Effects of nicotine,nicotine monomethiodide,lobeline, chlordiazepoxide., meprobamate and caffeine on a discrimination task in laboratory rats

Hungry rats were trained on a discrimination task in order to obtain food rewards. During each experimental session, discrete stimuli of 1 min duration were delivered through a small speaker in the experimental chamber at random intervals on the average of once every 2 min. Lever responses in the presence of a light and tone were correct and produced food rewards. Lever responses in the presence of the light stimulus were incorrect and were punished by total inactivation of the experimental chamber. Rats were selected for this experiment based on their inability to acquire the discrimination task even after six months of training. Administration of nicotine, lobeline, chlordiazepoxide and meprobamate produced an improvement in discrimination performance through a reduction of responses to incorrect stimuli. Caffeine and nicotine monomethiodide, the quaternary salt of nicotine, were without effect on the discrimination.     

Effects of chlordiazepoxide on discrimination performance

Chlordiazepoxide (0, 5, and 10 mg/kg), administered on eight successive sessions, significantly impaired the reinforcement-cued discrimination performance of male Sprague-Dawley rats. This performance partially recovered on two postdrug (saline) session. The discrimination impairment was due to less inhibition of responding during no-go phases and lower response rates during go phases of the task by the drugged than control animals.     

Effects of chlordiazepoxide upon differential heart rate conditioning in rats

Chlordiazepoxide (CDP) at 20 mg/kg, i.p. almost completely blocked classical differential conditioning in heart rate (HR) in unanesthetized rats. But it only slightly, if any, despressed simple HR conditioning to the same conditioned stimulus (CS). The simultaneously observed differential conditioning in respiratory rate (RR) was also inhibited by CDP with its little effect upon simple RR conditioning. Motor activity as measured by changes in EMG records immediately preceding as well as during the CS was not affected either by CDP or by the differential conditioning procedure. Results were explained in terms of the drug's disinhibitory action.     

Effects of drug-state changes upon black-white discrimination learning in rats

Rats were trained on a black-white discrimination task, being motivated by electric shock. After reaching a criterion of 18 out of 20 correct responses in the original discrimination learning (L1), the same discrimination learning was repeated twice (L 2 and L 3) to the same criterion. Rats were exposed to either a drug-induced state (20 mg/kg CDP) or an undrugged state (saline) at each stage of discrimination learning.Chlordiazepoxide (CDP) was generally found to retard the discrimination learning both in terms of correct responses and of running times, although the latter effect was more immediate. A shift in drug state produced a decrease in the percentage of correct responses and this effect was quantitatively about the same whether responses had been overlearned (L3) or not (L2). The same dissociative effect was not found in L3 for those rats which had previously been trained in both drug states. Contrary to some previous studies, running times were not state dependent.     

Effects of GABA agonists and GABA-A receptor modulators on cocaine discrimination in rhesus monkeys

RATIONALE: Dopaminergic systems thought to mediate the abuse-related effects of cocaine are under inhibitory control by GABAergic systems. These findings suggest that GABA agonists may attenuate some abuse-related effects of cocaine. OBJECTIVE: To assess the effects of GABA receptor agonists and GABA-A receptor modulators on cocaine discrimination in rhesus monkeys. METHODS: Rhesus monkeys were trained to discriminate 0.4 mg/kg cocaine from saline in a two-key, food-reinforced drug discrimination task. The effects of the GABA-A agonist muscimol, the GABA-B agonist baclofen, the barbiturate GABA-A receptor modulator pentobarbital, and the benzodiazepine GABA-A modulators triazolam and imidazenil were examined alone and as pretreatments to cocaine. For comparison, the effects of pentobarbital pretreatment on the cocaine-like discriminative stimulus effects of amphetamine were also examined. RESULTS: When administered alone, the GABA agonists and GABA-A receptor modulators produced primarily saline-appropriate responding. When administered as pretreatments to cocaine, pentobarbital attenuated the discriminative stimulus effects of cocaine in all monkeys tested, and the high efficacy benzodiazepine agonist triazolam attenuated cocaine's effects in three of five monkeys. Muscimol, baclofen and the low efficacy benzodiazepine agonist imidazenil did not alter cocaine's discriminative stimulus effects. Although pentobarbital blocked the effects of the monoamine reuptake blocker cocaine, it did not alter the cocaine-like effects of the monoamine releaser amphetamine. CONCLUSIONS: These results are consistent with the hypothesis that GABA-A receptor modulators attenuate the discriminative stimulus effects of cocaine in rhesus monkeys by decreasing the activity of dopaminergic systems. Direct GABA receptor agonists may be less effective in blocking the abuse-related effects of cocaine in rhesus monkeys.     

