The effects of Ro 15-4513 on the behavioral actions of ethanol in an operant reaction time task and a conflict test

Ro 15-4513, an analogue of the benzodiazepine receptor antagonist Ro 15-1788, has been reported to selectively block the anxiolytic and intoxicating properties of ethanol in rats. To examine the specificity and selectivity of this ethanol antagonism, the effects of Ro 15-4513 were tested on the actions of ethanol in an operant reaction time and conflict test in rats. The operant reaction time task involved holding down a lever for 0.25-2.0 seconds to obtain food, and animals treated with 1 g/kg of ethanol showed a significant disruption in performance. This disruptive effect was reversed by Ro 15-4513 in doses of 1.5-5.0 mg/kg. Ro 15-4513 was also tested in an operant conflict paradigm sensitive to alcohol effects. Ro 15-4513 (0, 1.5, 3.0, 6.0 mg/kg) produced a significant decrease in both punished and unpunished responding in the conflict test. Ethanol (0.75 g/kg), pentobarbital (5 mg/kg) and chlordiazepoxide (5 mg/kg) all produced a significant release of punished responding that was blocked by pretreatment with 6.0 mg/kg Ro 15-4513, but again Ro 15-4513 suppressed responding on its own at this dose. These results suggest that Ro 15-4513 has inverse agonist properties that may explain its ethanol-antagonist action.     

Role of GABAA alpha5-containing receptors in ethanol reward: the effects of targeted gene deletion, and a selective inverse agonist

GABA(A) receptors containing alpha5 subunits have been suggested to mediate the rewarding effects of ethanol. We tested this hypothesis in mice with deletion of alpha5 subunits. alpha5 knockout mice did not differ from wildtypes in operant responding for 10% ethanol/10% sucrose, but responded less for 10% sucrose. The benzodiazepine (BZ) site inverse agonist, Ro 15-4513, has higher affinity for GABA(A) receptors containing 5 subunits and dose-dependently (0-27 mg/kg, i.p.) reduced lever pressing for ethanol/sucrose in wildtype mice, but had less effect in knockout mice; lever pressing for sucrose was unaffected. These data suggest that alpha5 subunits are not essential for ethanol reward, but the reduction of operant responding for ethanol by Ro 15-4513 is mediated by alpha5-containing GABA(A) receptors. In measures of ethanol consumption, alpha5 knockout mice did not differ from wildtypes at low ethanol concentrations (2-8%), but consumed less ethanol at higher concentrations; these differences were not attributable to increased behavioural disruption of the knockout by ethanol, since no differences were seen in sensitivity to ethanol's sedative or ataxic effects. Ro 15-4513's ability to reduce ethanol consumption was unaffected, suggesting that this effect is not mediated by the alpha5 subtype. Secondly, we tested the ability of a novel alpha5-efficacy-selective benzodiazepine receptor ligand, alpha5IA-II, that possesses greater inverse agonist activity at alpha5- than at alpha1-, á2- or alpha3-containing GABA(A) receptors, to influence operant responding. alpha5IA-II (0.03-3 mg/kg) dose-dependently decreased lever pressing for 10% ethanol, the minimally effective dose of 1 mg/kg, corresponding to over 90% receptor occupancy, but did not affect lever pressing for 4% sucrose. Although inverse agonists acting at alpha5-containing receptors reduce ethanol self-administration, alpha5 subunits may not be essential to signaling ethanol reward.     

