Interaction between purine and benzodiazepine: Inosine reverses diazepam-induced stimulation of mouse exploratory behavior.

Inosine, 2-deoxyinosine, and 2-deoxyguanosine completely reversed the increase in exploratory activity elicited in mice by diazepam. The inhibition of exploratory behavior by purines occurred at doses that when given alone have no effect on exploratory behavior. 7-Methylinosine, which does not bind to the brain benzodiazepine binding site in vitro, had no effect on the diazepam-induced increase in exploratory behavior. Behavioral effects produced by various combinations of inosine and diazepam indicate that the interaction between purine and benzodiazepine is antagonistic and support the hypothesis that the naturally occurring purines function in anxiety-related behaviors that respond to benzodiazepine treatment.

A selective imidazobenzodiazepine antagonist of ethanol in the rat.

Ethanol, at pharmacologically relevant concentrations of 20 to 100 mM, stimulates gamma-aminobutyric (GABA) receptor-mediated uptake of 36Cl-labeled chlorine into isolated brain vesicles. One drug that acts at GABA-benzodiazepine receptors, the imidazobenzodiazepine Ro15-4513, has been found to be a potent antagonist of ethanol-stimulated 36Cl- uptake into brain vesicles, but it fails to antagonize either pentobarbital- or muscimol-stimulated 36Cl- uptake. Pretreatment of rats with Ro15-4513 blocks the anticonflict activity of low doses of ethanol (but not pentobarbital) as well as the behavioral intoxication observed with higher doses of ethanol. The effects of Ro15-4513 in antagonizing ethanol-stimulated 36Cl- uptake and behavior are completely blocked by benzodiazepine receptor antagonists. However, other benzodiazepine receptor inverse agonists fail to antagonize the actions of ethanol in vitro or in vivo, suggesting a novel interaction of Ro15-4513 with the GABA receptor-coupled chloride ion channel complex. The identification of a selective benzodiazepine antagonist of ethanol-stimulated 36Cl- uptake in vitro that blocks the anxiolytic and intoxicating actions of ethanol suggests that many of the neuropharmacologic actions of ethanol may be mediated via central GABA receptors.

Benzodiazepines: anxiety-reducing activity by reduction of serotonin turnover in the brain.

The anxiety-reducing effects of minor tranquilizers in the rat conflict test were mimicked by serotonin antagonists and by p-chlorophenylalanine, an inhibitor of serotonin synthesis; the depressant effects of the minor tranquilizers were mimicked by norepinephrine antagonists. Intraventricular injections of serotonin led to a suppression of behavior, and also antagonized the anxiety-reducing action of benzodiazeprines. Intraventricular injections of norepinephrine led to a release of punished behavior from suppression, and also antagonized the depressant action of benzodiazepines. The anxiety-reducing activity, and the decrease in serotonin turnover induced by benzodiazepines, were maintained over repeated doses, whereas depressant activity, and the decrease induced in norepinephrine turnover, both rapidly underwent tolerance. Tranquilizers may exert their anxiety-reducing effects by a reduction of serotonin activity in a behaviorally suppressive punishment system, and they may exert their depressant effects by a reduction of norepinephrine activity in a behaviorally facilitatory reward system.

Lorazepam in cancer patients treated with cisplatin: a drug having antiemetic, amnesic, and anxiolytic effects.

There currently is no pharmacologic approach to the problem of anticipatory nausea and vomiting (ANV). Lorazepam (Ativan, Wyeth Laboratories, Philadelphia) is an interesting candidate drug if it could block the recall of the unpleasant events associated with chemotherapy, especially if it also has antiemetic properties. Since ANV is a conditioned (learned) response, it may well depend on a memory imprint of the stimulus. This pilot study was designed to use intravenous lorazepam given before and after cisplatin infusion in 32 patients, and to make detailed measurements of nausea, vomiting, recent memory, anxiety, and sedation as well as toxicity. Satisfactory responses occurred in about 70%, as rated separately both by investigator and patient. Forty-six percent did not even recall receiving chemotherapy, regardless of whether or not they vomited; 80% had no significant anxiety after chemotherapy. Adverse reactions included some cases of perceptual disturbance, urinary incontinence, diarrhea, hypotension, and one case of severe transient amnesia. No long-term adverse effects were noted.

An efficacy study of isocarboxazid and placebo in depression, and its relationship to depressive nosology.

Isocarboxazid and placebo were evaluated in 130 anxious depressives. Drug was superior to placebo on depression, anxiety, interpersonal sensitivity, and global measures, and on symptoms of hostility, anxiety, obsessiveness, and psychological-cognitive components of depression. There were no significant differences between treatment effects on psychomotor and typical vegetative symptoms. Isocarboxazid was more effective than placebo in major, but not in minor, depression. It was significantly more effective in depression classified as endogenous depression or melancholia by various diagnostic criteria. Drug was more effective than placebo in atypical depression with vegetative reversal and in Brief Psychiatric Rating Scale (BPRS)-derived profiles of anxious and hostile depression; there were no drug-placebo differences in atypical depression without vegetative reversal, or in BPRS retarded and agitated/excited depression. Interpersonal sensitivity emerged as an important drug-responsive dimension.

