Aversive and compensatory classical conditioning with diazepam as conditional stimulus

The purpose of the first experiment was to investigate whether diazepam could acquire anxiogenic properties by signalling an aversive event. Rats were trained in an operant chamber in the pentylenetetrazol (PTZ) model of anxiety. Thereafter the animals were divided into groups that received classical diazepam conditioning (Group 1), and conditioning of diazepam + tone (Group 2). In the test phase diazepam was injected prior to placement in the operant chamber. Group 2 selected the PTZ-appropriate lever more often than the other groups, indicating that the tone induced anxiety, and diazepam did not. Tones and shock may therefore be more easily associated than diazepam and shock. The second experiment investigated this. Rats were trained the same way as in the first experiment. Thereafter the experimental group received injections of a small dose of diazepam prior to a second injection of a large dose of diazepam. The hypothesis was that a compensatory anxiogenic conditional response to diazepam's anxiolytic effect should be elicited by the small dose. There were no differences between the groups in lever selection, indicating that a compensatory anxiogenic response was not elicited.     

Some effects of methylphenidate on stimulus control of ratio avoidance behavior in the rat

After exposure to an avoidance schedule which included a warning signal, a rat was placed on a multiple schedule in which the first component was the same as before, i.e., a single response reset the response-shock interval, delaying shock, and the second component differed only in that four bar-presses were required to postpone shock. A fixed ratio requirement of four responses (FR 4) generated behavior resembling a fixed ratio requirement of one response (FR 1) since responding was controlled by the warning signal but more shocks were received. At a dosage of 2 mg/kg, methylphenidate given intraperitoneally decreased shock frequency during FR 4 periods while FR 1 behavior was not affected; at 4 mg/kg, stimulus control of avoidance responding was impaired during both components. Results at 4 mg/kg were partially confirmed by two animals exposed to an FR 4 avoidance schedule which included a warning signal but with different parameters. Response distributions showed that methylphenidate increased response rates in the absence of the warning signal, i.e., stimulus control of ratio-avoidance behavior was impaired although the increased response rates reduced shock frequency. One hour later responses again occurred more frequently during the signal than in its absence but shocks were less frequent than during control (non-drug) periods.     

Methylphenidate, amygdalectomy, and active avoidance performance in the rat

Amygdalectomized and control rats were given 400 active avoidance training trials in a shuttle box. Control animals received 0, 4, 8, or 16 mg/kg of methylphenidate throughout acquisition. Amygdalectomized animals were given the first 200 trials without drug, followed by 200 trials with drug. The administration of methylphenidate produced an abrupt and large improvement in performance in the amygdalectomized animals. One month after acquisition under the drug, retraining without drug revealed a significant retention effect for the three amygdaloid-drug groups relative to the nondrug-amygdaloid group. These results indicate that although amygdalectomy impairs the performance of avoidance responses, it does not prevent the learning or retention of such responses. Since methylphenidate appears to act primarily on dopaminergic mechanisms, the possible influence of amygdalectomy on such mechanisms is discussed.     

Relative efficacy of methylphenidate and behavior modification in hyperkinetic children: An interim report

Children reported to be hyperactive in school and with behavior difficulties at home were randomly assigned to methylphenidate, behavior therapy and placebo, or behavior therapy with methylphenidate for an 8-week period. Rating scales were obtained from teachers and parents. Independent blind observers rated childrens' classroom behavior on a weekly basis. A behavior therapy program was implemented in the home and at school. Methylphenidate dosage was individualized. Ratings of behavior deviance were significantly reduced by all treatments. However, a significant advantage for the groups receiving methylphenidate was found over the group receiving behavior therapy and placebo. No significant differences between methylphenidate alone and methylphenidate combined with behavior therapy were obtained. Global ratings of improvement done by teachers favored the combined treatment of behavior therapy and methylphenidate over behavior therapy and placebo. No differences among treatments were found in the mothers' global ratings of improvement. The results indicate that though all three treatments were effective, methylphenidate was significantly superior to behavior therapy alone.This study was supported in part by grant MH 18579, and by grant No. 3-621 from the Long Island Jewish-Hillside Medical Center. The authors wish to thank the behavior therapists, Drs. Jeffrey Felixbrod and Marion Pheterson, as well as Ms. Patricia Ramsey, who was responsible for data analysis.     

