Differential EEG effects of the anxiolytic drugs, deramciclane (EGIS-3886), ritanserin and chlordiazepoxide in rats

The influence of serotonergic and benzodiazepine type anxiolytic drugs on the cortical activation and sleep-wakefulness cycle were compared by evaluating the effects of ritanserin and deramciclane (EGIS-3886), two 5-HT₂ receptor antagonists, and chlordiazepoxide on the electroencephalogram (EEG) in freely moving rats. Following drug administration (1, 3, and 10 mg/kg, PO for all drugs), EEG was continuously sampled for 6 h and power spectra were calculated for every 5 s to assess changes in slow wave activity and sleep phases. In a separate test, anticonvulsant effects of the drugs were examined in mice. Both deramciclane and ritanserin slightly increased total time spent in deep sleep (DS) and lengthened sleep episodes. In contrast, chlordiazepoxide had a strong inhibitory action on DS, sleep time being shifted to more superficial light sleep (LS). The incidence and length of the high voltage spindle (HVS) episodes characteristic for the motionless, awake rat were increased at the highest dose of both deramciclane and ritanserin, while it was decreased by chlordiazepoxide. In mice, chlordiazepoxide had a marked anticonvulsant effect, while deramciclane was moderately effective and ritanserin ineffective. In conclusion, the 5-HT₂ receptor antagonist anxiolytic drugs seem to be superior compared to the benzodiazepine type anxiolytic drug, chlordiazepoxide, as ritanserin and deramciclane improved sleep quality by increasing sleep episode length and time spent in DS, while chlordiazepoxide enhanced sleep fragmentation and decreased DS. Received: 1 July 1998/Final version: 4 September 1998     

Effects of chronic chlordiazepoxide treatment on novel and familiar food preference in rats

Chlordiazepoxide (CDP) given acutely has been found to have dose-related effects in rats given food preference tests. Low doses selectively increase consumption of familiar food, while high doses increase novel food consumption. The present study examined the effects of three doses of CDP given chronically. All doses (2.5, 5.0 and 10.0 mg/kg) selectively increased novel food eating. There was some evidence for a selective retardation of eating rate for familiar food and an enhanced taste preference for sweet food in CDP-treated rats. However, the overall results suggest that increased consumption of novel food represents an antineophobic action of CDP, which is potentiated by chronic treatment over a low to medium dose range.     

Effects of acute and chronic aripiprazole treatment on choice between cocaine self-administration and food under a concurrent schedule of reinforcement in rats

Rationale  Dopamine D2-like partial agonists such as aripiprazole have received some attention as potential pharmacotherapies for the treatment of psychostimulant addiction. However, the preclinical evaluations so far have focused on acute effects of aripiprazole. Objectives  We tested the hypothesis that aripiprazole, both as acute and as chronic treatment, would preferentially decrease cocaine self-administration while sparing behavior maintained by a natural reinforcer, resulting in a shift in the allocation of behavior from cocaine-taking towards the alternative reinforcer. Materials and methods  Rats were trained to self-administer intravenous cocaine in a concurrent choice procedure, with a palatable food as the competing reinforcer, under a fixed ratio (FR) 1 FR 5 chain schedule. Aripiprazole was then administered as continuous infusion by osmotic minipumps for 5 days, during which performance in the choice procedure was assessed daily. Results  An intermediate dose of aripiprazole decreased cocaine self-administration and shifted the cocaine choice curve to the right as an acute treatment. However, as a chronic treatment, aripiprazole failed to decrease cocaine self-administration or cocaine choice, despite a dose-dependent decrease in overall response rates and food-maintained behavior. Conclusions  Our results confirm and extend earlier findings and indicate that acute administration of aripiprazole can decrease cocaine self-administration. However, based on the present data, chronic treatment with aripiprazole does not show much promise as a potential pharmacotherapy for cocaine addiction. Both acute and chronic treatment data are in agreement with published clinical findings, suggesting that the concurrent choice procedure in rats has predictive validity of efficacy in humans.     

