EEG effects of Ro 15-4513 and FG 7142 alone and in combination with ethanol

The electrophysiological effects of Ro 15-4513 and FG 7142 alone and in combination with ethanol were investigated. Intraperitoneal administration of Ro 15-4513 (3, 6 mg/kg) was found to significantly increase power in the 6-16 Hz frequency range, an effect which was antagonized by ethanol (1 g/kg). FG 7142 administration (2, 5 mg/kg IP) was found to enhance spectral power in the 6-8 Hz range, an effect which was also blocked by coadministration of ethanol. Both drugs also produced dose-related abnormal EEG activity in the form of episodic bursts of EEG spiking. These ictal episodes, which lasted 5-40 seconds, were associated with an arrest of behavior but no overt behavioral convulsions. Coadministration of ethanol caused an elimination or significant reduction in these episodes. These studies suggest that Ro 15-4513 and FG 7142 have potent electrophysiological actions of their own which are partially antagonized by ethanol.     

Ro 15-4513, like anxiogenic beta-carbolines, increases dopamine metabolism in the prefrontal cortex of the rat

The effects of Ro 15-4513, FG 7142 and beta-CCM on the activity of the mesocortical dopaminergic system were examined by measuring the changes in the content of the principal dopamine (DA) metabolite, dihydroxyphenylacetic acid (DOPAC) in the prefrontal cortex of the rat. Ro 15-4513 increased the DOPAC content in the prefrontal cortex in a dose-dependent manner (5-40 mg/kg i.p.) but had no effect on DA concentrations. A similar increase in DOPAC content was induced by FG 7142 (40 mg/kg i.p.) and beta-CCM (8 mg/kg s.c.), two beta-carboline derivatives that interact with benzodiazepine recognition sites as partial inverse agonists. These effects of Ro 15-4513, FG 7142 and beta-CCM on DA metabolism in the prefrontal cortex are mediated via benzodiazepine recognition sites, since they were prevented by the administration of the benzodiazepine antagonists Ro 15-1788 and ZK 93426. These data indicate that Ro 15-4513 is an inverse agonist at benzodiazepine recognition sites.     

Interactions of three benzodiazepine receptor inverse agonists with ethanol in a plus-maze test of anxiety

The effects of RO 15-4513, RO 15-3505 and FG 7142 on the anxiolytic properties of ethanol in mice were investigated using the plus-maze test of anxiety. Before being tested on the plus-maze, the mice were tested in a holeboard apparatus. All three inverse agonists attenuated the reduction in exploration caused by ethanol in the holeboard test. In the plus-maze, only RO 15-4513 and FG 7142, which possess anxiogenic properties when administered alone, attenuated ethanol's anxiolytic effect. RO 15-3505, which alone had no effect on anxiety, failed to significantly reduce ethanol's anxiolytic effect. Neither RO 15-4513 nor FG 7142 reduced the increase in the total number of arm entries caused by ethanol. These data indicate that the interaction between ethanol and benzodiazepine receptor ligands depends both on the intrinsic properties of the ligands and the behavior under investigation.     

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.     

beta-Carboline FG 7142-reduced aggression in male rats: reversed by the benzodiazepine receptor antagonist, Ro15-1788

The beta-carboline FG 7142 decreases conspecific aggression in male hooded rats. The purpose of this study was to examine the effects of pretreatment with Ro15-1788 or chlordiazepoxide (CDP) in this paradigm. The six groups (n = 8) were saline, FG 7142 (5 mg/kg, immediate, IP), CDP (5 mg/kg, -10 min, IP), CDP (5 mg/kg, -10 min) plus FG 7142 (5 mg/kg, immediate), Ro15-1788 (10 mg/kg, -10 min, IP), and Ro15-1788 (10 mg/kg, -10 min) plus FG 7142 (5 mg/kg, immediate). Following injection of the more aggressive member of a pair of isolation-housed rats, the pair was observed in a living cage over four 6-min trials interpolated over a 40 min session. In the first 20 min after the injection FG 7142 decreased aggression, decreased the pinning of the other animal, and increased avoiding behavior. These effects were the opposite of those seen in the Ro15-1788-injected rats and Ro15-1788 pretreatment reversed the effects of FG 7142. CDP alone caused prolonged aggressive behavior but as a pretreatment only partially reversed the effects of FG 7142.     

Interactions of the imidazodiazepine Ro 15-4513 with chemical convulsants.

1. The proconvulsant effects of the imidazodiazepine Ro 15-4513, were investigated in mice by use of intravenous infusion of a variety of convulsant drugs. 2. Dose-response and time course studies of Ro 15-4513 against gamma-aminobutyric acid (GABA) antagonists were performed. On the basis of these studies a maximally effective dose of 5 mg kg-1 was administered 5 min before the determination of seizure thresholds in subsequent experiments. 3. Ro 15-4513 (5 mg kg-1) significantly lowered seizure thresholds to pentylenetetrazole, bicuculline and the convulsant benzodiazepine Ro 5-3663, but failed to alter seizure thresholds to picrotoxin, strychnine, caffeine and quipazine. 4. Ro 15-4513 significantly raised seizure threshold to the benzodiazepine receptor inverse agonist methyl 6,7-dimethoxy-4 ethyl-beta-carboline-3-carboxylate (DMCM). 5. These results are discussed in relation to other studies investigating the proconvulsant and alcohol-antagonizing effects of Ro 15-4513.     