Antidepressants in black and white inpatients. Differential response to a controlled trial of chlorpromazine and imipramine.

Differential effects of chlorpromazine, imipramine hydrochloride, and a placebo were examined in 159 black and 555 white depressed patients in a multihospital collaborative study. In making these comparisons, the effects of age and social class were controlled. The major study findings were the differential effects of the active drugs for the black men and women. Chlorpromazine was the most efficacious treatment for black women, whereas imipramine was most efficacious for black men. These differences occurred on global ratings of improvement as well as on specific symptoms such as depression, anxiety, guilt-worthlessness, sleep disturbances, and social participation. Black patients also evidenced a higher improvement rate at one week, irrespective of treatment, than did the white patients.

Raised endogenous monoamine oxidase inhibitor output in postwithdrawal alcoholics: effects of L-dopa and ethanol.

Urinary output of endogenous monoamine oxidase inhibitor was significantly greater in a group of postwithdrawal alcoholics than in controls. An oral dose of 0.5 g of L-dopa reduced output to control values in the alcoholics, but in the controls themselves output was unaffected. A similar excretion pattern to unextracted samples was observed in ethyl acetate extracts of these urine samples, acidified to pH 1. In a second group of postwithdrawal alcoholics, where the L-dopa effect was confirmed, ethanol administration brought about a small but not significant reduction in inhibitor output.

Depression and anxiety in heroin addicts: a placebo-controlled study of doxepin in combination with methadone.

Narcotic addicts may manifest symptoms of depression that aggravate their addiction. In this double-blind study of 35 mildly depressed patients in a methadone maintenance program, subjects who received doxepin improved significantly more than control subjects. Even in this short-term study, the reduction in depression was associated with a trend toward better performance in other areas of rehabilitation.

Effect of beta blockade and beta stimulation on stage fright.

Stage fright, physiologically the "fight or flight" reaction, is a disabling condition to the professional musician. Because it is mediated by the sympathetic nervous system, we have investigated the effects of beta blockade on musical performance with propranolol in a double blind fashion and the effects of beta stimulation using terbutaline. Stage fright symptoms were evaluated in two trials, which included a total of 29 subjects, by questionnaire and by the State Trai Anxiety Inventory. Quality of musical performance was evaluated by experienced music critics. Beta blockade eliminates the physical impediments to performance caused by stage fright and even eliminates the dry mouth so frequently encountered. The quality of musical performance as judged by experienced music critics is significantly improved. This effect is achieved without tranquilization. Beta stimulating drugs increase stage fright problems, and should be used in performing musicians only after consideration of the detrimental effects which they may have on musical performance.

Pharmacologic treatment of agitation associated with dementia.

Pharmacotherapy of aggressive or agitated behaviors in the dementia patient has not been studied extensively, despite the prevalence of this problem. Neuroleptics have the most support for efficacy, with shorter acting benzodiazepines demonstrating benefit on occasion. However, studies done to date indicate that these drugs are effective only for a minority of patients and that side effects frequently make patients worse. Other medications, such as propranolol, carbamazepine, or lithium, may be helpful, but their efficacy in dementia patients has not been demonstrated in placebo-controlled studies. Until such studies are done, their use is most appropriate in special patient groups or in patients who have failed neuroleptic or benzodiazepine treatment. More studies are needed in elderly patients evaluating effectiveness of pharmacologic agents in specific types of dementia, particularly Alzheimer's disease. Most studies done to date have been of relatively short duration, usually two months or less. Because these medications often are given to dementia patients for prolonged periods, studies are needed to define the long-term clinical efficacy of these agents. In the clinical setting, these agents should be reduced periodically or discontinued to determine ongoing need. In addition, environmental, social, or behavioral methods of reducing agitated behaviors need to be explored as an adjunct to any medication trial.

Behavior of mother rats in conflict tests sensitive to antianxiety agents.