Ethanol and Ro 15-4513: behaviour maintained by operant procedures (DRL-72s and PTZ-drug discrimination) in rats

The proposed amethystic imidazobenzodiazepine Ro 15-4513 and ethanol (ETOH) were examined in rats using two operant procedures, differential reinforcement of low rates of responding (DRL), and drug discrimination learning (DDL). In the first bar-pressing responses occurring 72 s or longer after the last reinforcement were rewarded; responses occurring earlier reset the time schedule. In the latter, animals were trained to discriminate between the effects of the analeptic pentylenetetrazole (PTZ) and the non-drug condition; the schedule of reinforcement was FR-10. Water was the reinforcer. A dose of 1000 mg/kg ETOH decreased the rate of bar pressing in the DRL experiment; doses of 300 and 560 mg/kg ETOH did not. The decrease was not attenuated by Ro 15-4513. No significant deviations from baseline responding occurred with Ro 15-4513 (1, 3 10 mg/kg). The number of reinforcements increased significantly after ETOH (1000 mg/kg), but not after Ro 15-4513. Combinations of the two agents produced increases in the number of reinforcements. Changes in DRL behaviour induced by diazepam (1 and 10 mg/kg) were normalized by 3 mg/kg Ro 15-4513. In DDL, Ro 15-4513 (10 mg/kg) substituted for PTZ; ETOH did not. Diazepam and Ro 15-1788 attenuated the response generalization from Ro 15-4513 to PTZ; ETOH did not. There was a dose-related increase in the time to complete the DDL tests after ETOH treatment; addition of Ro 15-4513 increased the time further. In conclusion, antagonism between Ro 15-4513 and ETOH did not occur in the present studies; data are furthermore consistent with the view that Ro 15-4513 acts as a partial inverse benzodiazepine agonist.     

Effects of Ro 15-4513, fluoxetine and desipramine on the intake of ethanol, water and food by the alcohol-preferring (P) and -nonpreferring (NP) lines of rats

The effects of the IP administration of RO 15-4513 (1,2 and 4 mg/kg), fluoxetine (5 and 10 mg/kg) and desipramine (5 and 10 mg/kg) on the intake of 10% ethanol, H₂O and food were determined in the selectively bred alcohol-preferring (P) and -nonpreferring (NP) lines of rats with daily access to fluids being limited to single 2-hour sessions. The imidazobenzodiazepine Ro 15-4513 (a partial inverse benzodiazepine agonist) significantly reduced the intake of 10% ethanol by the P rats to 50–60% of control levels in the first 30 minutes without altering food or H₂O intake. The attenuating actions of 2 mg/kg Ro 15-4513 on ethanol intake could be completely blocked by the central benzodiazepine receptor antagonist Ro 15-1788 (10 mg/kg). Ro 15-1788, by itself, produced no effects on alcohol and H₂O consumption. The 5 mg/kg dose of fluoxetine significantly reduced 10% ethanol intake by the P rats to 20% of control values without altering either H₂O or food consumption. The 10 mg/kg dose of fluoxetine further reduced ethanol intake by the P rats, but this dose also reduced daily food intake to approximately 70% of normal. Desipramine at both doses significantly (p<0.05) reduced both ethanol and food uptake by the P rats and had a tendency to reduce H₂O consumption as well. In general, the three drugs had effects in the NP rats similar to those observed for the P group, although the effects on 10% ethanol intake were difficult to compare because of the low, variable intake of alcohol by the NP group. The data are consistent with the involvement of serotonin and the GABA-benzodiazepine receptor complex in alcohol drinking behavior.     

Failure of the partial inverse benzodiazepine agonist Ro15-4513 to block the lethal effects of ethanol in rats

The partial inverse benzodiazepine agonist Ro15-4513 has been found to antagonize some of the behavioral and physiological effects of low to moderate doses of ethanol. In the present study, pretreating rats with Ro15-4513 (1, 3, 10, and 30 mg/kg) at doses equal to or greater than those used in prior investigations failed to block the lethal effects of intraperitoneal injections of ethanol at a dose of 5.4 g/kg. These results suggest that the lethal actions of ethanol may involve a mechanism that is not blocked by Ro15-4513, which is known to selectively antagonize ethanol-stimulated chloride uptake via the GABA-coupled chloride ion channel.     

