Chlordiazepoxide modified exploration in rats

Effects of 2.5, 3.75 and 5.0 mg/kg chlordiazepoxide on locomotion, rearing and preferences for novelty in rats were observed in an exploration box comprising a novel and a familiar half. Whereas an inverted U relationship between dose strength and locomotion was evident, rearing declined with increasing dosage. However, the two lower doses had little effect on preferences for novelty but 5.0 mg/kg produced a marked decrease to the point where the familiar half of the apparatus was preferred. It was concluded that estimates of drug effects on measures of locomotion or general activity are specific to those behaviours alone and do not necessarily relate to environmentally oriented exploration. Different views of the effects of drugs on exploratory behaviour might arise from the use of more valid indices, such as preferences for novelty.This work was supported by a research grant from the University Grants Committee (New Zealand).     

Chlordiazepoxide and isolation induced timidity in rats

The effects of chlordiazepoxide (CDP) on emergence behavior was examined in socially reared and isolation reared rats. It was found that low doses of CDP decreased the emergence times of isolated animals but had little effect on the emergence of social animals. At higher doses the drug retarded emergence in all groups but there were no differential effects. The results do not support claims that rearing conditions influence the susceptability of rats to CNS depressants, rather they suggest that particular levels of CDP selectively influence emotional behavior.     

Chlordiazepoxide alters intravenous cocaine self-administration in rats

This investigation was designed to examine the effects of benzodiazepines on intravenous cocaine self-administration in rats. Pretreatment with low doses of the benzodiazepine receptor agonist, chlordiazepoxide (0.3 to 1.0 mg/kg, IP), resulted in small but nonsignificant increases in drug intake with 0.5 mg/kg cocaine, while higher doses (10 mg/kg, IP) significantly decreased drug intake in all rats tested. The effects of chlordiazepoxide on self-administration were attenuated when the concentration of cocaine was increased to 1.0 mg/kg, suggesting that chlordiazepoxide was opposing rather than augmenting the pharmacological actions of cocaine. Pretreatment with the benzodiazepine receptor antagonist, Ro 15-1788 (1.0 to 10 mg/kg, IP), had no effect on self-administration, suggesting that the reinforcing properties of cocaine do not result from direct interactions with benzodiazepine receptors. The result of this investigation demonstrate that chlordiazepoxide alters intravenous cocaine self-administration in rats. Although additional research will be necessary to confirm these data, the results of this investigation suggest that chlordiazepoxide may decrease the reinforcing efficacy of cocaine through indirect actions on dopaminergic neuronal activity potentially mediated through GABAergic mechanisms via benzodiazepine receptor activation.     

Chlordiazepoxide facilitates erections and inhibits seminal emission in rats

Two experiments have been conducted to clarify the effects of the benzodiazepine chlordiazepoxide (CDP) on the different components of male rat sexual behavior. In the first experiment the effects on penile erectile reflexes (PR) of two doses (10 and 30 mg/kg, IP) of CDP were compared with those of vehicle, no-treatment and baseline pre-test in a repeated measures design. In the second experiment the different components of male sexual behavior — PR, mating behavior and spontaneous seminal emission SSE) — were extensively studied after vehicle, 3 and 30 mg/kg CDP treatments. CDP was found to increase significantly the percentage of rats showing penile reflexes, enhance the number of erections per test and shorten the latency to onset of reflexes. It lowered the percentage of animals displaying seminal emission during the PR test. In the mating behavior test, CDP abolished copulatory (and other) behavior at 30 mg/kg. It decreased the number of animals achieving ejaculation at the subataxic 3 mg/kg dose level. In the SSE 3-day test, CDP significantly reduced the weight and the number of plugs of seminal material emitted by the CDP-injected animals. The possible involvement of the serotonergic system in determining the dose-dependent increase in erections and decrease in seminal emission following CDP treatments is discussed. Clinical implications are also briefly considered.     

Chlordiazepoxide and preference for free food in rats.

Rats continued to lever press for food when a bowl of free food was placed in the experimental chamber. Chlordiazepoxide increased the amount of free food consumed, and tended to reduce the amount of lever pressing. It is argued that the drug decreased container neophobia in the animals, rather than acting like an increase in food deprivation.     