Effects of haloperidol,trifluperidol, nitrazepam and chlordiazepoxide upon conditioned midbrain behavioral responses

A study was carried out of the actions of haloperidol, trifluperidol, nitrazepam and chlordiazepoxide upon the behavioral and EEG responses during the stages of reinforcement and differentiation of avoidance conditioning in cats with chronically implanted electrodes.The behavioral conditioned response was characterized by the presence of both attentional and emotional components. During reinforcement the emotional component was selectively depressed by all the administered compounds, while the attentional one and the EEG conditioned response were depressed only after the highest doses of haloperidol and trifluperidol. In the differential conditioning the same changes were present during the responses to the reinforced stimulus, although the conditioned responses were more sensitive to the disrupting effects of the drugs and a selective activity on the emotional component did not appear after the benzodiazepine derivatives administration.During both paradigms the EEG arousal patterns very frequently showed a delay after the presentation of the conditioned stimulus and were characterized by lower frequencies and higher amplitudes when compared with placebo.It is suggested that the selectivity of action of the butyrophenone and benzodiazepine derivatives on the emotional component of the conditioned response could be related with a specific action on neural substrates located in the limbic system.This study was supported by Grant MH 15754-01 from the National Institute of Mental Health.Chlordiazepoxide (Librinm^®) and Nitrazepam (Mogadon^®) were kindly supplied by Roche Laboratories, Montevideo, Uruguay.     

Dose-dependent impairment in the performance of a go-no go successive discrimination by chlordiazepoxide

After learning a light-cued, go-no go successive discrimination to criterion, male Sprague-Dawley rats received 0, 5, or 10 mg/kg chlordiazepoxide on six performance sessions, followed by two drug-recovery (saline) sessions. Chlordiazepoxide impaired discrimination performance in a dose-dependent manner, with animals in the 5 mg/kg dose condition demonstrating tolerance to the drug after two performance sessions. The degree of discrimination impairment in both drug dose conditions paralleled an increase in responding during no-go phases of the performance task. These findings are consistent with a disinhibitory hypothesis of performance impairment and suggest that CDP-drugged animals have difficulty in withholding incorrect responses.These data were presented at the Annual Meeting of the Psychonomic Society, San Antonio, Texas, 1984     

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.     

Effects of chlordiazepoxide upon habituation of open-field behavior in white rats

Open-field behavior including ambulation, rearing, defecation and urination were observed in naive rats during a 10 min session each day for 6 consecutive days following administration of D (chlordiazepoxide, 30 mg/kg, p. o.) to Group DD and of S (saline) to Group SS. Group DS received the same dose of D for the first 4 days and S for the last 2 days, while the drug sequence was reversed for Group SD.For the first few min in Session 1, ambulation was slightly more frequent under D than under S and rearing was almost identical in frequency under both states, but afterwards the frequency of both was considerably lowered by D. Defecation (observed twice a session) and urination (observed only after session) were also depressed in drugged rats. A clear intersession habituation was found in all four activities following both S and D, but the habituation was not apparent during the last 5 min of the daily session. The rats subjected to drug-state changes on Day 5 showed increases in these parameters over those with no state change, but this state-dependency was only relative and diminished on the next day.     