A discrimination based on punishment

Twelve white rats learned to press a bar or lever when this act was intermittently followed by pellets of food. Once a stable rate of pressing had been established, the animals were subjected to electric shock as a punishment for each response during alternate five minute periods within the experimental session. A difference in rates during the safe and punished phases was manifested both by the experimental group (8 rats), who were provided with a light as a signal when it was safe to respond, and also, contrary to expectation, by the control group (4 rats), who continued in darkness throughout the session. The differential responding by the control group was greatly reduced, however, when the duration of each phase was reduced from five minutes to one.

The investigation was then continued to determine the role of some of the other factors in the situation. Increasing the severity of the shock increased the difference between the light and the dark rates. Withholding the pellets of food reduced the overall rates but did not affect the light-dark discrimination. Withholding the shock, on the other hand, permitted an increase in rate and caused the animals to lose their discrimination; when food had previously been withheld, however, so that the rate of response was relatively low, this deterioration in the discrimination was not as rapid as before. Restoration of the discrimination training under a lower hunger drive confirmed the finding that the formation of the discrimination was quite rapid and showed that the level of drive did not affect the proportionality between the rates in the light and in the darkness. These findings were interpreted by comparing the current procedure with those previously used in studies of avoidance reactions and conflict.     

The Reinforcing Effect of a Differentiating Stimulus

Twenty Sprague Dawley rats, aged 22 to 26 months were given subcutaneous injections of 4.5 mg/kg methylphenidate or distilled water. Twelve minutes after the single injection was given, rats began 90 trials of avoidance conditioning. Drug animals made significantly more correct responses than did the control animals. Results indicate that use of methylphenidate in aged rats improved avoidance learning.     

Diazepam-stress interactions in the rat: effects on autoanalgesia and a plus-maze model of anxiety

On six occasions spaced at least a week apart, two groups of rats were subjected to a variety of stressful conditions consisting of a restraint/bright light complex, either alone or in combination with a tail pinch, whole-body inversion, or partial immersion in cold water. One of these groups was injected with diazepam (2.0 mg/kg) 30 min prior to the stressors, while the other group experienced the drug in their home cages the following day. A third group also received the diazepam but was not exposed to the stressors. In three test sessions all animals were injected with either diazepam or saline and were then exposed to a novel stressor: a plus-maze used as a screening device for anxiolytic drugs. This was immediately followed by a tail-flick measure of analgesia. The longest tail-flick latencies, indicating stress-induced analgesia ("autoanalgesia"), were observed in the group that had not been exposed to stress prior to testing. The other two groups exhibited substantially shorter latencies but did not differ from one another, thus showing a "stress inoculation" effect that was uninfluenced by diazepam. In the plus-maze, diazepam tends to increase the amount of time rats will spend in the two exposed arms of the maze relative to the two enclosed arms. This effect was significantly attenuated in the group that had previously experienced the variety of stressors after a diazepam injection, suggesting a learned association between drug and stress that resulted in a diminution of the drug's anxiolytic property.     

Effects of diazepam on schedule-controlled and schedule-induced behavior under signaled and unsignaled shock.

Schedule-controlled lever pressing and schedule-induced licking were studied in rats under a multiple fixed-interval fixed-interval schedule of food reinforcement upon which was superimposed a multiple variable-time variable-time schedule of electric-shock delivery. Shocks were signaled in one component of the multiple schedule and unsignaled in the other. The effects of diazepam upon the suppression of behavior during the signal (conditioned suppression) and during signaled and unsignaled shock (differential suppression) were studied under several shock intensities (Experiment 1) and at increased body weight (Experiment 2). In each study, diazepam led to dose-dependent increases in the rate of pressing and licking during signaled and unsignaled shock, but had little effect on conditioned suppression. the rate-enhancing effects of diazepam depended upon the intensity of shock, nature of the response, and whether or not shocks were signaled. The data was discussed in terms of (1) implications for understanding the effects of signaled and unsignaled shock on behavior, (2) the effects of diazepam on behavior suppressed by response-independent shock, and (3) comparison between operant and schedule-induced behavior.     