Attenuation of the biphasic effects of ethanol on avoidance extinction by RO 15-4513 in rats

Ethanol had biphasic effects on jump-up avoidance extinction with low doses (1 g/kg) increasing, and high doses (2.5 g/kg) decreasing number of trials to extinction criterion. In Experiment 1 these doses of ethanol were studied alone, and in combination with RO 15-4513 (0.3, 3 or 6 mg/kg). The stimulation of responding produced by low ethanol doses was reversed by 3 and 6 mg/kg doses of RO 15-4513 which had intrinsic suppressive effects, but the depressed responding produced by higher ethanol doses was not attenuated by RO 15-4513. Experiment 2 analysed the interaction between ethanol and benzodiazepine antagonists RO 15-1788 and CGS 8216. RO 15-1788 did not have intrinsic action and did not interact with ethanol. CGS 8216 showed an intrinsic suppressive action much like RO 15-4513, and also reversed the stimulation produced by low dose ethanol, but not the effects of the high dose. Experiment 3 showed that the benzodiazepine agonist, chlordiazepoxide, had effects much like low dose ethanol which were reversed by CGS 8216 and RO 15-4513. The major conclusions were that RO 15-4513 and CGS 8216 possess inverse agonist properties which may cancel out the effects of alcohol under certain circumstances.     

Interactions of Ro 15-4513 with diazepam, sodium pentobarbital and ethanol in a holeboard test

Ro 15-4513 (1.5 mg/kg) decreased the exploratory activity of mice in a holeboard test. This effect was reversed by diazepam (1 mg/kg), ethanol (1 g/kg) and sodium pentobarbital (15 mg/kg). Higher doses of these three agents reduced the number of exploratory head-dips, and Ro 15-4513 antagonised these effects. These observations are consistent with the suggestion that Ro 15-4513 is a partial inverse agonist at benzodiazepine receptors and acts by reducing the efficacy of GABA. Ro 15-4513's interaction with ethanol in the holeboard closely resembled its interaction with the barbiturate.     

Antagonism by CGS 8216 and Ro 15-1788, benzodiazepines antagonists, of the action of chlordiazepoxide on a timing behavior in rats

Rats were trained to respond under a differential reinforcement of low rate (DRL) schedule of reinforcement. Pretreatment with relatively low doses of chlordiazepoxide (1-10 mg/kg) produced increases in total DRL responses and decreases in the numbers of reinforced responses. Chlordiazepoxide produced a shift in the interresponse time (IRT) distribution of DRL responses. Low doses of chlordiazepoxide shifted the IRT distribution of DRL responses. Low doses of chlordiazepoxide shifted the IRT distribution from the reinforced to the non-reinforced bins. In addition there was marked increase in the number of responses that occurred in the earliest IRT bin (0-3.75 sec). The highest dose of chlordiazepoxide (32 mg/kg) produced a decrease in total DRL responses and resulted in an even IRT distribution of responses. Both CGS 8216 and Ro 15-1788 had minimal effect on DRL responding when given alone. Ro 15-1788 had no effect at either 10 or 32 mg/kg, while CGS 8216 produced decreases in DRL responding at 32 and 100 mg/kg. Both Ro 15-1788 and CGS 8216 antagonized the effects of high and low chlordiazepoxide doses on total DRL responding and on the IRT distribution of responding.     

A comparison of dehydroepiandrosterone and 7-keto dehydroepiandrosterone with other drugs that modulate ethanol intake in rats responding under a multiple schedule

