Incentive contrast undiminished by extended testing,imipramine, or chlordiazepoxide

In three experiments rats were given alternating 1-minute access periods to two tubes containing sucrose solutions. When the tubes contained disparate concentrations (32% versus 4%), lick-rate was higher for the 32% solution than it was when both tubes contained 32% (a positive contrast effect) and less for 4% that when both tubes contained 4% (a negative contrast effect). Similar, but generally less pronounced, contrast effects were obtained in latency to initiate drinking. These contrast effects showed no sign of diminution with repeated exposure (32 days of repeated shifts in Experiments 1 and 3); they were not greatly influenced by injections of imipramine (Experiment 2) or chlordiazepoxide (Experiment 3), nor by deprivation conditions (Experiment 3). The results supported an explanation of simultaneous contrast in terms of sensory-perceptual processes rather than in terms of generalization decrement or emotional responses.     

Conditions under which chlordiazepoxide influences gustatory contrast

Rats shifted from 32% sucrose to 4% sucrose consumed less 4% than animals without prior experience with 32% sucrose. The influence of chlordiazepoxide (CDP) on this successive negative contrast obtained in sucrose ingestion was investigated in four experiments. The results indicated that (1) rats injected with CDP during both preshift experience with 32% sucrose and post-shift experience with 4% sucrose showed an essentially unchanged contrast effect compared with saline-injected rats, (2) CDP injection for the first time on post-shift day 2 eliminated contrast but post-shift day 1 injections had little effect, (3) animals injected with CDP throughout preshift and switched to saline coincident with the sucrose shift showed a contrast effect at least as great as control animals, and (4) injections of CDP tended to elevate lick rate regardless of other conditions. These results indicate a disinhibitory effect of CDP and possible neophobia operating on the first post-shift day.     

Effect of diphenylhydantoin sodium and chlordiazepoxide alone and in combination on punishment behavior

Summary Punishment behavior was obtained in rats by simultaneously punishing and rewarding all lever presses made during the presentation of a non-aversive tone. When stable control performances were established, animals were given various doses of diphenylhydantoin or chlordiazepoxide. In addition, drug interaction studies were conducted with a non-effective dose of the former and selected doses of chlordiazepoxide. When diphenylhydantoin was given at effective anti-convulsant doses it did not diminish the suppressant effect of response produced shock. When the animals were given chlordiazepoxide after doses as low as 1.875 mg/kg, significant diminution was obtained in certain rats; and effects were dose-dependent until a clearly depressant dose was given. Both agents reduced variable interval responding after a dose of 15 mg/kg. Diphenylhydantoin did not enhance or antagonize the effects of chlordiazepoxide in the punishment phase of the schedule. However, some animals given non-depressant doses of each in combination did show a significant reduction in response rate in the variable interval component of the schedule.     

The effects of the beta-carboline FG 7142, on intracranial self-stimulation in the rat

The effects of FG 7142 were examined, alone and in combination with chlordiazepoxide, on self-stimulation of the mid-lateral hypothalamus. Rewarding stimuli were delivered according to a 10-sec variable-interval schedule of reinforcement. FG 7142 (1-20 mg/kg) produced a dose-related depression in responding, and chlordiazepoxide (5 mg/kg) enhanced it. When these two drugs were given together, response rates did not differ significantly from control rates.     

MR/Har and MNRA/Har Maudsley rat strains: differential response to chlordiazepoxide in a conflict task

