Anxiolytic Effects Of Chlordiazepoxide Research Articles

The contribution of contextual fear in the anxiolytic effect of chlordiazepoxide in the fear-potentiated startle test

This study evaluated the extent to which a reduction in contextual fear contributes to the anxiolytic effect of benzodiazepines in the fear-potentiated startle response. To this end, chlordiazepoxide, an anxiolytic often used as positive control in preclinical drug studies, and zolpidem, known to have sedative properties and to be devoid of anxiolytic effects, were tested in two contexts: the same context as training had taken place and an alternative context. In addition, the level of muscle relaxation was assessed in a grip strength test. Chlordiazepoxide (2.5–10 mg/kg) decreased the fear-potentiated startle response, confirming its anxiolytic activity. In addition, it dose-dependently decreased the overall startle response in the same, but not the alternative context, and did not affect grip strength, indicating that chlordiazepoxide inhibits contextual fear in the absence of non-specific drug effects. Zolpidem (1.0–10 mg/kg) reduced the overall startle response in both contexts equally and decreased grip strength, indicating that its effects on fear-potentiated startle are due to non-specific drug effects, and not anxiolytic effects. The present findings show that chlordiazepoxide reduces contextual conditioned fear in the absence of non-specific drug effects. In addition, they show that training and testing rats in different contexts makes it possible to distinguish between cued, contextual and non-specific drug effects. As exaggerated contextual fear conditioning contributes to the fear generalization processes implicated in pathological anxiety, focus in screening of anxiolytic effects could be directed more towards the suppression of contextual fear and, therefore, this approach would be a valuable addition to standard preclinical screening.

Overlapping and Distinct Brain Regions Associated with the Anxiolytic Effects of Chlordiazepoxide and Chronic Fluoxetine

Little is known about the sites of action for the behavioral effects of chronic antidepressants. The novelty-induced hypophagia (NIH) test is one of few animal behavioral tests sensitive to acute benzodiazepines and chronic antidepressants. The goals of these experiments were to examine patterns of brain activation associated with the behavioral response to novelty and identify regions that could regulate the anxiolytic effects of acute benzodiazepine and chronic antidepressant treatments, measured using the NIH test. In the first experiment, rats were treated acutely with the anxiolytic, chlordiazepoxide (2.5 or 5 mg/kg, i.p.). In separate experiments, animals were implanted with osmotic minipumps delivering vehicle or fluoxetine (5 or 20 mg/kg per day s.c.) for 3 or 28 days. NIH was assessed by giving animals access to a familiar palatable food in a novel environment. Associated brain areas were identified using c-fos immunohistochemistry. NIH was mitigated by acute chlordiazepoxide and chronic fluoxetine. Both drugs reversed novelty-induced changes in c-fos expression in the lateral division of the posterolateral part of the bed nucleus of the stria terminalis (STLP), cingulate cortex (Cg), and dorsal field CA2 of the hippocampus (dCA2). Chronic fluoxetine additionally increased c-fos expression in the anterior nucleus accumbens (aAcb) and the piriform cortex (Pir). The effects of the drugs on c-fos expression in many regions correlated with anxiolytic efficacy. These findings identified brain regions where the effects of chronic antidepressants and benzodiazepines may converge to produce anxiolytic activity, as well as distinct sites of action for the two classes of drugs.

Naltrexone potentiates both amnestic and anxiolytic effects of chlordiazepoxide in mice

Studies have suggested that opioid antagonists potentiate the anxiolytic effect but not the amnestic action of chlordiazepoxide (CDZ). We investigated the effects of naltrexone (NAL) on the anxiolytic and amnestic effects of CDZ in mice tested in the plus-maze discriminative avoidance task (DAT). Mice are conditioned to choose between two enclosed arms (one of which aversive) while avoiding the two open arms of the apparatus. This task measures memory (time spent in the aversive vs. time in the non-aversive enclosed arms) and anxiety (time spent in the open arms). Mice treated with saline (SAL) or 5 mg/kg NAL, and SAL or 2.5 mg/kg CDZ were submitted to DAT training. The test was performed 24 h later, without aversive stimuli. In the training, NAL + CDZ group showed higher percent time spent in the open arms than all the other groups. In the test, NAL + CDZ (but not SAL + CDZ) group showed higher percent time spent in the aversive enclosed arm than SAL + SAL and NAL + SAL groups. The data suggest that NAL potentiates the small decreases in anxiety and retention induced by a subeffective dose of CDZ.

Possible involvement of nitric oxide in chlordiazepoxide-induced anxiolysis in mice

Mice challenged with the anxiolytic benzodiazepine chlordiazepoxide exhibited significant increases in the percent of total entries into and percent of total time spent on open arms of an elevated plus maze. Systemic pretreatment with the nitric oxide synthase-inhibitor L-N G-nitro arginine (L-NOARG) antagonized these effects of chlordiazepoxide. This inhibitory effect of L-NOARG was stereospecifically and completely reversed by intracerebroventricular administration of L-arginine but not D-arginine. These findings suggest a possible role of nitric oxide in the anxiolytic effect of chlordiazepoxide in the elevated plus maze.