Dehydroepiandrosterone (DHEA), 7-keto DHEA, and several comparison drugs (ethanol, chlordiazepoxide, rauwolscine, and RO15-4513) were administered to male rats responding under a multiple schedule of food and ethanol presentation to determine their selectivity for decreasing ethanol-maintained responding. DHEA and 7-keto DHEA significantly decreased both ethanol-maintained and food-maintained responding, compared with the control, while also decreasing the blood ethanol concentration (BEC). Acute ethanol administration also decreased responding for both food and ethanol; however, ethanol-maintained responding was more potently decreased than food-maintained responding. BEC remained relatively stable after increasing ethanol doses. Among the other drugs tested, RO15-4513 was the most selective for decreasing ethanol-maintained responding compared with food-maintained responding, and it decreased BECs as ethanol-maintained responding decreased. The largest dose of rauwolscine significantly decreased responding for food, whereas it did not affect ethanol-maintained responding compared with the control. Low to intermediate doses of rauwolscine produced small, nonsignificant increases in ethanol-maintained responding and BECs. Chlordiazepoxide produced significant decreases in food-maintained responding and the dose of ethanol presented, but only at the highest dose tested. Although DHEA and 7-keto DHEA did not decrease ethanol-maintained responding as selectively as ethanol or RO15-4513 under the multiple schedule, these neurosteroids may be valuable pharmacological tools in the development of new treatments for alcohol abuse and dependence.     

Effects of Ro 15-4513 on the motor impairment and hypnotic effects of ethanol and pentobarbital

The selectivity of Ro 15-4513 in reversing the actions of sedative-hypnotic drugs was examined. The motor impairment induced by i.p. administration of 1.8 g/kg of ethanol was partially reversed by doses of Ro 15-4513 ranging from 2-8 mg/kg. Antagonism of the similar effect induced by 20 mg/kg of pentobarbital was observed only at the 8 mg/kg dose of Ro 15-4513. Treatment with 4 mg/kg of Ro 15-4513 shifted the dose-effect curve for motor impairment by ethanol to the right but did not affect the corresponding curve for pentobarbital. Ro 15-4513 also increased the onset latency and shortened the duration of sleep time induced by ethanol but not by pentobarbital. Blood ethanol and pentobarbital levels measured at 32 min after drug administration were not affected by Ro 15-4513. The selectivity of Ro 15-4513 and the mechanism(s) underlying its proconvulsant effect in reversing the actions of ethanol are discussed.     

The effect of Ro 15-4513, an inverse agonist at the benzodiazepine receptor, on the exploratory response to novelty in the playground maze

The effects of chlordiazepoxide and the inverse agonist, Ro 15-4513, were compared on the exploratory response of rats to a novel object introduced into a familiar environment containing seven familiar objects. While chlordiazepoxide (5 mg/kg) increased the novelty response, Ro 15-4513 reduced the response in a dose-dependent manner (0.5-5.0 mg/kg). This action was specific to novelty since the response to the familiar objects was unaffected. Both drugs produced some reduction in ambulation. The effects of both drugs were blocked by flumazenil (10 mg/kg), which at this dose did not itself have any intrinsic effect on the response. Muscimol (0.001 mg/kg) had a weak chlordiazepoxide-like effect and baclofen (3 mg/kg) had a weak effect in the opposite direction.     

The calcium channel antagonist, nimodipine, decreases operant self-administration of low concentrations of ethanol

This study examined effects of the dihydropyridine calcium channel antagonist, nimodipine, on operant self-administration of ethanol, under a progressive-ratio schedule of reinforcement, by hooded Lister rats. Calcium channel antagonists have been reported to decrease the ethanol withdrawal syndrome, the development of tolerance to ethanol and ethanol consumption; and dihydropyridine binding site density in the central nervous system (CNS) is increased by chronic alcohol treatment. In addition, these drugs decrease reinforcing effects of psychostimulants. In the present studies, nimodipine was administered, once weekly, at either 10 or 50 mg/kg intraperitoneally (i.p.). At 10 mg/kg, nimodipine decreased the break point, and number of reinforcers obtained, for ethanol concentrations of 5, 10 and 15%. At 50mg/kg, nimodipine only decreased the break point, and number of reinforcers, for 5% ethanol. Responding for higher concentrations of ethanol was unaffected by nimodipine, as was responding when ethanol was replaced by water. The break point for 10% sucrose, but not for 1% or 0.1%, was decreased by 50 mg/kg nimodipine, but 10 mg/kg nimodipine had no effect on sucrose-reinforced responding. The 50 mg/kg dose of nimodipine decreased motor activity, but 10 mg/kg nimodipine only slightly decreased static activity counts. The results suggest that nimodipine, at the lower dose tested, decreased the reinforcing properties of low concentrations of ethanol.     