The Maudsley Reactive (MR/Har) and Non-Reactive (MNRA/Har) rat strains, selectively bred for differences in open field defecation, have also been shown to differ in their baseline behavior in the Conditioned Suppression of Drinking (CSD) procedure, a second "model" behavior for the study of anxiety and/or emotionality in rats. The present studies were designed to compare the responsiveness of these two strains to the typical antianxiety agent chlordiazepoxide in the CSD paradigm. In daily 10-minute sessions, water-deprived rats were trained to drink from a tube that was occasionally electrified (0.5 mA), electrification being signaled by a tone. Consistent with previous reports, after several weeks of CSD testing, MNRA/Har rats accepted significantly more shocks than did MR/Har rats during control (nondrug) sessions. In both strains, the number of shocks accepted was inversely related to the intensity of the shock used (0.25-1.0 mA), with MNRA/Har rats accepting significantly more shocks than MR/Har rats at all intensities examined. The effects of various doses (1.25-28.4 mg/kg, IP) of chlordiazepoxide were determined in subjects of the MNRA/Har strain at the original training intensity (0.5 mA), while a lower intensity (0.25 mA) was utilized in MR/Har rats. Although punished responding in control (i.e., nondrug) CSD sessions did not differ under these conditions, MNRA/Har rats were found to be more responsive to the anticonflict effects of chlordiazepoxide than rats of the MR/Har strain. This strain difference in anticonflict efficacy of chlordiazepoxide was quite dramatic, with MNRA/Har rats accepting twice as many shocks as MR/Har rats following maximally effective doses of chlordiazepoxide. Low doses of chlordiazepoxide increased water intake slightly, while higher doses decreased water intake. Surprisingly, the chlordiazepoxide-induced depression of water intake was greater in rats of the MR/Har strain. Thus, these Maudsley Reactive and Non-Reactive rat strains, bred originally for their differences in open field behavior, also differ markedly in their responsiveness to chlordiazepoxide in the CSD paradigm. These findings further support the hypothesis that the MR/Har and MNRAHar rat strains may represent a genetically-based "animal model" for the study of emotionality and/or anxiety.     

Sedative effects of PK 9084 and PK 8165, alone and in combination with chlordiazepoxide

1 The sedative effects in rats of two phenylquinolines, PK 9084 and PK 8165 (5-50 mg/kg), were examined in a holeboard: both when given alone and when given in conjunction with chlordiazepoxide (5 mg/kg). 2 Both phenylquinolines produced significant dose-related decreases in locomotor activity and rearing, with an ED50 about twice that for chlordiazepoxide. 3 When the phenylquinolines were combined with chlordiazepoxide the degree of sedation was equal to that seen with either drug given alone, whichever produced the greater sedation; the sedative effects of the two drugs were never additive. 4 PK 9084 (10 and 50 mg kg) significantly reduced rectal temperature, as did chlordiazepoxide (5 mg/kg), but there was no addition nor interaction of their effects. 5 Both phenylquinolines also reduced exploratory head-dipping, as did chlordiazepoxide, but in combination they antagonized each other's effects. 6 The classification of the phenylquinolines as non-sedative anxiolytics, acting as agonists at the benzodiazepine receptors needs revision.     

Influence of ethanol on contrast in consummatory behavior

Negative contrast that occurs when rats are shifted from 32% to 4% sucrose was reduced by IP injections of ethanol (1.0 g/kg) on postshift day 2, but not on postshift day 1. Smaller doses (0.25 and 0.5 g/kg) were ineffective, while larger doses (1.5 and 2 g/kg) produced sedation. A dose of 0.75 g/kg had effects similar to the 1.0 g/kg dose when administered on post-shift day 2. These results parallel those obtained with chlordiazepoxide and differ somewhat from amobarbital treatment.     

Chlordiazepoxide and ethanol additively reduce gustatory negative contrast

Negative contrast that occurs when rats are shifted from 32% to 4% sucrose has been shown to be reduced by chlordiazepoxide (CDP) and ethanol (ETOH). In a previous experiment, doses of 0.75 and 1.0 g/kg ETOH substantially reduced contrast while doses of 0.25 and 0.5 g/kg ETOH were much less effective. In this study, doses of 6 and 8 mg/kg CDP were shown to attenuate the negative contrast effect while smaller doses (2 and 4 mg/kg) influenced contrast to a lesser degree. Evidence for an additive effect of CDP and ETOH on contrast reduction was obtained when 4 mg/kg CDP and 0.5 g/kg ETOH were administered together.     