Diazepam impairs place learning in the Morris water maze

The effect of diazepam (0.3, 1.0, and 3.0 mg/kg) on the acquisition and retention of place learning was evaluated. The analysis of escape latencies indicates that 1.0 and 3.0 mg/kg diazepam significantly impaired the retention of spatial information. When a free swim trial was carried out only control animals showed spatial bias to the target quadrant. The absence of spatial bias in the group that received 0.3 mg/kg suggests that the amnesic effect of diazepam can be seen at doses similar to or even lower than the anxiolytic ones, and that the GABA/benzodiazepine receptor complex is highly sensitive to the cognitive impairment induced by diazepam in spatial tasks.     

Reciprocal inhibition of a laboratory conditioned fear

Electric shock was used to establish a conditioned fear in 48 college Ss, who then received either deep muscle relaxation training, cognitive relaxation training or anxiety relief conditioning. Relaxation was conditioned to a slide of the word NOW and the aversive stimulus was a pure red slide. The compound stimulus NOW on a red background was presented to generate counterconditioning, followed by a re-presentation of pure red as a measure of transfer. GSR and Blood Volume Pulse were recorded for evaluation of the fear reduction generated by each training procedure. All group differences were non-significant. The two relaxation procedures were equally effective, while the Anxiety Relief group manifested consistently smaller response-reduction. Implications and the usefulness of the paradigm were discussed.     

Methylphenidate and stimulus control of avoidance behavior

The introduction of a warning signal that preceded a scheduled shock modified the temporal distribution of free-operant avoidance responses. With response-shock and shock-shock intervals held constant, response rates increased only slightly when the response-signal interval was reduced. The result is consistent with Sidman's (1955) findings under different conditions, but at variance with Ulrich, Holz, and Azrin's (1964) findings under similar conditions. Methylphenidate in graded doses increased response rates, modifying frequency distributions of interresponse times. Drug treatment may have disrupted a "temporal discrimination" formed within the signal-shock interval. More simply, methylphenidate influenced response rates by increasing short response latencies after signal onset; this effect was more prominent than the drug's tendency to increase the frequency of pre-signal responses. When signal-onset preceded shock by 2 sec, individual differences in performance were marked; methylphenidate suppressed responding in one rat as a function of increasing dose levels to a greater degree than in a second animal, but both subjects received more shocks than under control conditions.     

Reduction of appeasement‐related affect as a concomitant of diazepam‐induced aggression: evidence for a link between aggression and the expression of self‐conscious emotions

Aggressive responding following benzodiazepine ingestion has been recorded in both experimental and client populations, however, the mechanism responsible for this outcome is unclear. The goal of this study was to identify an affective concomitant linked to diazepam‐induced aggression that might be responsible for this relationship. Thirty males (15 diazepam and 15 placebo) participated in the Taylor Aggression Paradigm while covertly being videotaped. The videotapes were analyzed using the Facial Action Coding System with the goal of identifying facial expression differences between the two groups. Relative to placebo participants, diazepam participants selected significantly higher shock settings for their opponents, consistent with past findings using this paradigm. Diazepam participants also engaged in significantly fewer appeasement expressions (associated with the self‐conscious emotions) during the task, although there were no group differences for other emotion expressions or for movements in general. Aggr. Behav. 35:203–212, 2009. © 2008 Wiley‐Liss, Inc.     