Ethanol self-administration in freely feeding and drinking rats: effects of Ro15-4513 alone,and in combination with Ro15-1788 (flumazenil)

Recent work in our laboratory demonstrated that Ro15-4513, a partial inverse benzodiazepine (BDZ) agonist, decreases ethanol (ETOH) self-administration in rodents under fluid deprivation conditions. The present study further examined the effects of Ro15-4513 (2.5 and 5.0 mg/kg) alone and in combination with Ro15-1788, (flumazenil) (8.0 and 16.0 mg/kg), a BDZ receptor antagonist on ETOH self-administration in freely feeding and drinking rats. Animals were trained to consume ETOH (11% v/v) using a limited access procedure. Measurements were taken at 10- and 60-min intervals. Ro15-4513 (2.5 and 5.0 mg/kg) markedly attenuated ETOH consumption at both intervals. The antagonistic actions of Ro15-4513 were completely blocked by the higher dose of flumazenil at both intervals; the lower dose failed to antagonize the Ro15-4513-induced reduction of ETOH intake. When flumazenil was given alone, both doses reduced ETOH self-administration at 60 min; although the magnitude of the antagonism was comparable to that of Ro15-4513 only with the highest does of flumazenil (16.0 mg/kg). Neither Ro15-4513 nor flumazenil alone or in combination significantly altered water intake at any of the tested doses. Rats pretreated with Ro15-4513 showed a substantial reduction in blood ethanol concentration (BEC) compared with the Tween-80 vehicle condition at the 10-min interval. However, the BEC of animals given Ro15-4513 in combination with flumazenil were similar to rats given Tween-80 vehicle. The present study extends our previous research by demonstrating that Ro15-4513 and flumazenil attenuate ETOH self-administration in non-food or water deprived rats. These studies suggest that the suppressant effects of Ro15-4513 and flumazenil on ETOH self-administration are associated with actions at the BDZ site of the GABA_A receptor complex. These data are discussed in relation to the possible mechanism(s) by which Ro-15-4513 and flumazenil exert their antagonism on ETOH self-administration.Portions of this work were presented at the Annual Meeting of the Research Society on Alcoholism under the symposium entitled GABA/BDZ Receptor Update, Marco Island, FL, June 10, 1991.We would like to dedicate this paper to the late Dr. Richard G. Lister, a friend, teacher, colleague and exceptional scientist who contributed substantially to the area of alcohol abuse and alcoholism. Over the past years, Dr. Lister investigated the interactions of alcohol with inverse benzodiazepine agonists and benzodiazepine receptor antagonists. His seminal and more recent papers played an important role in delineating the GABA benzodiazepine systems in the neurobehavioral actions of alcohol. Richard, we will miss you.     

Effects of Ro 15-4513 on schedule-controlled responding of pigeons

The partial inverse benzodiazepine agonist Ro 15-4513 has been found to antagonize some of the behavioral and physiological effects of ethanol, but relatively little is known about the behavioral effects of the drug alone. In the present study, pigeons responding under a multiple fixed-ratio 25 interresponse-time-greater-than-6-sec schedule of food delivery were exposed acutely and chronically to Ro 15-4513. Acute administrations of the drug (1.0, 1.8, 3.2, and 5.4 mg/kg) reduced response rates under the fixed-ratio component at some doses, although two birds were more sensitive to the drug than the third subject. Response rates under the interresponse-time-greater-than-6-sec component were not affected by acute administrations of Ro 15-4513. When 5.4 mg/kg Ro 15-4513 was administered prior to 15 consecutive sessions, tolerance developed to the rate-reducing effects of the drug under the fixed-ratio component. These findings, in contrast to those of early investigations in which gross measures of behavior were employed, suggest that Ro 15-4513 is behaviorally active at relatively low doses.     