Chlordiazepoxide directly enhances positive ingestive reactions in rats

Benzodiazepines such as chlordiazepoxide (CDP) promote feeding in a number of species. This effect has been interpreted generally to be an indirect consequence of benzodiazepine anti-anxiety action, although some have questioned whether it might not reflect instead a direct action upon the reinforcing properties of foods. The present study employed a behavioral measure that can discriminate between these possibilities: palatability-dependent consummatory actions elicited in rats by tastes. The results suggest that chlordiazepoxide enhances the positive palatability of tastes selectively while having little or no effect on aversive palatability. The net effect is to make tastes more reinforcing following CDP administration.     

Chlordiazepoxide and diazepam induced mouse killing by rats

Chlordiazepoxide HCl, at dose levels from 2.5 mg/kg to 80 mg/kg, significantly increased the low base rates of mouse killing (3–9%) observed in large samples (N=100/ dose) of Holtzman strain albino male rats. Maximal killing rates were obtained at doses from 7.5 mg/kg to 20 mg/kg. Diazepam was equally effective, and several times more potent than chlordiazepoxide. Pentobarbital did not increase killing. Killing induced by chlordiazepoxide was blocked by d-amphetamine SO₄, but not by l-amphetamine, at dose levels similar to those that block undrugged killing in this strain (ED₅₀=1.5 mg/kg). Unlike pilocarpine-induced killing, the effects of chlordiazepoxide were not increased or decreased significantly by either peripherally or centrally active anticholinergic drugs, over wide dose ranges of these agents; nor were the effects of chlordiazepoxide increased by repeated daily administration.A preliminary report of the findings described here was made at the Spring 1974 meeting of the American Society for Pharmacology and Experimental Therapeutics (Wnek, Gay, and Leaf, 1974).     

Chlordiazepoxide antinociception: Cross-tolerance with opiates and with stress

Chlordiazepoxide (CDP) has been previously shown to possess antinociceptive properties that are resistant, except at high doses, to the opiate antagonist naloxone. The present study evaluated whether CDP's antinociceptive effects were subject to tolerance following repeated injections and whether cross-tolerance might develop between the antinociceptive action of CDP and that of either morphine or cold water swims. CDP increased flinch-jump thresholds following acute administration and exhibited tolerance following repeated injections. Neither morphine-tolerant nor cold water swim-adapted rats displayed an antinociceptive effect when tested with CDP. On the other hand, chronic pretreatment with CDP attenuated the antinociceptive effects of cold water swims, but did not produce any clear effect upon morphine analgesia.     

Chlordiazepoxide and morphine reduce pressor response to brain stimulation in awake rats

The effects of intravenous as well as dorsal midbrain injections of morphine and chlordiazepoxide on the blood pressure rise induced by electrical stimulation of the dorsal periaqueductal gray matter (DPAG) were studied in unanesthetized rats. Chlordiazepoxide applied systemically or locally into the DPAG, as well as locally applied but not systemically injected morphine were found to attenuate the centrally-induced hypertension. These data together with others suggest that benzodiazepines as well as local injections of morphine into the DPAG decrease the aversive effect induced by DPAG stimulation.     

Chlordiazepoxide and conditioned suppression

Summary Chlordiazepoxide (12 mg/kg) reduced the suppressive effects of a CER stimulus if the drug was given prior to CS-shock pairings. No attenuation of suppression occurred if the drug was given prior to the test for suppressive effects of the CS. This attenuating effect of chlordiazepoxide upon CER learning occurred if the behavior suppressed by the CS was either milk licking or lever pressing for food. The effect was dose-related with higher dosages causing a greater attenuation of CER learning.Preliminary parts of this research were performed while the first author was at Lakeside Laboratories, Milwaukee, Wisconsin.     

Chlordiazepoxide increases the force of two topographically distinct operant responses in rats

By using operant conditioning techniques one group of 8 rats was trained to reach through a hole in the wall of an operant chamber, and to exert downward responses on a force-sensing circular disk. Eight other rats learned to reach through the hole and grasp and pull toward them a wire bail attached to a force transducer. Both behaviors were maintained on a fixed ratio 20 schedule of water reinforcement. The effects of chlordiazepoxide (CDP, 2.5, 5.0, 10.0 mg/kg) on response force and rate were assessed for both groups. CDP significantly increased response force in a dose-related manner in both groups; regardless of topography, response rate was little affected by the 2.5- and 5.0-mg/kg doses but was decreased by the highest dose. Results were discussed in terms of CDP's antipunishment and neuromuscular effects.     