A placebo-controlled multicenter trial of Limbitrol versus its components (amitriptyline and chlordiazepoxide) in the symptomatic treatment of depressive illness

In a multicenter, placebo-controlled, clinical trial, the efficacy of Limbitrol was compared with that of its components, amitriptyline and chlordiazepoxide. All patients had a diagnosis of primary depression. Data from 279 patients were evaluated using the Hamilton depression scale, the Beck depression inventory, and physician and patient global change measures.Statistically significant differences favoring Limbitrol occurred after 1 week of treatment, and a trend in favor of Limbitrol continued throughout the remaining 3 weeks. In most efficacy comparisons, the combination was as good as, or better than, amitriptyline alone. It was superior to chlordiazepoxide alone after 2 and 4 weeks of treatment. Each component produced an independent contribution to the total therapeutic effect: the chlordiazepoxide effect was more prominent in the first 2 weeks and the amitriptyline effect in the latter 2 weeks. A trend favoring amitriptyline over chlordiazepoxide was evident by week 4.The overall incidence of side effects was comparable in both Limbitrol- and amitriptyline-treated groups. Limbitrol-treated patients exhibited more sedation, but significantly fewer Limbitrol patients discontinued treatment prematurely because of side effects.     

Effect of clonidine on consummatory negative contrast and on novelty-induced stress

In Experiments 1 and 1a rats were shifted from 32% to 4% sucrose solutions. The resultant negative contrast effect in consummatory behavior was not alleviated by clonidine (3.12, 6.25, 12.5, 25.0 and 50.0 micrograms/kg). The lower dose of the drug had no effect on behavior, the higher doses reduced consumption in shifted and unshifted rats in a dose dependent fashion. In Experiment 2 clonidine (6.25, 12.5 micrograms/kg) raised plasma glucose levels in a dose dependent fashion when the animals were exposed to a novel environment. These results are at variance with those obtained with chlordiazepoxide (and other anxiolytics in the case of contrast effects) and suggest limits on the degree to which clonidine can be considered to function as an anxiolytic.     

Effects of amisulpride on consummatory negative contrast

Two groups of rats, 'shifted' (32-4% sucrose) and 'unshifted' (4-4% sucrose), were given access to sucrose solutions for 5 min/day for 10 days. On day 11, shifted animals had access to a devalued incentive (4% sucrose) and subgroups of each group received doses of amisulpride (10 or 60 mg/kg, i.p.) or its vehicle before a 10-min access period to sucrose solutions. Lick frequency was measured both pre- and post-shift. A high dose of amisulpride reduced successive negative contrast (SNC) after a brief period of exposure to the devalued stimulus, whereas a low dose had no effect. The acute effects of high doses of amisulpride seem to act on contrast effects in a similar way to anxiolytic compounds such as the benzodiazepine, chlordiazepoxide.     

Despite various drugs,cats continue to kill mice

Amphetamines (d- at 0.5–4 mg/kg; 1- at 2–4 mg/kg) inhibited spontaneous mouse killing by some, but not all cats. Various other drugs (drugs and maximum tested doses were: imipramine, 64 mg/kg; amitriptyline, 32 mg/kg; tranylcypromine, 2 mg/kg; tripelennamine, 4 mg/kg; scopolamine, 1 mg/kg; methyl scopolamine, 1 mg/kg; chlordiazepoxide 16 mg/kg; diazepam 4 mg/kg; meprobamate, 80 mg/kg; pentobarbital, 16 mg/kg; chlorpromazine, 8 mg/kg; and haloperidol, 0.5 mg/kg) did not reliably inhibit such killing. In contrast with rats, mouse killing by cats was not consistently blocked by antidepressants or amphetamines. When individual cats were inhibited, their reduction of killing seemed related to anorexia rather than to affective arousal.     