Some contextual and historical determinants of the effects of chlordiazepoxide on punished responding of rats

Abstract Rationale. A host of factors that modulate the increases produced by benzodiazepines on responding suppressed by punishment have been described. Nonetheless, the necessary and sufficient conditions for the anxiolytic-like activity in this animal model have not been fully delineated. Objectives. The present experiments sought to determine the necessity of the reinforcing event (food delivery), the role of the relationship of food delivery to the punishing stimulus, and the prevailing historical context of behavior in determining the effects of chlordiazepoxide (CDAP) from 1 to 17 mg/kg, i.p. on punished responding. Methods. Male, Sprague-Dawley rats pressed a lever under a multiple schedule. In the presence of one stimulus, every 30th response produced food and, in the presence of an alternate stimulus, every 10th response produced food, a brief electric shock, or food plus shock. Additionally, the baseline schedule was manipulated to determine antecedent experience that may contribute to the efficacy of CDAP. Results. Chlordiazepoxide generally produced little or no effect under the FR 30 schedule but increased response rates under the FR 10 schedule when responding produced either food plus shock (to 600% of control) or shock alone (300% of control) but not food alone. The increases produced when shock alone was delivered were eliminated when rats did not have a history of food plus shock pairings. In addition to increasing suppressed responding, CDAP also prevented the suppression in both punished and non-punished response rates that resulted from adding a food plus shock or shock alone contingency. Conclusions. Chlordiazepoxide and perhaps benzodiazepines in general have robust efficacy for both reducing response suppression and for preventing its occurrence. This efficacy is modulated by conditions present at the time of drug exposure and by the history of the organism with respect to response contingencies. Electronic Publication     

Absence of withdrawal effects of ritanserin following chronic dosing in healthy volunteers

The possible development of withdrawal symptoms following abrupt discontinuation of ritanserin after chronic administration of 10 mg daily for 8 weeks was investigated in a placebo controlled trial in 40 healthy subjects. The study consisted of two phases. In the first phase, under single blind conditions, all subjects received placebo for 2 weeks followed by a single daily dose of ritanserin (10 mg) for 8 weeks. In the second phase, under double blind conditions, subjects were randomised to receive either placebo or to continue on ritanserin (10 mg) for a further 4 weeks. Psychological assessments were performed at the start of and at intervals throughout the study. Levels of anxiety, concentration, quality of sleep and morning vigilance were measured throughout by daily visual analogue scales. No significant changes were detected in any of the measures in the group of subjects who received ritanserin compared to the group who received placebo during the second phase of the study. Ritanserin discontinuation following chronic dosing in healthy volunteers does not appear to be associated with withdrawal symptoms.     

Caffeine and chlordiazepoxide: Effects on motor activity in the chronic thalamic rat

Summary The effects of three doses of caffeine and of chlordiazepoxide (CDX) on motor activity were tested in the chronic thalamic rat. In this preparation virtually all cortical, striatal and limbic structures were ablated. A small dose of caffeine had only a weak motor stimulant effect which was succeeded by sedation. Larger doses that are stimulatory in intact animals, depressed motor activity in the thalamic rat. Amphetamine, in contrast to caffeine, produced a substantial motor stimulation. CDX caused a dose-dependent reduction of motor activity, similar to its effect in the intact rat. It is concluded that (a) telencephalic structures are involved in mediating the stimulatory action of caffeine; (b) a sedative component of caffeine may be present, but masked, in the intact animal, and may be due to serotoninergic mechanisms; (c) the presence of limbic structures is not necessary for the sedative effect of CDX.     

Effects of prenatal cocaine on behavioral adaptation to chronic stress in adult rats

Prenatal exposure to cocaine in rats has previously been shown to alter the behavioral and hormonal responses to acute stressors, although no work has yet examined stress adaptation in these animals in adulthood, a possibility examined in this experiment. Male and female offspring of Sprague–Dawley rat dams given 40 mg/kg/3 ml subcutaneously daily from gestational days 8–20 (C40), saline injected and pair-fed dams (PF), and non-treated dams (NT) were tested in adulthood (90–120 days). Offspring were given a 5-min open field test 24 h following the last of 1 (Acute), 9 (Chronic) or 0 (control) daily 15-min intermittent footshock sessions. Substantially more behavioral adaptation was evident in NT offspring than in C40 and PF animals. The attenuated stress adaptation seen in C40 offspring extends prior work showing altered stress responsiveness in these animals, although the PF data caution against the conclusion that this lack of stress adaptation necessarily reflects gestational exposure to cocaine per se.     

