Diazepam (Valium): its dependency liability

Reports of the withdrawal syndrome following discontinuation of diazepam and drug dependence fears have contributed to diazepam's displacement as the most popular anxiolytic agent. Reports of the withdrawal syndrome, the factors involved in withdrawal, and the remedies proposed for diazepam withdrawal symptoms are reviewed.     

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 More pointedly, we first evidenced that 1W and 6W alcohol-withdrawn mice exhibited working memory deficits in a sequential alternation task, associated with sustained exaggerated corticosterone rise and decreased pCREB levels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 Diazepam was not detected in the blood of withdrawn mice at the time of memory testing, occurring 24 hours after the last diazepam injection.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improved alternation rates and normalized levels of glucocorticoids and pCREB activity in the PFC in 1W but not in 6W withdrawn mice.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only transitorily canceled out the working memory impairments and glucocorticoid alterations in the PFC of alcohol-withdrawn animals.     

Demenz durch Benzodiazepin-Medikation (ICD 10: F13.73)

A case of an elderly patient, suffering from renal insufficiency and depression is decribed, who presented with a syndrome of dementia caused by diazepam intake.     

Conditioning in human opiate addicts

Eight volunteers maintained on daily methadone participated in a classical conditioning procedure to determine which if any of the elements of narcotic withdrawal could be conditioned. The unconditioned stimulus was the injection of a small dose of naloxone. The unconditioned response was a brief precipitated withdrawal syndrome. The conditioning stimulus was a tone, odor, and injection of saline. Conditioning was successful in the pilot study in 5 of 8 subjects. The conditioned response consisted of tearing, yawning, lacrimation, systolic blood pressure increase, respiratory irregularities and subjective feelings of narcotic withdrawal sickness (nausea, muscle aches, chills). A second group of 8 subjects showed, in addition to the above, evidence of conditioning of heart rate, respiratory rate and skin temperature decrease. These laboratory findings support the clinical reports of a conditioned withdrawal syndrome and suggest ways to improve treatment results by detecting and extinguishing or modifying conditioned responses.     

Conditioned behavioral and physiological changes associated with injections of a narcotic antagonist in morphine-dependent monkeys

Environmental stimuli which are repeatedly associated with the nalorphine-induced withdrawal syndrome in morphine-dependent monkeys acquire the ability to produce a variety of conditioned behavioral and physiological responses. Morphine-dependent rhesus monkeys were studied under a fixed-ratio schedule where every tenth lever press produced a food pellet. After several pairings of a stimulus (light or tone) with intravenous injection of a dose of nalorphine which produced an immediate and severe withdrawal syndrome, onset of the stimulus alone produced conditioned suppression of lever pressing, heartrate decrease, vomiting and salivation. Conditioned suppression of responding and conditioned heart-rate changes persisted in post-dependent monkeys for one to four months after termination of chronic morphine treatment. No conditioned electrocardiogram, respiration or temperature changes were ever seen. A second group of morphine-dependent rhesus monkeys was studied under a schedule where every lever press produced an intravenous injection of morphine. After 10 pairings of a light with the intravenous injection of a dose of nalorphine which produced marked withdrawal signs and increased responding for morphine, presentation of the light and injection of sahne produced conditioned increases in responding for morphine. A third group of morphine-dependent rhesus monkeys was studied under a schedule where every nth lever press (n = 1 to 10) terminated a stimulus light associated with periodic injections of nalorphine or naloxone; lever-press responding was engendered and subsequently maintained. Thus, stimuli associated with the nalorphineor naloxone-induced withdrawal syndrome can either suppress, enhance or maintain behavior depending on the schedule conditions.     

Flight from Unfairness: Effects of Perceived Injustice on Emotional Exhaustion and Employee Withdrawal

Purpose  

The purpose of this study is to examine emotional mechanisms by which perceived injustice is translated into forms of employee withdrawal. Based on person–environment fit theory, we develop arguments predicting mediation between perceived justice and withdrawal by an emotional suffering syndrome and emotional exhaustion.     

Cellular mechanisms underlying neuronal excitability during morphine withdrawal in physical dependence: lessons from the magnocellular oxytocin system

Opiates are used clinically as analgesics, but their euphoric actions can lead to continued use and to dependence and addiction. While there are many factors involved in drug abuse, avoidance of stressful withdrawal symptoms is a key feature of addiction and its treatment. Fundamental to this is the need to understand the cellular processes that induce dependence and lead to the withdrawal syndrome. Many neurones in the brain express opioid receptors but only a few types of neurone develop dependence during chronic morphine exposure. The physiology of opiate-dependent cells is altered such that they require the continued presence of the drug to function normally and this is revealed, in cells that are inhibited by initial acute exposure to opiate, by a rebound hyperexcitation upon opiate withdrawal. Hypothalamic oxytocin neurones robustly develop morphine dependence and provide an exceptional opportunity to probe the cellular mechanisms underlying morphine dependence and withdrawal excitation. Although expression of morphine withdrawal excitation by oxytocin cells requires afferent inputs, the underlying mechanisms appear to reside within the oxytocin neurones themselves and probably involve changes in the intrinsic membrane properties of these neurones.     