Chronic oral methylphenidate induces post-treatment impairment in recognition and spatial memory in adult rats

Recent pre-clinical research has indicated that chronic treatment with methylphenidate (Ritalin^®) in young animals can result in lasting and potentially detrimental alterations in brain function that can persist into adulthood. Chronic methylphenidate-induced neuronal alterations may result in behavior and cognitive deficits that include increases in behavioral responses and impairment in recognition memory. This study compared the cognitive consequences following chronic treatment with two doses (5 and 10 mg/kg) of methylphenidate on recognition and spatial memory in adult male Long-Evans rats using an established oral dosing procedure. The animals were then tested in the Object Recognition test at 14 days post treatment and the Object Placement test at 21 days post treatment. The results indicate that repeated exposure to oral methylphenidate impaired the performance of rats in these tests. The current findings add to recent research demonstrating negative consequences in rats pre-treated with methylphenidate, and extend previous findings to include deficits in spatial recognition memory.     

Pavlovian Conditioning to a Diazepam Cue with Yohimbine as the Unconditional Stimulus

On multiple occasions, rats were administered diazepam (2.0 mg/kg, ip) followed 30 min thereafter by yohimbine hydrochloride (2.5 or 5.0 mg/kg) or isotonic saline (forward conditioning groups). Three additional groups (backward conditioning controls) were given equivalent injections, but in reverse order. After eight such pairings, the effects of a single injection of diazepam on motor performance (balancing on a rotating drum) was assessed. Rats that had received either dose of yohimbine during forward conditioning trials maintained their balance longer than the saline controls. After four additional conditioning trials, the animals’ activity patterns in a plus-maze screening test for anxiolytics were examined. Placed into the maze after a single test injection of isotonic saline, the behavior of all groups was virtually identical: less than 16% of total entries into or time spent in the four arms of the maze was spent in the two “open” arms (unprotected by surrounding walls). When tested in the maze again, but 35 min after a single injection of diazepam, the groups that had received diazepam but not yohimbine during the conditioning phase exhibited the expected increase in open-arm activity, and equivalent increases were found in backward conditioning groups. However, the group previously conditioned with 2.5 mg/kg of yohimbine following diazepam also showed an increased open-arm activity when tested with diazepam alone, but it was significantly greater than that seen in the control group. In contrast, the group conditioned with 5.0 mg/kg yohimbine following diazepam exhibited no effect of diazepam upon their plus maze activity; consequently, these animals spent less time in the open arms than either of the other groups. Yohimbine alone normally decreases open-arm activity (a putative “anxiogenic” effect) in a linear dose-dependent fashion. The fact that it had a bidirectional conditional effect on the diazepam cue drug demonstrates that a conditional response in drug → drug conditioning cannot always be predicted on the basis of the behavioral response to the signaled drug. Consideration is given to possible reasons for these effects of diazepam → yohimbine pairings in terms of the known neuropharmacological properties of yohimbine.     

Motor timing deficits in community and clinical boys with hyperactive behavior: the effect of methylphenidate on motor timing

In a previous paper we showed that community children with hyperactive behavior were more inconsistent than controls in the temporal organization of their motor output. In this study we investigated: (1) various aspects of motor timing processes in 13 clinically diagnosed boys with attention deficit hyperactivity disorder (ADHD) who were compared to 11 community boys with hyperactive behavior and to a control group and (2) the effect of methylphenidate on the motor timing processes in the clinical group with ADHD in a double blind, cross-over, medication-placebo design, including 4 weeks of medication. The clinical group with ADHD, like the community group with hyperactivity, showed greater variability in sensorimotor synchronization and in sensorimotor anticipation relative to controls. The clinical group was also impaired in time perception, which was spared in the community group with hyperactivity. The persistent, but not the acute dose, of methylphenidate reduced the variability of sensorimotor synchronization and anticipation, but had no effect on time perception. This study shows that motor timing functions are impaired in both clinical and community children with hyperactivity. It is the first study to show the effectiveness of persistent administration of methylphenidate on deficits in motor timing in ADHD children and extends the use of methylphenidate from the domain of attentional and inhibitory functions to the domain of executive motor timing.     