Chlordiazepoxide specifically impairs nonspatial reference memory in the cued radial arm maze in rats

Anxiolytic benzodiazepines, at low doses, reportedly impair the radial arm maze with nonspatial visual/tactile but not spatial cues. We replicated the former result controlling for changes in drug state and cue effectiveness. Rats learned an eight-arm radial maze with reward in only four arms. The reward varied in spatial position from trial to trial but was always cued by a piece of sandpaper at the entry to the arm. Chlordiazepoxide (5 mg/kg, ip) impaired acquisition. Rats that switched from saline during acquisition to chlordiazepoxide showed an impairment of performance that only lasted for 1 day. Removal of the cues reduced the performance of controls and switched rats to the level of the rats that received chlordiazepoxide during acquisition but did not affect the latter. These data suggest that chlordiazepoxide does indeed impair nonspatial reference memory in the radial arm maze while leaving working memory, and, possibly, spatial reference memory, intact but that the previous report of this effect was the result of a change in drug state rather than of the drug itself.     

Chlordiazepoxide,expectation and hostility

Summary An experiment is described in which chlordiazepoxide or placebo was administered to a group of low anxious normal male volunteers with and without instructions of a set (expectation) that the drugs would decrease their feelings of hostility and anxiety. The data indicated that chlordiazepoxide alone, and expectation alone, each increase hostility scores, but that when combined together, there was no such increase in baseline hostility levels. Introduction of set after hostility levels were increased served to further increase rather than reverse these scores. Drug, placebo, expectation or the combination of drug and expectation had no effect on anxiety scores.Supported by: NIMH Grant # MH 12279-02.     

Morphine tolerance in male and female rats

Several studies indicate greater sensitivity to morphine (MOR) analgesia in male compared to female rats under the acute dosing condition. The present study investigated whether the same sex difference in sensitivity persists in MOR-tolerant rats. MOR was administered chronically (7 mg/kg twice daily) until tolerance developed in each rat. Tolerant rats were treated randomly with higher graded doses of MOR (10-25 mg/kg). Analgesia (tail-flick test) and spontaneous motor activity (total locomotion) were measured. The present data confirmed previous studies showing a greater sensitivity to acute MOR in male than in female rats. However, the sex differences seen in MOR sensitivity were abolished in tolerant rats. The rate of acquisition of tolerance was similar in male and female rats. The analgesic response was not affected by motor depression.     

Chlordiazepoxide and the drinking of water by rats: effects of shock and other suppressive measures

The effects of chlordiazepoxide (5 and 10 mg/kg) on fluid consumption in water deprived rats were assessed. Drinking was inhibited to approximately equal extents by a water preload, by d-amphetamine (1.5 mg/kg), by neophobia and by shock at mild (0.3 mA) or moderate (0.5 mA) intensities, the latter condition having an enhanced level of deprivation also. At both doses chlordiazepoxide significantly enhanced drinking in the neophobia, mild shock and, especially, the moderate shock condition but failed to increase drinking suppressed by preload or d-amphetamine. It is concluded that the increases in drinking suppressed by neophobia or shock which chlordiazepoxide induces may be due to anxiolytic actions of the drug or to enhanced palatability since they cannot be explained in terms of nonspecific enhancement of fluid consumption.     

Acute tolerance to amphetamine in rats

Two groups of rats were given amphetamine intravenously at 5-min intervals (5 or 10 mg/kg/h) for 8h. Two control groups received saline infusions. On the second day a test dose of 10 mg/kg amphetamine was given to all groups. Body temperature, food intake, and motor behavior were registered every 30 or 60 min. The results showed the development of acute tolerance to the hyperthermic effect within 3–5 h. Tolerance was still visible on the 2nd day. There was also tolerance to the anorectic effect, which was evident on the 2nd day. One element of stereotyped behavior (swaying) also decreased during the amphetamine infusions.