Effects of histamine on mechanical performance and biochemical and electrical activity in the heart of monkeys (Macaca fuscata)

The properties of the cardiac effects of histamine on the isolated heart muscles of the Japanese monkey (Macaca fuscata) were investigated. Histamine had a concentration-dependent positive inotropic effect on left atria and papillary muscles and a positive chronotropic effect on right atria. Histamine increased the levels of cyclic AMP and shortened the duration of the action potential in Purkinje fibers, measures of its biochemical and electrophysiological effects. All of these effects of histamine were blocked by 10(-5) M cimetidine. These results indicate that histamine H2-receptors mediate the cardiac effects of histamine on the monkey heart. Histamine (10(-5) M) also restored the action potentials and contractility of K+-depolarized preparations. These effects were inhibited by verapamil (10(-6)-10(-5) M) but not by TTX (10(-5) M), suggesting that, in the monkey heart, histamine may act by increasing the slow inward current.     

Effects of chlordiazepoxide upon spontaneous alternation and the hippocampal electrical activity in white rats

Chlordiazepoxide (CDP) at 20 mg/kg, i. p. reduced the rate of spontaneous alternation in hungry rats on 6 successive trials with no particular reward in a T-maze (Experiment I). The result could not be ascribed simply to the drug-produced changes in running speeds; although alternation is usually assumed to be higher in rate with shorter inter-choice intervals, CDP rats ran slightly faster than saline rats. The same dose of CDP depressed the hippocampal theta activity by decreasing its frequency and facilitating regular fast activity of about 30 Hz which was superimposed on the theta rhythm (Experiment II). The reduction of alternation after CDP was explained in terms of the drug's depressant action upon one of the hippocampal functions, characterized by the theta activity, which is assumed to have a significant role in internal inhibition underlying such behaviors as discrimination reversal, passive avoidance, extinction, frustration, habituation and spontaneous alternation.     

Effects of psychotropic drugs on discrimination conditioning in olfactory bulbectomized rats

In the acquisition process of discrimination avoidance conditioning, bilateral olfactory bulbectomized rats showed poor discrimination conditioning since both the avoidance responses to positive conditioned stimuli (CS) and the incorrect responses to negative CS increased. The effects of various psychotropic drugs upon this poor discrimination conditioning were examined. Chlordiazepoxide 5 mg/kg, IP, produced an increase in the avoidance responses with simultaneous decrease in the incorrect responses, thus making the discrimination possible. Chlorpromazine 2 mg/kg, IP, worsened the discrimination by decreasing both the avoidance and incorrect responses as compared with saline-treated rats. Amitriptyline 10 mg/kg, IP, decreased the incorrect responses without affecting the avoidance responses, thus making the discrimination possible. Methamphetamine 0.5 mg/kg, IP, increased both the avoidance and incorrect responses resulting in poor discrimination conditioning. From these results, it was found that the poor discrimination conditioning of O.B. rats was improved by psychotropic drugs like chlordiazepoxide and amitriptyline.     

Effects of training dose on discrimination and cross-generalization of chlordiazepoxide,pentobarbital and ethanol in the rat

Six groups of rats (N=8), trained to discriminate chlordiazepoxide (5 or 20 mg/kg), pentobarbital (5 or 15 mg/kg) or ethanol (750 or 1500 mg/kg) from saline in a two-lever food-reinforced procedure, were tested for stimulus generalization with the three drugs. Training drug, but not training dose, affected the extent of generalization to a test drug; symmetrical generalization between chlordiazepoxide and pentobarbital and asymmetrical generalization between chlordiazepoxide and ethanol and between pentobarbital and ethanol was observed. Training dose level affected (1) slope and ED₅₀ of the generalization gradients of training drugs and substitution drugs, (2) discriminative performance, (3) response bias and (4) threshold dose for response suppression. Indices of lever selection and percentage drug-appropriate lever responses yielded similar generalization maxima, slopes and ED₅₀s. The potency of chlordiazepoxide relative to the potency of pentobarbital to induce drug stimulus generalization varied across the experimental groups. The results indicate differences between the discriminative effects of chlordiazepoxide, pentobarbital and ethanol. It is suggested that the discriminative effects of chlordiazepoxide, pentobarbital and ethanol are not based on their response rate modulating effects and that training dose is not a determinant for the extent of cross-generalization between these compounds. Offprint requests to: J. De Vry     

