods to increase reliabilities of differences in reaction times are explored. Correlations of measures of personality and trait affect with decision times were mostly consistent with the trait–congruency hypothesis, particularly for decision times in the go/no‐go task that measured individual differences in valence‐specific decision times more reliably. The findings suggest that trait‐related concept accessibility is one source of trait congruity. Copyright © 2006 John Wiley & Sons, Ltd.     

Effects of chlorpromazine on lateralization, cued reaction time, and dichotic listening

In a double-blind cross-over design sixteen subjects took 50 mg of chlorpromazine or placebo in tablet form 2 hours prior to completing a dichotic listening and simple reaction time task with and without warnings. In the simple reaction time task, blocks of 80 stimuli were presented to each ear with and without warning cue under drug and placebo conditions. On the dichotic listening task the expected right ear advantage for reporting digits was obtained. While the drug had no main effect on the number of errors, there were more trials on which an ear advantage was present than in the placebo condition. In the reaction time task there were main effects of drug, warning cue and foreperiod: warnings facilitated reaction; chlorpromazine retarded reaction; and reaction times were most facilitated by warning foreperiods in excess of 1200ms. Several findings were of interest: On uncued trials, with placebo, right ear responses were faster than those for stimuli presented to the left ear. Drug also interacted with foreperiod duration. These results were interpreted in the light of Tucker and Williamson’s (1984) review of the role of Pribram and McGuinness’s Arousal and Activation sytems in lateralized behavior.     

Effects of chlorpromazine on lateralization,cued reaction time,and dichotic listening

In a double-blind cross-over design sixteen subjects took 50 mg of chlorpromazine or placebo in tablet form 2 hours prior to completing a dichotic listening and simple reaction time task with and without warnings. In the simple reaction time task, blocks of 80 stimuli were presented to each ear with and without warning cue under drug and placebo conditions. On the dichotic listening task the expected right ear advantage for reporting digits was obtained. While the drug had no main effect on the number of errors, there were more trials on which an ear advantage was present than in the placebo condition. In the reaction time task there were main effects of drug, warning cue and foreperiod: warnings facilitated reaction; chlorpromazine retarded reaction; and reaction times were most facilitated by warning foreperiods in excess of 1200ms. Several findings were of interest: On uncued trials, with placebo, right ear responses were faster than those for stimuli presented to the left ear. Drug also interacted with foreperiod duration. These results were interpreted in the light of Tucker and Williamson’s (1984) review of the role of Pribram and McGuinness’s Arousal and Activation sytems in lateralized behavior.     

The effects of intravenous diazepam and hyoscine upon human memory

Diazepam and hyoscine are known to have amnesic effects when administered intravenously. The two drugs are pharmacologically quite different from each other and might be expected to produce qualitatively distinct patterns of impairment in formal memory tasks. Groups of normal volunteers received intravenous administrations of diazepam, hyoscine and saline following a double-blind procedure and were then tested on immediate serial recall. Diazepam and hyoscine produced similar deficits on concrete and abstract words whether scored for ordered recall or item recall. In terms of ordered recall, phonemic similarity produced impaired performance under all three administrations, but semantic similarity did not. In terms of item recall, diazepam and hyoscine produced impaired performance on unrelated words, but the impairment was reduced under conditions of either phonemic or semantic similarity. There were also some interesting differences between diazepam and hyoscine in terms of their effects upon the shape of the serial-position curve and upon the types of intrusion error. The results confirm that both diazepam and hyoscine impair acquisition processes but fail to distinguish the effects of the two drugs upon different categories of encoding operations.     

Repeated diazepam administration reversed working memory impairments and glucocorticoid alterations in the prefrontal cortex after short but not long alcohol-withdrawal periods

The study was designed to assess whether repeated administration of diazepam (Valium®, Roche)—a benzodiazepine exerting an agonist action on GABA_A receptors—may alleviate both the short (1 week, 1W) and long-term (6 weeks, 6W) deleterious effects of alcohol withdrawal occurring after chronic alcohol consumption (6 months; 12% v/v) in C57/BL6 male mice. More pointedly, we first evidenced that 1W and 6W alcohol-withdrawn mice exhibited working memory deficits in a sequential alternation task, associated with sustained exaggerated corticosterone rise and decreased pCREB levels in the prefrontal cortex (PFC). In a subsequent experiment, diazepam was administered i.p. for 9 consecutive days (1 injection/day) during the alcohol withdrawal period at decreasing doses ranging from 1.0 mg/kg to 0.25 mg/kg. Diazepam was not detected in the blood of withdrawn mice at the time of memory testing, occurring 24 hours after the last diazepam injection. Repeated diazepam administration significantly improved alternation rates and normalized levels of glucocorticoids and pCREB activity in the PFC in 1W but not in 6W withdrawn mice. Thus, repeated diazepam administration during the alcohol-withdrawal period only transitorily canceled out the working memory impairments and glucocorticoid alterations in the PFC of alcohol-withdrawn animals.     

d-Amphetamine-chlorpromazine antagonism in a food reinforced operant

Dose effect curves for d-amphetamine and chlorpromazine were obtained with rats on a milk reinforced FR 10 schedule. A dose of d-amphetamine (2.5 mg/kg, i.p.) which completely suppressed all responding for 60 min was administered simultaneously (concomitant with the pretreatment times) with various doses of chlorpromazine. The d-amphetamine-induced cessation of responding was removed by several of the doses of chlorpromazine with maximal antagonism occurring at a dose of 1.5 mg/kg i.p. This dose of chlorpromazine, when administered independently, produced no observable side effects and showed no effect on the FR 10 schedule. One animal appeared to develop tolerance to the repeated dosages of d-amphetamine.     