Previous studies of freezing and open-field activity have demonstrated that lactating rats are less fearful or less anxious than nonpregnant ones. The purpose of this investigation was to observe the behavior of mother rats in conflict tests, which are frequently used in studies on the neurobiology of anxiety. In the punished drinking test, in which licking from a water spout is punished by electric shocks, mothers (observed on Day 1 postpartum following 24 hr of water deprivation) were found to drink more than virgins. Mothers (Day 1 postpartum) also consumed more food than controls in an unfamiliar open field. In contrast, no difference between mothers (Day 5 postpartum) and virgins was present in the exploration of an electrified shock probe. The largest maternal anticonflict effects in the drinking and feeding tests were recorded when the females were tested with their pups. Increased punished drinking was also observed in virgin rats treated with the anxiolytic benzodiazepine midazolam. Water-deprived virgins and mothers did not differ in the shock titration test, a result suggesting that diminished pain reactivity was unlikely to account for the increased punished drinking in mothers. Moreover, females in late pregnancy, which are hypoalgesic (Gintzler, 1980), did not lick more than virgins in the punished drinking test. Following 24 hr of water deprivation, unpunished drinking was higher in lactating females than in virgins, so the increased acceptance of punishment by mothers might have been due to their being more thirsty than virgins.(ABSTRACT TRUNCATED AT 250 WORDS)

A controlled comparison of doxepin h.s. and doxepin q.i.d.

A controlled double-blind study of 40 depressed psychiatric outpatients who received doxepin either q.i.d. or h.s. showed that doxepin may be administered h.s. without loss of efficacy or increase in side effects. The patients who received doxepin h.s. felt significantly better rested in the morning than the patients who received doxepin in divided doses.

Effect of a new benzodiazepine derivate, clobazam, in anxious patients with gastrointestinal disorders.

Thirty-four anxious patients with gastrointestinal disorders were studied in order to evaluate the effectiveness of a new 1,5-benzodiazepine antianxiety agent (HR 376). The disorders were classified as organic or functional according to the presence or absence of radiologic signs of ulcer. Dietetic measures, gastric antacids, anticholinergic agents, and antianxiety treatment were applied for six weeks. Anxiolytic treatment consisted of 30 mg/day clobazam (HR 376) or 15 mg/day diazepam, given in a randomized, double-blind manner. Clinical follow-up was performed with the PEN Personality Inventory (PEN), Taylor Manifest Anxiety Scale (TMAS), Hamilton Anxiety Scale (HAS), and Wittenborn Psychiatric Rating Scales (WPRS). The score of the psychoticism dimension of the PEN inventory was significantly higher in organic than in functional patients. Significant differences occurred in the reduction of the rating scores of HAS and WPRS before/after treatment in the clobazam and diazepam groups. This would express a modification of state anxiety. The TMAS, which evaluates trait anxiety, disclosed statistically significant improvement in the clobazam group. This group showed an early reduction of the HAS and TMAS scores, which would suggest an early onset of action.

Anxiogenic action of a convulsant benzodiazepine: reversal by chlordiazepoxide.

Ro5-3663, a convulsant benzodiazepine and a ligand for CNS picrotoxin sites, but not for benzodiazepine sites, had a significant dose-related (2 and 4 mg/kg) anxiogenic action in the social interaction test of anxiety. This anxiogenic effect was reversed by chlordiazepoxide (5 mg/kg).

The effects of FG 7142 upon local cerebral glucose utilization suggest overlap between limbic structures important in anxiety and convulsions.

The effects of the beta-carboline benzodiazepine receptor ligand FG 7142 upon local cerebral glucose utilization have been examined in conscious rats using the quantitative [14C]2-deoxyglucose autoradiographic technique. FG 7142 (1-10 mg/kg i.v.) produced behavioural changes consistent with an anxiogenic action. At the largest dose of FG 7142 (10 mg/kg) 30% of the animals experienced overt convulsions. In the data analysis animals were divided according to the behavioural response elicited by the drug. In animals not expressing convulsions, FG 7142 (1-10 mg/kg) effected increases in glucose utilization in 33 of the 65 regions examined. The majority of changes were confined to limbic structures with pronounced effects occurring in the mammillary body, anterior thalamic nuclei, septal nuclei and the oriens and molecular layers of the hippocampus. Glucose use in other structures associated with auditory and visual processing, such as the medial and lateral geniculate body, and associated cortical areas, was also significantly increased. However, brain regions involved in motor control were minimally affected. The patterns of local cerebral glucose use in animals expressing FG 7142-induced convulsions were contrasted with those from an equivalent non-seizure group. Some limbic structures which were significantly affected by FG 7142 (non-seizure group) displayed a further increase in glucose utilization during convulsions. These included the mammillary body and septum. Many other limbic structures (anterior thalamic nuclei, CA fields of the hippocampus and basolateral amygdala) did not display this further rise in glucose utilization. In the cortical amygdala, lateral preoptic area of the hypothalamus, nucleus accumbens and lateral elevations in glucose utilization were restricted to those animals experiencing overt convulsions.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence against the involvement of a noradrenergic mechanism in the release by diazepam of novelty-induced hypophagia in rats.