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.     

Discriminative stimulus effects of diazepam and buspirone in normal volunteers.

A within-subject design was used to characterize the effects of dose manipulations on discriminative and self-reported effects of oral diazepam and buspirone. Subjects were trained to discriminate diazepam (10 mg) versus placebo (n = 10), or buspirone (10 or 15 mg) versus placebo (n = 9). The compounds were identified to subjects by letter code before discrimination training began. In later sessions, correct identifications at 2 hr after the oral administration of drug earned money. All subjects showed accurate discrimination performance during the test-of-acquisition phase. In a low-dose generalization phase, diazepam and buspirone produced dose-related increases in drug identifications across a four-fold range of doses. In a subsequent low-dose training phase, in which subjects were trained to discriminate progressively lower drug doses, the median lowest discriminable dose of diazepam and buspirone was 2.5 and 7.5 mg, respectively. Dose-response functions for drug identifications were shifted leftward in the low-dose training phase relative to the low-dose generalization phase, suggesting that reinforcement of progressively lower doses enhances drug discriminability. The self-reported effects of diazepam and buspirone were similar (e.g., both drugs increased ratings of drug strength and clumsy/uncoordinated) and different (e.g., diazepam but not buspirone increased ratings of drowsy/sleepy; buspirone but not diazepam increased ratings of tense/nervous). This study demonstrates discriminative and self-reported effects of diazepam and buspirone at doses lower than previously shown to be behaviorally active, and suggests that at commonly used clinical doses, diazepam is relatively more discriminable than buspirone.     

Repeated diazepam administration: effects on the acquisition and performance of response chains in humans.

The effects of repeated diazepam administration (80 mg) were assessed across a 12-hr time course with humans responding under a two-component multiple schedule of repeated acquisition and performance of response sequences. Subjects resided in an inpatient clinical research ward for the duration of the study. In each component of the multiple schedule, subjects completed sequences of 10 responses in a predetermined order using three keys of a numeric keypad. In the acquisition component, a new response sequence was to be acquired each session. In the performance component, the response sequence always remained the same. After stable responding was obtained and the effects of the placebo assessed, diazepam was administered for 3 consecutive days. The effects of repeated diazepam administration on overall percentage of errors across the two components of the multiple schedule were selective. In the acquisition component, the first dose of diazepam increased percentage errors with the magnitude of effects decreasing across the second and third days of diazepam administration. In the performance component, the percentage of errors was either minimally affected across all 3 days of diazepam administration or substantively increased on Day 1 with subsequent diazepam administrations having minimal effects. Effects on response rate were not selective. Diazepam decreased rates of responding in both schedule components, with the magnitude of effects decreasing across successive administrations. These results replicate previous findings in humans and nonhumans on the selective effects of diazepam on acquisition versus performance baselines. Also, the results suggest that the selective effects do not result from differences in reinforcement rate. Finally, the present results demonstrate that the selective recovery from repeated drug administration previously demonstrated in nonhumans using a repeated acquisition arrangement has generality to human behavior.     

Reaction time and diazepam plasma concentration in subjects with normal gastric pH

The present study investigated the relationship of reaction time with the plasma concentration of four different formulations of diazepam (liquid, original, new, and generic). On four separate days, over a 4-month period, subjects with normal gastric pH (N=7) were administered each of the diazepam formulations. Blood samples were obtained prior to each dose and at subsequent intervals. Likewise, reaction times were evaluated prior to dosing and then at ten different intervals post-dosing. As hypothesized, reaction time performance was associated with plasma diazepam concentration, regardless of formulation type. This suggests that reaction time is a sensitive measure of cerebral functioning for individuals who are treated with diazepam. In addition to providing a measure of drug effects on cognitive functioning, the results of this study have implications concerning possible hazards of operating machinery or driving motor vehicles for individuals being treated with diazepam.     

Reaction time and diazepam plasma concentration in subjects with normal gastric pH

The present study investigated the relationship of reaction time with the plasma concentration of four different formulations of diazepam (liquid, original, new, and generic). On four separate days, over a 4-month period, subjects with normal gastric pH (N=7) were administered each of the diazepam formulations. Blood samples were obtained prior to each dose and at subsequent intervals. Likewise, reaction times were evaluated prior to dosing and then at ten different intervals post-dosing. As hypothesized, reaction time performance was associated with plasma diazepam concentration, regardless of formulation type. This suggests that reaction time is a sensitive measure of cerebral functioning for individuals who are treated with diazepam. In addition to providing a measure of drug effects on cognitive functioning, the results of this study have implications concerning possible hazards of operating machinery or driving motor vehicles for individuals being treated with diazepam.     