ADHD and Behavioral Inhibition: A Re-examination of the Stop-signal Task

The current study investigates two recently identified threats to the construct validity of behavioral inhibition as a core deficit of attention-deficit/hyperactivity disorder (ADHD) based on the stop-signal task: calculation of mean reaction time from go-trials presented adjacent to intermittent stop-trials, and non-reporting of the stop-signal delay metric. Children with ADHD (n = 12) and typically developing (TD) children (n = 11) were administered the standard stop-signal task and three variant stop-signal conditions. These included a no-tone condition administered without the presentation of an auditory tone; an ignore-tone condition that presented a neutral (i.e., not associated with stopping) auditory tone; and a second ignore-tone condition that presented a neutral auditory tone after the tone had been previously paired with stopping. Children with ADHD exhibited significantly slower and more variable reaction times to go-stimuli, and slower stop-signal reaction times relative to TD controls. Stop-signal delay was not significantly different between groups, and both groups’ go-trial reaction times slowed following meaningful tones. Collectively, these findings corroborate recent meta-analyses and indicate that previous findings of stop-signal performance deficits in ADHD reflect slower and more variable responding to visually presented stimuli and concurrent processing of a second stimulus, rather than deficits of motor behavioral inhibition.     

Influence of anabolic steroid on anxiety levels in sedentary male rats

The aim of this study was to evaluate the influence of nandrolone decanoate on anxiety levels in rats. Male Wistar rats were treated with nandrolone decanoate (5mg/kg, two times per week, i.m.) or vehicle (propylene glycol--0.2 ml/kg, two times per week, IM) for 6 weeks. Control rats were subject only to procedures related to their routine husbandry. By the end of 6 weeks, all groups (24-29 rats/group) were submitted to the elevated plus maze test in order to evaluate their anxiety level. Some of these animals (12-14/group) were treated with diazepam (1 mg/kg i.p.) 30 min before the elevated plus maze test. Nandrolone decanoate significantly decreased the percentage of time spent in the open arms (1.46+/-0.49%) compared with control (3.80+/-0.97%) and vehicle (3.96+/-0.85%) groups, with no difference between control and vehicle treatments. The percentage of open arm entries was also reduced in the group treated with nandrolone decanoate in comparison with the vehicle and control. No changes in the number of closed arm entries were detected. Diazepam abolished the effects of nandrolone decanoate on the percentage of time in, and entries into the open arms. The present study showed that chronic treatment with a high dose of nandrolone decanoate increased the anxiety level in male rats.     

Fractioned Reaction Ttme in Power-Trained and Endurance-Trained Athletes under Conditions of Fatiguing Isometric Exercise

Fractionated knee extensor and plantar flexor reaction time (RT) components were assessed in a group of eight weightlifters and eight long distance runners. Following a 4-day period of baseline stabilization for each muscle group, a 50% maximal voluntary contraction (MVC) holding-time exercise was administered. Results showed that the runners had longer premotor times (PMT) than the weightlifters in the knee extensors, but had much faster PMTs than the lifters in the plantar flexor condition. Compared to previously reported investigations using non-athletes, the data for the present sample of athletes indicated faster total reaction times (TRT) in both the knee extensors and the plantar flexors. A resistance of 15% MVC applied during the RT task resulted in a lengthening of the motor time (MT) component in both groups prior to exercise. However, while knee extensor resisted motor time was lengthened by the exercise task, no such lengthening occurred in plantar flexor resisted RT. It is concluded that power-trained and endurance-trained athletes exhibit differences in response to a fractionated RT task, under both baseline and fatiguing exercise conditions.     

Fractioned reaction time in power-trained and endurance-trained athletes under conditions of fatiguing isometric exercise

Fractionated knee extensor and plantar flexor reaction time (RT) components were assessed in a group of eight weightlifters and eight long distance runners. Following a 4-day period of baseline stabilization for each muscle group, a 50% maximal voluntary contraction (MVC) holding-time exercise was administered. Results showed that the runners had longer premotor times (PMT) than the weightlifters in the knee extensors, but had much faster PMTs than the lifters in the plantar flexor condition. Compared to previously reported investigations using non-athletes, the data for the present sample of athletes indicated faster total reaction times(TRT) in both the knee extensors and the plantar flexors. A resistance of 15% MVC applied during the RT task resulted in a lengthening of the motor time (MT) component in both groups prior to exercise. However, while knee extensor resisted motor time was lengthened by the exercise task, no such lengthening occurred in plantar flexor resisted RT. It is concluded that power-trained and endurance-trained athletes exhibit difference in response to a fractionated RT task, under both baseline and fatiguing exercise conditions.     

SUBJECTIVE ESTIMATION OF DRUG-INDUCED CHANGES IN ACTIVATION LEVEL

For comparative evaluation of the subjective effects of 50 mg chlorpromazine, 0.10 g amobarbital and 10 mg amphetamine (phenopromine. sulf.) two types of formalized rating procedures—a verbal check list and graphic rating scales—were administered to 187 university students. Repeated self-ratings were performed 45, 90 and 180 minutes after oral intake. By the check-list method the expected difference between amphetamine and chlorpromazine was significantly established in all the three ratings. Only in the 45-minute rating was a significant difference obtained between amobarbital and amphetamine. The graphic rating scales were clearly less efficient as judged from the greater proportion reporting 'no change'.