The use of a plus-maze to measure anxiety in the mouse.

To investigate whether an elevated plus-maze consisting of two open and two closed arms could be used as a model of anxiety in the mouse, NIH Swiss mice were tested in the apparatus immediately after a holeboard test. Factor analysis of data from undrugged animals tested in the holeboard and plus-maze yielded three orthogonal factors interpreted as assessing anxiety, directed exploration and locomotion. Anxiolytic drugs (chlordiazepoxide, sodium pentobarbital and ethanol) increased the proportion of time spent on the open arms, and anxiogenic drugs (FG 7142, caffeine and picrotoxin) reduced this measure. Amphetamine and imipramine failed to alter the indices of anxiety. The anxiolytic effect of chlordiazepoxide was reduced in mice that had previously experienced the plus-maze in an undrugged state. Testing animals in the holeboard immediately before the plus-maze test significantly elevated both the percentage of time spent on the open arms and the total number of arm entries, but did not affect the behavioral response to chlordiazepoxide. The plus-maze appears to be a useful test with which to investigate both anxiolytic and anxiogenic agents.

The role of GABA in the anticonflict action of sodium valproate and chlordiazepoxide

The anxiolytic effects of chlordiazepoxide (CDP) in the Geller-Seifter rat conflict test have been compared with those of muscimol and sodium valproate in order to evaluate the possible role of GABA in the anxiolytic action of the benzodiazepines. The anticonflict activity of CDP was inhibited by the benzodiazepine antagonist Ro15-1788, as well as by bicuculline and picrotoxin. The weaker anticonflict effect of muscimol was overcome by both bicuculline and picrotoxin. Sodium valproate had a marked anticonflict effect which was only inhibited by picrotoxin. Thus, while the anxiolytic action of CDP depends on GABA function in some way, it can be distinguished from the effects of muscimol and sodium valproate which appear to act at the GABA receptor and the chloride ion channel, respectively.

Tracazolate: A novel nonsedative anxiolytic

AbstractTracazolate (ICI 136,753; 4‐butylamino‐1‐ethyl‐6‐methyl‐1H‐pyrazolo [3,4‐b] pyridine‐5‐carboxylic acid ethyl ester) exhibited dose‐related anticonflict activity in mice, rats, and squirrel monkeys. The potency of tracazolate appears to be one‐quarter to one‐half that of chlordiazepoxide, and their durations of activity are similar in rats. No tolerance to the anticonflict activity of either chlordiazepoxide or tracazolate was evident following 12 consecutive days of treatment. Tracazolate exhibits a much greater separation between sedative and therapeutic doses than does chlordiazepoxide; thus, it is predicted that tracazolate will not be sedative at anxiolytic doses in man. Furthermore, based upon studies in rodents, tracazolate should be much less likely than the benzodiazepines to potentiate the actions of barbiturates and ethanol in man. Although tracazolate is an anticonvulsant in rodents, it is considerably less potent in this respect than chlordiazepoxide. In contrast to benzodiazepine anxiolytics, tracazolate enhances the binding of 3H‐benzodiazepines to their binding sites in brain. Consistent with this finding, tracazolate potentiated both the anticonvulsant and anxiolytic effects of chlordiazepoxide in rodents. Although the benzodiazepine antagonists (RO 15‐1788 and CGS 8216) clearly antagonize the anticonflict activity of chlordiazepoxide, the activity of tracazolate was not significantly altered by either antagonist. Both chlordiazepoxide and tracazolate significantly enhanced 3H‐γ‐aminobutyric acid (GABA) binding. These results suggest that tracazolate is a novel psychoactive agent that should be a useful anxiolytic drug in man.

Pharmacological properties of tracazolate: A new non-benzodiazepine anxiolytic agent

Tracazolate (ICI 136,753, 4-butylamino-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester) demonstrated dose-related anticonflict activity in rats and mice. The potency of tracazolate appears to be one-quarter to one-half that of chlordiazepoxide. No tolerance to the anticonflict activity of either tracazolate or chlordiazepoxide was evident following 12 consecutive days of treatment. Tracazolate exhibits a much greater separation between sedative and therapeutic doses than does chlordiazepoxide. Furthermore, based on rodent studies, tracazolate should be much less likely than the benzodiazepines to potentiate the actions of barbiturates and ethanol in man. Tracazolate potentiated both the anticonvulsant and anxiolytic effects of chlordiazepoxide in rodents. Unlike benzodiazepines, tracazolate enhances the binding of benzodiazepines to its receptor site. These results suggest that tracazolate is a novel agent with potential clinical utility as an anxiolytic drug.