Effects of chlordiazepoxide,oxazepam, chlorpromazine,andd-Amphetamine on sexual responses in male and female hamsters

The acute effects on sexual behavior of oxazepam (16–64 mg/kg), chlordiazepoxide (8–64 mg/kg), chlorpromazine (2–8 mg/kg), andd-amphetamine (0.8–3.2 mg/kg) were examined in intact male and female golden hamsters (Mesocricetus auratus). Intraperitoneal injections were given 45 min before the first behavioral test. In 10-min tests lordosis was observed in estrous females both before and after copulation, and mounts, intromissions, and ejaculations were observed in males. Dose-response related decrements in male sexual behavior were observed following chlorpromazine and chlordiazepoxide. All dose levels of oxazepam depressed male sexual behavior. The highest dose of chlordiazepoxide and oxazepam attenuated the onset of female sexual behavior, and all dose levels reduced postcopulatory lordosis durations. Amphetamine did not interrupt either male or female sexual behavior, and chlorpromazine disrupted male but not female behavior.     

Effects of chlordiazepoxide,amitriptyline, imipramine,and their combinations on avoidance behaviour in mice

Chlordiazepoxide, imipramine, and amitriptyline, given alone or in combination, were tested in mice subjected to 5 daily 100-trial avoidance sessions in the shuttle-box. When the drugs were given alone, chlordiazepoxide and the lower doses of imipramine facilitated avoidance behaviour. The higher doses of the two antidepressants impaired avoidance behaviour. Mixtures of chlordiazepoxide and imipramine produced some facilitating effects, while depressant effects prevailed in the chlordiazepoxide-amitriptyline combinations.     

Effects of chlordiazepoxide training dose on the mixed agonist-antagonist properties of benzodiazepine receptor antagonist Ro 15-1788, in a drug discrimination procedure

In experiment 1, rats (n=12) were trained to discriminate the benzodiazepine (BDZ) compound chlordiazepoxide (CDP, 20 mg/kg, IP) from saline in a two-lever food-reinforced procedure, and subsequently were tested for stimulus control with different doses of CDP, Ro 15-1788 (a proposed BDZ receptor antagonist) and Ro 15-1788 plus 20 mg/kg CDP. Ro 15-1788 (0.63–40 mg/kg) dose-dependently antagonized CDP, and induced predominantly saline appropriate responding when administered alone. Thereafter, the same rats were retrained by progressively decreasing the training dose, to discriminate 2.5 mg/kg CDP from saline, and were tested again with the same compounds. Ro 15-1788 (0.16–40 mg/kg) now failed to antagonize CDP (2.5 mg/kg) and increased the percentage of drug-appropriate responding in a dose-related manner when administered alone. In experiment 2, separate groups of rats (n=10) were similarly trained to discriminate either 15 or 3 mg/kg CDP from saline. Tests with CDP, Ro 15-1788 and Ro 15-1788 plus CDP (either 15 or 3 mg/kg) yielded similar results to experiment 1, suggesting that the training dose effects on generalization and antagonism of Ro 15-1788 were not affected by the manner in which the lower CDP dose acquired drug stimulus control. It is concluded that mixed agonist-antagonist properties are apparent after-variations of the BDZ training dose in a drug discrimination procedure.     