Crossmodal divided attention in rats: effects of chlordiazepoxide and scopolamine

Divided attention is a psychological construct that hinges on assumptions about a fixed finite capacity of subjects to simultaneously process multiple sets of information. A model of a crossmodal divided attention task was developed in rats. Initially, rats were trained consecutively in operant auditory and visual conditional discrimination tasks. The final task consisted of two successive blocks of 20 trials per modality (modality certainty), followed by 60 trials comprising a semi-randomized sequence of stimuli of both modalities (auditory or visual) and qualities (flashing/pulsing or constantly turned on; modality uncertainty). In comparison to unimodal blocks of trials, performance in the mixed condition was assumed to reflect the demands on the parallel processing of two sets of stimulus-response rules. While response accuracy remained unchanged, response latencies were generally longer in the bimodal condition. Administration of scopolamine (0.03, 0.06, 0.1 mg/kg) or chlordiazepoxide (1, 3, 5, 8 mg/kg) dose-dependently increased response latencies. The scopolamine-induced increase in response latencies was greater in the mixed condition. Cost-benefit analyses demonstrated that the absolute divided attention costs (in ms) were generally higher for visual than for auditory stimuli. Both drugs produced qualitatively similar effects; however, scopolamine was more potent in increasing the absolute divided attention costs than chlordiazepoxide. These data are discussed in terms of the validity of this animal paradigm, and of hypotheses about the effects of benzodiazepine receptor agonists and muscarinic antagonists on brain information processing capacity.     

Effects of chlordiazepoxide on tail pinch-induced eating in rats

The effects of 5, 10, and 20 mg/kg chlordiazepoxide on tail pinch (TP)-induced behavior were investigated. Five mg/kg enhanced TP-induced eating in terms of both latency and duration. Twenty mg/kg had decremental effects. All doses of the drug reduced the incidence of clip-directed behavior, but increased locomotor activity during the TP trials in a dose-dependent manner. On control trials, the drug increased locomotor activity at the low dose and eating at the high dose. The results are examined in terms of the various behavioral actions of the minor tranquilizers. The implications for the behavioral and neuropharmacological mechanisms underlying TP-induced and other forms of stimulus-bound behavior are discussed.     

Interactions between chronic haloperidol treatment and cocaine in rats: an animal model of intermittent cocaine use in neuroleptic treated populations

This experiment investigated the possibility that rats maintained on chronic haloperidol treatment would show increased behavioral responsiveness to cocaine, similar to that observed in human stimulant abusers who are chronically treated with neuroleptics. Thus, the effects on locomotion and stereotyped behavior of intermittent injections of cocaine were investigated in female rats receiving chronic haloperidol treatment. Daily injections of haloperidol (0.2 mg/kg, IP) or vehicle were administered for 6, 12 or 18 days prior to the start of testing with cocaine and were then continued throughout cocaine testing. All rats received four doses of cocaine (0.0, 3.0, 7.5, or 15.0 mg/kg, IP) in random order with an intervening vehicle day between successive drug days. The four dose sequence of cocaine was repeated a total of four times. Initial cocaine administration produced dose dependent increases in locomotion and stereotyped behavior. When the sequence of cocaine doses was repeated, differences among treatment groups emerged. Groups treated with haloperidol exhibited heightened locomotion in response to cocaine and with repeated injections, showed a higher rate of behavioral sensitization than control animals. These differences in the behavioral response to cocaine were maintained for at least 2 months following termination of daily haloperidol treatment. In order to examine the mechanisms underlying this heightened responsiveness to cocaine, apomorphine-induced locomotion (dose range, 0–250 µg/kg, SC) was determined. Regardless of dose, rats treated with haloperidol showed different temporal patterns of locomotion in response to apomorphine suggesting that the increased response to cocaine was related to changes in dopaminergic receptor sensitivity.     