Selective antagonism of acute ethanol-induced motor disturbances by centrally administered Ro 15-4513 in mice.

Results of the present investigation demonstrated that Ro 15-4513 when given ICV selectively antagonized ethanol-induced motor disturbances at doses that did not produce motor incoordination and lacked proconvulsant activity. Ro 15-4513 in 10-, 15-, and 22-ng doses antagonized, roughly in a dose-dependent manner, ethanol-induced motor incoordination. The 10-ng dose produced an optimal effect with nearly complete antagonism within 30 min postethanol. The higher, 15 and 22 ng, doses of Ro 15-4513 antagonized, as well as probably reversed, ethanol-induced motor incoordination. The stimulation and inhibition of spontaneous motor activity by 1 and 2 g/kg IP ethanol, respectively, were also selectively antagonized by Ro 15-4513. Neither an alteration in the latency and/or duration of pentylenetetrazol-induced convulsions nor an antagonism to sodium pentobarbital-induced motor incoordination and inhibition of spontaneous motor activity by Ro 15-4513 at dose levels that showed antiethanol effects were observed. Only the 150-ng dose of Ro 15-4513, which exhibited intrinsic activity as proconvulsant, attenuated sodium pentobarbital-induced motor incoordination. When given alone at doses higher than those used in motor coordination experiments, Ro 15-4513 markedly increased spontaneous motor activity dose dependently.     

Antagonism of the effects of the atypical benzodiazepine, Ro 5-4864 on intracranial self-stimulation in the rat

The effects of Ro 5-4864 (chlordiazepam) were examined on responding for self-stimulation of the mid-lateral hypothalamus. Rewarding stimuli were delivered according to a 10-sec variable interval schedule of reinforcement. Ro 5-4864 (10-30 mg/kg, subconsulsive doses in these rats) decreased responding. This effect was antagonized by chlordiazepoxide (5-10 mg/kg) and phenobarbitone (35 mg/kg) but not by the benzodiazepine receptor antagonist Ro 15-1788 (10-20 mg/kg), the ligand for peripheral benzodiazepine receptors PK 11195 (60 mg/kg) or phenytoin (60 mg/kg). The pattern of interactions of Ro 5-4864 with these compounds differs from the pattern obtained with other procedures, and suggests that Ro 5-4864 has effects on systems unrelated to anxiety, convulsive activity or sedation.     

Ethanol suppression of schedule-controlled responding: interactions with Ro 15-4513, Ro 15-1788 and CGS 8216

Rats (N = 14) were trained to respond under a five seconds differential reinforcement of low rate (DRL 5') schedule and under a fixed ratio 10 (FR10) schedule of reinforcement. Ro 15-1788 did not influence the number of responses in the DRL 5' schedule, but increased responding in the FR10 schedule. Ethanol (ETOH, 1250 mg/kg) and CGS 8216 (5 mg/kg) suppressed responding in both schedules and these effects were not antagonized by Ro 15-1788. The response suppressing effects of ETOH in both schedules were not influenced by CGS 8216. These results indicate that the response suppressing effects of ETOH and CGS 8216 are not mediated by the BDZ receptor. Ro 15-4513 suppressed responding strongly in the FR10 schedule. The response suppressing effects of Ro 15-4513 were additive with the response suppressing effects of ETOH. In rats (N = 11) trained to respond under a variable interval 40 seconds-fixed ratio 10 (VI 40'-FR10) schedule Ro 15-4513 dose-dependently suppressed responding. These results indicate that Ro 15-4513 has sedative effects and is not able to antagonize all the behavioral actions of ETOH.     