Response persistence in the rat following intermittent punishment and partial reward: Effects of trial sequence

Thirty-six rats were given 16 days of partial reward training in a runway. During the final 12 days each of the animals received one foot-shock experience each day. One group received shock on an N trial preceding an R trial (P-R), a second group was shocked on N trials not followed by an R trial (R-P), and the third group received shock after completing all daily trials (Control). Following acquisition the rats were split within each group (one half received 24 trials of unpunished extinction and one half continued to receive partial reward but were punished on every trial). During consistent punishment the P-R animals were more persistent than the R-P or Control rats and during unpunished extinction the P-R and Control animals were equal in persistence but both were superior to the R-P animals. The results were discussed in terms of Capaldi's sequential trial theory.     

The type a behavior pattern,sex differences,and cardiovascular response to and recovery from stress

Sixty-one subjects performed a Stroop Color-Word Interference task, a mental arithmetic task (serial subtraction of 7s), and a shock avoidance task (repeating digits backward while expecting to be shocked for mistakes). Systolic and diastolic blood pressure and pulse rate were recorded while subjects anticipated, undertook, and recovered from the shock avoidance task, and undertook and recovered from the Stroop and mental arithmetic tasks. The results revealed that, compared to Type B subjects, Type A subjects manifested higher diastolic blood pressure during the Stroop and shock avoidance tasks and higher pulse rate following the mental arithmetic and shock avoidance tasks. No significant interactions were found between sex and A/B Type. The results are congruent with the notion that greater sympathetic nervous system activity among Type A individuals, both men and women, contributes to greater coronary atherosclerosis and heart disease in this group.     

Continuous punishment of free-operant avoidance in the rat

Three groups of albino rats were trained under a free-operant avoidance (Sidman) procedure with equal shock-shock and response-shock intervals. After stable performance was achieved, the animals were concurrently exposed to a brief electric shock after each response. The procedures were as follows: Punishment Schedule I: punishment shock was introduced at an intensity approximately one quarter that of avoidance shock; increments of nearly this same size were made as stable performance was achieved at succeeding punishment shock intensities. Punishment Schedule II: punishment shock was introduced at approximately one-half the intensity of avoidance shock; after stable performance, punishment shock was increased to the same intensity as avoidance shock. Punishment Schedule III: punishment shock was introduced and maintained at the same intensity as avoidance shock. Punishment was continued for all groups until one of two suppression criteria was attained. All animals made fewer responses and received more avoidance shocks as a function of increasing punishment shock. Half of the animals under Punishment Schedule I required punishment shock higher than avoidance shock to meet their assigned suppression criterion. A comparison of all procedures showed that suppression was greater when punishment shock was initially at high intensity.     

Effects of methylphenidate (Ritalin) on selective attention in hyperactive children

This study investigated the effect of methylphenidate (Ritalin) on the selective attention of hyperactive children designated as favorable or adverse responders to stimulant medication. Using a type II incidental learning paradigm, it was found that children in the drug condition recalled more central and less incidental stimuli than those children in the placebo condition. While no differential effects on recall were found for responder type, methylphenidate did affect the spontaneous overt labeling of central stimuli by the favorable responder group. Results were interpreted in terms of the role of methylphenidate in narrowing the focus of attention. Implications for the classification of hyperactive children as favorable and adverse responders were also discussed.This paper is based on a master's thesis completed by the first author in the Department of Psychology, University of Guelph, under the supervision of the second author. The authors wish to thank J. Thomas Dalby for his assistance in the conducting of this experiment.     

Modulation of the effective salience of a stimulus by direct and associative activation of its representation

In 2 experiments, rats received exposure to presentations of a footshock preceded by a given cue. In the PRf (partial reinforcement) condition, this cue also occurred in the absence of the shock; in the CRf (continuous reinforcement) condition, it did not. Subsequent testing in which a new stimulus was used to signal the shock (Experiment 1) showed that the shock was more effective as a reinforcer for the PRf than for the CRf group. In Experiment 2, the shock was used as a conditioned stimulus signaling food delivery, and it was found that conditioning occurred more readily in the PRf than in the CRf group. These results accord with the hypothesis that preexposure to the shock results in a decline in its effective salience but that experience of a cue that signals shock in the absence of the shock itself attenuates this effect and helps maintain stimulus salience.