Maternal aggression in rats: Effects of chlordiazepoxide and fluprazine

Although maternal agression in rats is confined to a restricted post-partum period, the high and stable aggression level and the constancy of its behavioural structure make it an attractive experimental procedure for studying the behavioural effects of psychotropic drugs. Female rats were tested against naive male intruder rats for 5 or 10 min on post-partum days 3–9, during which aggression is stable.Chlordiazepoxide (CDP; 5, 10 and 20 mg/kg, orally) had a biphasic effect on aggression; it increased aggression considerably at 5 and (to a lesser extent) at 10 mg/kg. At 20 mg/kg aggression returned to control level. CDP shortened the latency to the first attack at 5 mg/kg, but not at higher dosages. CDP enhanced aggression, particularly in the first 2 min of an encounter. It did not change the structure of the aggressive behaviour, but did induce a dosedependent increase in feeding. Fluprazine (Flu; 5, 10 and 20 mg/kg IP), a specific antiaggressive (serenic) drug, induced a dose-dependent decrease in aggression and exerted its largest effect in the first 2 min of an encounter. In accordance with the reduced aggression, latencies to the first attack increased. Maternal aggression in rats represents an extension to other (male) aggression paradigms in psychopharmacology. First, it has no male counterpart. Secondly, the hormonal mechanisms underlying this behaviour differ from those of male aggression. Thirdly, the morphology of maternal aggression is different from that shown in male models of agonistic behaviour (e.g. resident-intruder). These features make maternal aggression an attractive paradigm for pharmacological studies of female behaviour.     

Effects of chlordiazepoxide and pentobarbital on conflict behavior in rats

A punishment discrimination (conflict) was conditioned in rats by simultaneously rewarding with food (sweetened, condensed milk) and punishing with shock all lever responses made in the presence of an auditory stimulus. Chlordiazepoxide and pentobarbital were administered in order to compare degrees of attenuation of conflict behavior relative to the production of behavioral debilitation. Chlordiazepoxide produced the maximum attenuation at doses that produced only minimum debilitation. In general, conflict attenuation (anti-anxiety) was greater under chlordiazepoxide while general debilitation (behavioral toxicity) was greater for pentobarbital.     

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.     

Effects of septal lesions and chlordiazepoxide (Librium) on avoidance behavior in rats

The combined effects of septal lesions and chlordiazepoxide (CDP) were observed during 5 consecutive procedures involving active avoidance, and passive avoidance during approach-avoidance conflict. The Maier paradigm on a Lashley jumpingapparatus was used. The studies led to the following results and conclusions. Septal lesions had no effect on response latency in an active avoidance test. Septal lesions reduced latencies during conflict and learning tests when negative incentives were salient features. Adding CDP reduced latencies further. During extinction tests when negative incentives were withdrawn, response latency for the controls declined to that of the septal-lesioned rats. (Thus, the disinhibitory effects of septal-lesioned rats.) Thus, the disinhibitory effects of septal lesions that become manifest during passive avoidance tests, are enhanced by CDP. This suggests that the septum is not a significant site for CDP action.     

Resistance to extinction of an avoidance response in rats following the administration of chlordiazepoxide (Librium) or diazepam (Valium)

In a one-way avoidance task with rats, injections of Librium (chlordiazepoxide) following avoidance acquisition resulted in prolonged resistance-to-extinction of the avoidance response. This effect occurred regardless of whether the rats had had prior experience with Librium or whether they were naive with respect to the drug. The same results were found with the same task when low doses of Valium were used. However, at a higher dosage an extreme reaction of either no responding or a high number of responses to extinction occurred in the naive animals. The Librium and Valium effects were compared to similar effects obtained using ethanol and hashish resin. These results indicate that the novelty hypothesis as originally stated by Amit and Baum cannot be supported because experience with the drugs prior to avoidance training did not attenuate the drug effect on avoidance.Supported in part by a grant to the Center for Research on Drug Dependence given to Dr. Z. Amit and a RODA summer studentship given to D. Ziskind.     