Characteristics of coping behavior of rats exposed to a long-term hardly escapable aversive stimulus: a possible depression model

The purpose of the present study was to induce a state of depression including both the elements of behavioral despair and chronic stress. Therefore, this study was performed under the hypothesis that a long-term exposure of rats to the experimental situation of difficult to escape from foot-shock in a Skinner box might produce animals with a state of depression containing both the elements. Male Wistar strain rats were trained to press a lever to escape from foot-shock under a fixed ratio (FR) schedule. After the training, rats were exposed daily to a schedule consisting of 20 trials (the early 10 trials, FR 5; the later 10 trials, FR 20) once a day. The exposure resulted in reduction of the number of lever presses and successful escape in FR 20. Only the animals whose number of escapes, reduced to under 20% in FR 20 were treated with psychotropic drugs once a day for 4 days. The results showed that the reduced number of escapes was most improved by antidepressants (imipramine or mianserin), but not by haloperidol and methamphetamine. Although subchronic treatment with chlordiazepoxide partially recovered the reduced escape, the efficiency of lever pressing to escape from foot-shock was lower than that with the antidepressants. The results of the present study suggest that the behavioral suppression observed in this study might include characteristics similar to a state of depression.     

Effects of chlordiazepoxide (librium) on the acquisition and extinction of avoidance responses

Summary The major purpose of the present experiment was to assess the differential effectiveness of chlordiazepoxide on avoidance response acquisition and extinction. Two groups of rats, one as control and the other treated with chlordiazepoxide were compared on avoidance response acquisition. No significant differences were noted between the two groups, indicating that chlordiazepoxide was not effective in modifying the rate of avoidance response acquisition. The chlordiazepoxide group was then divided into two subgroups, one continued on chlordiazepoxide and the other deprived of chlordiazepoxide for the extinction training. The control group was also divided into two subgroups, one continued as control and the other treated with chlordiazepoxide for the extinction training. These divisions resulted in closely matched subgroups in the number of avoidance response acquisition, making intergroup comparisons of extinction performance possible. This intergroup comparison showed that chlordiazepoxide was effective in modifying the rate and degree of extinction. Less resistance to extinction was shown by the groups specifically treated with chlordiazepoxide during the extinction period, demonstrating that the effectiveness of chlordiazepoxide was confined mainly to the extinction process. These results were evaluated with the view that a conditioned avoidance response is mediated by fear, and an attempt was made to account for the effects of chlordiazepoxide on fear upon which the condition avoidance response is thought to depend.Chlordiazepoxide supplied by Roohe Laboratories, Division of Hoffmann-La Roche, Inc.     

Development and retention of tolerance to the sedative effects of chlordiazepoxide: Role of apparatus cues

Groups of rats were pretreated for 5 days with chlordiazepoxide (5 to 50 mg/kg) or with control water injections. On the sixth day the rats were given a test dose of chlordiazepoxide (10 mg/kg), or water. The rats that had received 5 days of pretreatment with chlordiazepoxide were significantly less sedated by the test dose than were those given chlordiazepoxide for the first time, i.e. they had developed tolerance. There were no significant differences between the two pretreatment groups in the extent of tolerance. A second experiment examined the effects of associating drug injections with apparatus cues. This had no effect on the development of tolerance, but had a significant effect on its retention: rats pretreated and replaced in their home cages showed complete recovery from tolerance after two drug-free days, whereas those placed in the apparatus after each day's injection retained some tolerance even after two drug-free weeks.     

Effects of chlordiazepoxide on passive avoidance responses in rats

The effect of chlordiazepoxide on the retention of a passive avoidance response was determined in rats. Chlordiazepoxide or saline was given before testing in a two compartment passive avoidance response (PAR) apparatus or in an open field, and again after 48 and 72 h.The PAR was usually depressed by chlordiazepoxide (CDP) given during acquisition, and it remained present after 48 and 72 h. Treatment with chlordiazepoxide before the second and third testing abolished the depression of PAR. CDP had most effect on the acquired PAR.Shock treatment resulted in an increase in defecation and urination and a decrease in ambulation and rearing in the PAR apparatus as well as in the open field. These effects were reduced by CDP, irrespective of drug-state changes. A clear-cut reduction in defecation and urination under CDP in well-habituated home cages was also seen. The depressant effect of CDP upon the PAR is discussed in relation to the drug's inhibitory action upon the hippocampal theta activity.     