Effects of Ro 15-4513, alone or in combination with ethanol, Ro 15-1788, diazepam, and pentobarbital on instrumental behaviors of rats

Intraperitoneally administered Ro 15-4513 and ethanol (ETOH), singly and in combination, were examined in rats. Leaping, climbing, bar-pressing, open-field (O-F) activity, as well as concentrations of ETOH in rebreathed air, were studied. Rats in the ETOH (1.2 g/kg) plus Ro 15-4513 (3 mg/kg) condition evinced a jumping performance significantly better than that of the ETOH singly-treated rats; the ETOH (1.2 g/kg) plus Ro 15-4513 (10 mg/kg) condition was intermediate to those of the ETOH and vehicle conditions. In the climbing and bar-pressing experiments, Ro 15-4513 did not attenuate the ETOH-induced impairments. Yet, ETOH improved performance of the Ro 15-4513 high dose (10 mg/kg) condition in the climbing situation. Additional findings were that a) intrinsic activity was noted with Ro 15-4513 in the climbing and bar-pressing situations, and b) the Ro 15-4513/ETOH combination in the O-F test resulted in reduced defecation (antagonism) and rearing activity similar to that of the ETOH-treated rats (lack of antagonism). Concentrations of ETOH in rebreathed air suggested no significant differences between the ETOH singly as compared to the ETOH plus Ro 15-4513 groups. Thus the antagonism of ETOH by Ro 15-4513 was dependent on the parameter examined. Additional experiments examined combinations of Ro 15-4513, Ro 15-1788, diazepam, and pentobarbital in the bar-pressing situation. Results were compatible with the view that Ro 15-4513 acts as a partial benzodiazepine inverse agonist.     

Disruption of schedule-controlled behavior by Ro 15-1788 one day after acute treatment with benzodiazepines

The behavioral effects of the benzodiazepine antagonist Ro 15-1788 were studied in squirrel monkeys after acute injections of benzodiazepines. Monkeys responded under a multiple schedule of food presentation with alternating fixed-interval (FI) and fixed-ratio (FR) components. Chlordiazepoxide (10 mg/kg) increased FI responding and had little effect on FR responding 1 h after it was administered; FI responding was still elevated during the session on the following day. When Ro 15-1788 (0.1–3 mg/kg) was administered 1 h after chlordiazepoxide, it antagonized the effects of chlordiazepoxide in a dose-related manner. When Ro 15-1788 was administered 1 day after chlordiazepoxide, however, doses of 1 or 3 mg/kg suppressed both FI and FR responding. Suppression of schedule-controlled responding was also observed when Ro 15-1788 (3 mg/kg) was administered 1 day after diazepam (3 or 5.6 mg/kg) or N-desmethyldiazepam (5.6 mg/kg). The results show that Ro 15-1788 can precipitate disruption of schedule-controlled behavior 1 day after acute treatment with benzodiazepines.Animals used in this study were maintained in accordance with the guidelines of the Committee on Animals of the Harvard Medical School and of the Committee on Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council; DHEW publication (NIH) 78-23, revised 1978     

The effects of Ro 15-4513 on ethanol-induced taste aversions

Ro 15-4513 is an imidazobenzodiazepine that has been reported to block a range of behavioral effects of ethanol. In the present experiments, the effects of Ro 15-4513 were assessed on the acquisition of an ethanol-induced conditioned taste aversion. Specifically, rats were given a novel saccharin solution to drink followed by an injection of one of a range of doses of Ro 15-4513 (0.5 and 1.0 mg/kg, Experiment 1A, and 2.0 and 3.0 mg/kg, Experiment 1B) and an injection of ethanol (1.75 g/kg). Ro 15-4513 failed to block the acquisition of the ethanol-induced taste aversion. Possible reasons for this failure were discussed.