Effects of scopolamine on shuttle-box avoidance and go-no go discrimination: Response-stimulus relationships,pretreatment baselines,and repeated exposure to drug

Summary The effects of scopolamine on shuttle-box avoidance and go-no go discrimination in pretrained rats have been shown to vary as a function of performance baselines, of response-CS (or response-S⁺) relationships, and of previous experience in the drug condition. Scopolamine induced a slight depression of active avoidance responding in rats with high baselines when the CS was terminated by the response, while a significantly greater depression was observed when a CS of fixed duration was not immediately terminated by the response. Animals with low baselines were significantly facilitated by the drug when the CS was terminated by the response, but not when it had a fixed duration.As concerns go-no go discrimination, the overall impairment of performance provoked by scopolamine was about the same with a fixed or a variable duration of the S⁺. However, the impairment consisted entirely of an increase of errors of commission (punished crossing responses to S^–) when the S⁺ was terminated by the response. Both errors of commission and errors of omission (absence of response to S⁺) increased after treatment when the S⁺ had a fixed duration.The differences between the two groups of animals increased with repeated exposure to drug. In the group performing with an S⁺ of fixed duration the suppression of responses to S^– was often accompanied by a further marked increase of errors of omission. With repeated exposure most animals gradually compensated for the performance deficit induced by scopolamine in the go-no go situation. Repeated testing in the drug condition was shown to be necessary to obtain this desensitization, since neither overlearning per se, nor overlearning accompanied by repeated post-session administration of scopolamine caused a reduction of sensitivity to drug.The Authors wish to acknowledge the expert assistance of Mr. Luigi AmoricoFellow (1966/1967) of the Istituto Superiore di Sanità     

Effects of chlordiazepoxide,food familiarization,and prior shock experience on food choice in rats

Chlordiazepoxide (5, 10 mg/kg) increased the time devoted to eating familiar laboratory chow without altering the response to a range of novel, palatable foods which were also available to the food-deprived rats. Prior experience with the same range of alternative foods (food familiarization) radically changed the effect of the drug. After familiarization with these foods, chow was virtually ignored as a food choice, indicating its low relative palatability; chlordiazepoxide then prolonged the time eating the familiarized foods without significantly increasing the response to chow. These results are not consistent with an anti-food neophobia action of chlordiazepoxide. They suggest instead that chlordiazepoxide enhances feeding responses related to food saliency. Footshock, delivered two days before the food choice test affected performance within the test. Its effects were opposite those of chlordiazepoxide, but they competed additively with the drug's effects. These results indicate that chlordiazepoxide's action was not simply to remove any inhibitory effect on feeding produced by fear; instead the drug promoted approach to food antagonizing any deficit in approach associated with fear. These findings are viewed as consistent with an action of chlordiazepoxide to augment the level of feeding motivation. Chlordiazepoxide (15 mg/kg) may act to overcome food neophobia.     

Effects of d-amphetamine, chlordiazepoxide and promazine on responding of squirrel monkeys maintained under fixed-interval schedules of food presentation and stimulus-shock termination.

Responding of two squirrel monkeys was maintained under a multiple 5-min fixed-interval schedule of food presentation and termination of a stimulus in the presence of which shocks occurred. Under the stimulus-shock termination schedule, shocks occurred independently of responding, on the average of every three minutes; a response after 5 min terminated the prevailing stimulus and shock-presentation schedule. Response rates and patterns of responding under both schedules were comparable although they differed slightly between monkeys. d-Amphetamine increased and promazine decreased responding under both fixed-interval schedules. Chlordiazepoxide increased responding maintained by food presentation but decreased responding maintained by termination of the stimulus-shock complex. Under certain conditions and with certain drugs, the event that maintains responding can determine the effects a drug will have on behavior.     

Effects of chlordiazepoxide on food anticipation, drinking and other behaviors in food-deprived and satiated rats

Two groups of rats, Deprived and Satiated, were presented with food according to a fixed time 60-sec schedule. They were then injected with saline, 5, 10, and 15 mg/kg of chlordiazepoxide hydrochloride according to a Latin square design. During saline administration time spent visiting the food tray, time spent drinking, number of tray entries and the amount of water ingested were always greater in the Deprived than in the Satiated group; whereas the opposite was true for grooming. As chlordiazepoxide dose increased time spent visiting the food tray increased in both groups, but the effect was bigger in the Satiated than in the Deprived group. Drinking was not affected by the drug. Grooming and sniffing-rearing were reduced as the dose increased.