The involvement of noradrenergic processes in both the behavioral suppression and release of food intake induced by diazepam, was investigated using the novelty-induced inhibition of food consumption model. Clonidine (7.5-60 micrograms/kg i.p.) and another alpha 2-noradrenergic receptor agonist, guanfacine (0.25-1 mg/kg i.p.), increased the food intake of rats placed in an unfamiliar situation. The effects of clonidine (15 micrograms/kg) were antagonized by yohimbine (0.5-2 mg/kg i.p.). Clonidine (7.5 micrograms/kg) was unable to enhance the efficacy of diazepam (0.5 and 1 mg/kg i.p.) in stimulating food consumption, whereas yohimbine (0.5-2 mg/kg) did not reduce and even increased the potency of diazepam (2 mg/kg) to facilitate food intake. These findings suggest that although noradrenergic processes (and in particular alpha 2-adrenoreceptors) are involved in the hyponeophagia model they do not mediate the releasing effect exerted by benzodiazepines on novelty-induced suppression of food intake.

The thymoleptic action of two salts of flurazepam ('Dalmane').

A double-blind comparison was made of two dose levels (15 and 30 mg.) of the monohydrochloride and dihydrochloride salts of flurazepam ('Dalmane') in 40 hospitalised patients requiring a night-time hypnotic. Each patient in the four drug/dose groups was his own control and took a placebo for 3 nights followed by the active compound for a further 3 nights. On waking each morning a mood state questionnaire was completed. The results indicate that flurazepam is not only an effective hypnotic, but that it has an apparent anxiolytic effect the following morning. Patients report feeling less anxious and more cheerful following drug administration and this result was most noticeable with the 15 mg. monohydrochloride dose.

Effects of beta-carbolines in animal models of anxiety.

Animal models of anxiety can be classified into three main groups: those based on conflict or conditioned fear; those exploiting the anxiety produced by novelty; those in which anxiety or aversion is chemically induced. This review briefly describes the existing tests and, where available, the results obtained with beta-carbolines. Many of the beta-carbolines are anxiogenic in the tests, however ZK 91296 and ZK 93423 appear to have anxiolytic properties, and ZK 93426 has a similar profile to that of the benzodiazepine receptor antagonist RO 15-1788. By the results across the spectrum of tests, the reliability and sensitivity of the tests is assessed. The evidence that the anxiogenic and anxiolytic actions of the beta-carbolines are mediated by the BDZ binding sites is also discussed.

Anxiogenic effects in benzodiazepine withdrawal are linked to the development of tolerance.

Rats were tested in the elevated plus-maze test of anxiety after a probe injection of chlordiazepoxide (CDP 5 mg/kg) following short-term (5 days) or long-term (20 days) pretreatment with 5 or 20 mg/kg/day. After short-term pretreatment with either dose, the probe dose had anxiolytic effects (it increased the % number of entries, and % of time spent, on the open arms). After long-term pretreatment with either dose of CDP there was tolerance to these effects. When the rats were tested 24 hours after their last dose of CDP, there was no indication of spontaneous withdrawal responses in the rats from the short-term pretreatment groups, but the rats in the long-term pretreatment groups showed increased anxiety (decreases in the % number of entries, and the % of time spent, on the open arms, compared with controls). These results support suggestions that the development of tolerance and the incidence of withdrawal anxiety may both be manifestations of the underlying changes occurring during drug dependence.

Changes in GABAergic transmission induced by stress, anxiogenic and anxiolytic beta-carbolines.

The cerebral cortex of unstressed (handling-habituated) rats has a higher number of low affinity GABA receptors than stressed (naive) rats. Foot shock stress delivered to unstressed rats decreases the density of cortical low affinity GABA receptors to the level found in the naive animals. The effect of stress on GABA receptors is mimicked by anxiogenic beta-carbolines, both after in vitro addition (10(-6) M) to cortical membrane preparations or after the in vivo administration (20 mg/kg IP) to unstressed rats. Vice versa, benzodiazepines or anxiolytic beta-carbolines (ZK 93423, 10(-5) M) added to membranes from naive rats increase GABA binding to the level of unstressed rats and remove the decrease in the density of GABA receptors elicited by anxiogenic beta-carbolines. Rats chronically treated with the anxiogenic beta-carboline, FG 7142 (15 mg/kg IP twice a day for 10 consecutive days) have an enhanced sensitivity to punishment at 5 and 15 days after the last treatment. The behavioural effect is paralleled by a marked decrease in the total number of cortical low affinity GABA receptors. Both biochemical and behavioural effects elicited by chronic FG 7142 are prevented by the concurrent administration of the benzodiazepine antagonist Ro15-1788. These results suggest that (a) anxiolytic beta-carbolines, like benzodiazepines, increase the GABAergic transmission, (b) acute and chronic anxiogenic beta-carboline administration, like stress, decreases GABAergic transmission. Since all these effects are antagonized by the benzodiazepine receptor blocker Ro15-1788, it is tempting to speculate that stress releases an endogenous ligand for benzodiazepine recognition sites.