Pentylenetetrazole-like stimulus is produced in rats during withdrawal from ingested chlordiazepoxide

The present study was undertaken to determine whether withdrawal from chlordiazepoxide administered via a liquid diet would produce a pentylenetetrazole (PTZ)-like stimulus. Rats were trained with food reward in a two-lever operant task. Presses on one lever were reinforced after injections of PTZ (20 mg/kg, i.p.) and on the other lever after saline (1 ml/kg, i.p.). After rats had acquired the PTZ discrimination, training was halted, and chlordiazepoxide (240 mg/kg/day) was administered via a nutritionally balanced liquid diet to three groups of rats for 3, 4, or 6 days. Upon termination of chronic administration, withdrawal was precipitated with the benzodiazepine receptor blocker flumazenil (Ro 15-1788) given intraperitoneally. During precipitated withdrawal, the rats selected the PTZ-appropriate lever, indicating the presence of a PTZ-like stimulus, and this stimulus was blocked by phenobarbital (80 mg/kg, i.p.). The percentage of rats selecting the PTZ-appropriate lever depended on the duration of chlordiazepoxide treatment and dose of flumazenil. At 10 days after the last chlordiazepoxide dose, the rats had recovered baseline discrimination, as indicated by their selection of the saline appropriate lever following saline injections and the PTZ-appropriate lever following PTZ. These data indicate that a subjective effect of withdrawal similar to that produced by the anxiogenic drug PTZ is present during withdrawal from oral chlordiazepoxide.     

Attenuation of reperfusion hyperalgesia in the rat by systemic administration of benzodiazepines.

1. An investigation into whether reperfusion hyperalgesia is modulated by prior systemic administration of two benzodiazepine agonists (diazepam and chlordiazepoxide), and an antagonist (flumazenil) was conducted. 2. Transient ischaemia was induced in conscious rats by applying an inflatable tourniquet to the base of the tail; when the rats exhibited a co-ordinated escape response, the tourniquet was deflated and reperfusion of the tail was allowed. Reperfusion hyperalgesia manifested as a decrease in tail flick latency, following tail immersion in 49 degrees C water, after the release of the tourniquet. 3. Intraperitoneal administration of diazepam, chlordiazepoxide and flumazenil had no effect on the co-ordinated escape to the noxious ischaemic stimulus nor on tail flick latency after application of a sham tourniquet. 4. The hyperalgesia evident during reperfusion, was abolished by diazepam (1 and 5 mg kg-1) and chlordiazepoxide (5 and 25 mg kg-1). The antihyperalgesic effects of both diazepam (5 mg kg-1) and chlordiazepoxide (25 mg kg-1) were inhibited by flumazenil (1 mg kg-1). 5. Rotarod performance was impaired in rats given diazepam and chlordiazepoxide at the same doses at which the benzodiazepines were antihyperalgesic. The impairment to motor function did not extend to the motor systems involved in the tail flick response. 6. In conclusion, benzodiazepines have antinociceptive properties during hyperalgesia.     

Self administration of minor tranquilizers as a function of conditioning

Summary An attempt was made to develop pronlonged preferences in rats for quinine, LSD, nicotinic acid, meprobamate and chlordiazepoxide. It was found that forced ingestions of the drugs had no enduring effects on subsequent free choice preference intakes. When the animals were conditioned to drink the drugs in order to obtain food pellets, it was found that they developed increased preferences for meprobamate and chlordiazepoxide which endured over a 21 day free choice period. The results are interpreted as showing that through pairing with food several of the drugs acquired secondary reinforcing properties which were responsible for their sustained drinking by the animals.     

Propranolol and chlordiazepoxide on experimentally induced conflict and shuttle box performance in rodents

Propranolol failed to attenuate the suppression of behavior caused by experimentally induced conflict in rats and failed to enhance the avoidance performance of partially trained mice in a shuttle-box situation, effects which are observed after chlordiazepoxide. When given in combination with chlordiazepoxide, propranolol did not influence the effects of the tranquilizer in either procedure.