Combined action of diazepam and d-amphetamine on fixed-interval performance in cats

Cats trained under a fixed-interval 5-min schedule of milk presentation were injected with diazepam, amphetamine, and combinations of amphetamine and diazepam. Diazepam increased overall response rate as a function of the dose and disrupted the temporal pattern of responding. Low doses of amphetamine (0.5 mg/kg) usually increased the response rate; higher doses (1 to 2 mg/kg) either decreased the response rate or had little effect. Amphetamine always disrupted the temporal pattern of responding, even though it did not affect the overall rate. When doses of amphetamine that increased the response rate or left it unchanged were combined with diazepam, a potentiated increase in response rate occurred. When doses of amphetamine that decreased the response rate were combined with diazepam, the amphetamine-induced rate decreases were reversed at least partially. Less clear potentiation of disruption of the temporal pattern of responding was observed when amphetamine and diazepam were combined.     

Addiction motivation reformulated: an affective processing model of negative reinforcement

This article offers a reformulation of the negative reinforcement model of drug addiction and proposes that the escape and avoidance of negative affect is the prepotent motive for addictive drug use. The authors posit that negative affect is the motivational core of the withdrawal syndrome and argue that, through repeated cycles of drug use and withdrawal, addicted organisms learn to detect interoceptive cues of negative affect preconsciously. Thus, the motivational basis of much drug use is opaque and tends not to reflect cognitive control. When either stressors or abstinence causes negative affect to grow and enter consciousness, increasing negative affect biases information processing in ways that promote renewed drug administration. After explicating their model, the authors address previous critiques of negative reinforcement models in light of their reformulation and review predictions generated by their model.     

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.     

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.     

ANALYZING THE INFLUENCE OF TIC‐RELATED TALK ON VOCAL AND MOTOR TICS IN CHILDREN WITH TOURETTE'S SYNDROME

This study examined the effect of tic‐related talk on the vocal and motor tics of 2 boys with Tourette's syndrome. Using ABAB withdrawal designs, the boys were alternately exposed to conditions with and without talk of their tics. For both boys, vocal tics markedly increased when talk pertained to tics and decreased when talk did not pertain to tics, but motor tic covariance was less consistent.     

Effects of diazepam on approach, self-reported fear and psychophysiological responses in snake phobics

The effects of diazepam was assessed on a number of measures of phobic anxiety. Snake-phobic subjects underwent two sessions on either diazepam or placebo in a crossover design. In addition to a habituation series, a slide with the phobic object was displayed as well as a live snake which subjects were asked to approach. The anxiolytic effect of diazepam was manifest in only one measure of fear, namely self-rated fear at the point of closest approach when it also attained the highest level. The result would indicate that diazepam has an anxiolytic only on high levels of subjective anxiety. The magnitude of the phasic cardiac reaction to the slide was highly and positively correlated with self-rated fear of the slide.     

Differential diagnosis of steroid-dependent nephrotic syndrome with psychosis: Practical and ethical issues

The present case illustrates practical and ethical issues that can be encountered by clinical psychologists providing consultation services in medical settings. The neuropsychological consultation service was asked to evaluate a 22-year-old male with psychosis, steroid-dependent nephrotic syndrome, and a family history of schizophrenia. MRI revealedmarked cortical atrophy. Clinical findings were consistent with (1) steroid inducedapparent atrophy, which has been shown to be reversible with withdrawal of steroids; (2) uremia secondary to steroid withdrawal; (3) cortical atrophy, found in some schizophrenics; or (4) an atypical, diffuse degenerative disorder. Clinical interview and psychological testing revealed significant thought disorder, prominent delusions, somatic hallucinations, and mood disturbance. Deterioration in social and academic functioning was also present. Except for impaired attention and concentration, neuropsychological evaluation showed no clear evidence of brain-based dysfunction. Further, neuropsychological results effectively ruled out a degenerative process and were not consistent with a steroid effects profile. A conclusive differential diagnosis of steroid induced psychosis versus severe psychopathology would require withdrawal from steroids and antipsychotics. In addition to the practical and ethical issues of withholding antipsychotics, steroid withdrawal would require either dialysis or renal transplant surgery. Decision making regarding dialysis dependency and the possibility of postsurgical psychosis secondary to true psychopathology were salient issues to both the patient and the treatment team.     

Prevalence of cigarette smoking in Iran.

The current research assessed the prevalence of cigarette smoking in Shiraz, Iran by randomly selecting 1,335 subjects (782 men and 553 women) from the city for a face-to-face interview and completion of a questionnaire. Of the participants, 205 (26%) of the men and 20 (3.6%) of the women reported being current smokers. The mean ages of smokers and nonsmokers were 41.8 and 37.0 yr., respectively (range between 16 and 90 years for smokers and nonsmokers). The mean age of starting to smoke cigarettes was 21.3 yr. (range of 10 to 60). The most common reasons for current cigarette smoking were Need to avoid withdrawal symptoms, Release of tension, and Pleasurable purposes. Foreign filter-tipped cigarettes were the most common type consumed. The mean number of cigarettes per day was 13.4 (SD = 10.3). Reports for onset of cigarette smoking included Modeling, Release of tension, and Pleasurable purposes. Cigarette smoking was reported by more males than females. The most common reason for onset of cigarette smoking was different from that for current smoking. Frequencies of smokers within age groups were varied.