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 ovariectomy,castration, and chronic lithium chloride treatment on stereotyped behavior in rats

The effects of ovariectomy, castration, and chronic lithium chloride treatment on stereotyped behavior (SB) induced by apomorphine (APO) (0.3–0.6 mg/kg) were investigated in rats. Duration of stereotyped behavior (interval between APO injection and termination of SB) increased in ovariectomized rats compared to female control rats. Castration had no effect on the duration of stereotyped behavior. On the other hand, ovariectomized rats that were treated chronically with LiCl (2 mEq/kg daily) showed no difference in duration of stereotyped behavior compared to female controls chronically treated with LiCl. Neither treatment group showed a significantly altered intensity of stereotyped behavior compared with the appropriate control. These findings are consisten with the hypothesis that estrogen deficit contributes to a greater incidence of neuroleptic-induced tardive dyskinesia in postmenopausal women than in men of comparable age. Furthermore, LiCl may attenuate the symptoms associated with increased postsynaptic dopamine receptor sensitivity following ovariectomy.     

Effects of the calcium antagonist isradipine on cocaine intravenous self-administration in rats

The effect of isradipine, a dihydropyridine calcium antagonist, on cocaine intravenous self-administration in rats was investigated. Administration of (±)isradipine (1.25–5 mg/kg SC) 2 h before the cocaine self-administration session induced a significant and dose-dependent increase in the number of coacine injections with respect to basal values. This effect was sterospecific, with the (+) form of isradipine being active, while the (–) stereoisomer was ineffective. These results suggest that isradipine antagonizes the rewarding properties of cocaine, possibly by inhibiting those dopaminergic systems related to reward mechanisms. These results further indicate a possible use of isradipine, or structurally similar compounds, in the treatment of cocaine related disorders.     

Effects of isoproterenol and chlordiazepoxide on drinking and conflict behaviors in rats

Isoproterenol, a beta-adrenergic agent, induced drinking in water-satiated rats. Isoproterenol exhibited significant anti-conflict activity in water-deprived rats in the Shock-induced Suppression of Drinking (SSD) procedure. Chlordiazepoxide (CDP), at the highest dose tested, also increased drinking in non-deprived naive rats. As expected, CDP demonstrated highly significant anti-conflict activity in thirsty rats (SSD test). These results suggest that in conflict procedures, where food or water is used as a reward, agents that affect the consumatory drive mechanisms could show up as “false positives.” Moreover, agents that affect primary drives (e.g., CDP), in addition to their anti-anxiety activity, could show additive activity in such conflict procedures.     

Dissociation of multiple effects of acute LSD on exploratory behavior in rats by ritanserin and propranolol

Rats tested for 1 h in the Behavioral Pattern Monitor (BPM) after injection of the mixed serotonergic agonistd-lysergic acid diethylamide (LSD) exhibit a behavioral profile similar to that produced by various hallucinogenic 5HT-2 agonists. The characteristic effects of the hallucinogens include suppression of locomotor and exploratory behavior and a preferential decrease in entries into the center of the BPM during the initial half of the test session. After LSD, the initial suppression of responding is followed by a subsequent increase in locomotor activity that is not observed with other serotonergic agonists. In the present studies, the 5HT-1 andβ-adrenergic antagonistd,1-propranolol and the 5HT-2 antagonist ritanserin were administered individually or in combination prior to the acute administration of LSD to test for the involvement of these receptor subtypes in the mediation of the effects of LSD in the BPM paradigm. Propranolol (20 mg/kg) abolished the initial suppression of activity induced by 60 μg/kg LSD without affecting the subsequent increase in locomotion. Conversely, 2.0 mg/kg ritanserin failed to block the initial suppressive effects of 60 or 120 μg/kg LSD, but attenuated the LSD-induced increases in activity during the second half of the session. The combination of propranolol and ritanserin prevented both these effects of LSD. By contrast, the more selective 5HT-2 agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) (0.27 mg/kg) produced an initial suppression of activity in the BPM that was blocked by 2.0 mg/kg ritanserin and was not followed by a subsequent increase in activity. These findings suggest that the initial suppressive effects of LSD in the BPM paradigm are dissociable from the subsequent increases in locomotion and that the two effects are mediated via different serotonergic orβ-adrenergic receptors.