Ethanol and the GABA receptor complex: studies with the partial inverse benzodiazepine receptor agonist Ro 15-4513

Ethanol potentiates GABA-receptor-mediated Cl- ion flux in vitro and, at similar concentrations, has anxiolytic and intoxicating properties in vivo. The imidazobenzodiazepine, Ro 15-4513 (ethyl-8-azido-5,6-dihydro-5-meth-6-oxo-4H- imidazo(1,5-a)(1,4)benzodiazepine-3-carboxylate), is a potent partial inverse agonist of the benzodiazepine/GABA receptor which can antagonize the in vitro actions of ethanol in potentiating GABA receptor-mediated Cl- ion flux. Moreover, several of the behavioral effects of ethanol are also antagonized by Ro 15-4513, and these effects can be demonstrated in several paradigms at doses of Ro 15-4513 that do not produce opposite behavioral effects. In contrast, in our studies, other benzodiazepine receptor antagonist and inverse agonists, including Ro 15-1788, FG-7142, and beta-CCE were not able to antagonize these biochemical or behavioral effects of ethanol at doses that were without intrinsic effects. However, both Ro 15-1788 and beta-CCE blocked the antagonism of ethanol's effects by Ro 15-4513, suggesting a role for the GABA receptor complex in the actions of ethanol. These studies provide further evidence that GABAergic neurones may mediate at least some of the behavioral and biochemical actions of low-to-moderate doses of ethanol.     

Effects of benzodiazepine receptor ligands on the performance of an operant delayed matching to position task in rats: opposite effects of FG 7142 and lorazepam

The effects of a series of benzodiazepine (BZ) receptor ligands, ranging from a full agonist through to partial inverse agonists, were examined on short term working memory in the rat. The behavioural paradigm used was a discrete trial, operant delayed matching to position task, as originally described by Dunnett (1985), with delays of 0, 5, 15 and 30 s. The benzodiazepine receptor (BZR) full agonist lorazepam (0.25, 0.375 and 0.5 mg/kg) dose and delay dependently impaired matching accuracy. Lorazepam also increased the latency to respond and decreased the number of nose pokes made into the food tray during the delays. In contrast, the BZR partial agonist ZK 95 962 (1, 3, 10 mg/kg) did not affect matching accuracy, but did increase the speed of responding. The BZR antagonist ZK 93 426 (1.25, 5, 25 mg/kg) had no effects in this paradigm. The BZR weak partial inverse agonists Ro 15-4513 (0.1, 1 and 10 mg/kg) and ZK 90 886 (1, 3 and 10 mg/kg) did not affect accuracy of performance. However, both of these drugs increased the latency to respond and decreased nose poke responses. These motoric effects were particularly strong following 10 mg/kg Ro 15-4513. This shows that the effects of drugs on the accuracy of responding and on the speed of responding can be dissociated. The BZR partial inverse agonist FG 7142 had effects on matching accuracy that were dependent upon dose. The lowest dose of FG 7142 (1 mg/kg) significantly improved accuracy, whereas the highest dose (10 mg/kg) impaired accuracy. This impairment induced by FG 7142 (10 mg/kg) was accompanied by an increase in the latency to respond and a decrease in the number of nose pokes. Taken together, these results show that the accuracy of delayed matching performance can be modulated in opposite ways by the BZR full agonist lorazepam and a low dose of the BZR partial inverse agonist, FG 7142.     

Reversal of alcohol-induced amnesia by the benzodiazepine inverse agonist Ro 15-4513

We investigated the effects of benzodiazepine inverse agonists on ethanol-induced amnesia using a passive avoidance task. Pretraining treatment of mice with ethanol significantly impaired the passive avoidance response: there was a significant reduction in the % retention and step-down latency. The benzodiazepine inverse agonists, Ro 15-4513 and beta-CCM, significantly increased the % retention and prolonged the step-down latencies in mice treated with ethanol, but FG 7142 did not. The anti-amnesic effects of Ro 15-4513 were completely antagonized by co-administration of Ro 15-1788, a benzodiazepine antagonist. These results suggest that the anti-amnesic effect of Ro 15-4513 on alcohol-induced amnesia is mediated by benzodiazepine receptors.     

Strain differences in sensitivity to the hypothermic effects of benzodiazepine receptor ligands in mice

The hypothermic effects of intraperitoneal (IP) administration of the full benzodiazepine agonist lop razolam (1, 10 mg/kg); the partial agonist Ro 17-1812 (1, 10 mg/kg); the benzodiazepine receptor antagonist flumazenil (10, 20 mg/kg); the benzodiazepine inverse agonists Ro 15-4513 (1, 3, 10 mg/kg) and Ro 19-4603 (0.03, 0.1, 0.3 mg/kg) and the-carboline inverse agonists FG 7142 (10, 30 mg/kg) and DMCM (1, 3, 10 mg/kg) were investigated in three strains of mice. TO mice were less sensitive than CBA/cA and DBA/2 mice, since only loprazolam and the partial and full-carboline inverse agonists FG 7142 and DMCM lowered body temperature in these animals. CBA/cA mice were particularly sensitive to the hypothermic effects of loprazolam and Ro 17-1812, and also responded to the-carboline but not the benzo diazepine inverse agonists. In contrast, DBA/2 mice responded with moderate hypothermia to loprazolam, Ro 17-1812, and to the partial inverse agonist Ro 15-4513, and exhibited marked hypothermia in response to the more efficacious benzodiazepine inverse agonist Ro 19-4603 and to FG 7142 and DMCM. Flumazenil did not alter body temperature. DBA/2 mice were also more sensitive to the convulsant activity of inverse agonists than TO mice. CBA/cA mice exhibited enhanced sensitivity to the convulsant, but not the hypothermic, effects of Ro 19-4603, showing dissociation of these responses. The mechanisms underlying the genetic differences in sensitivity of mice to the hypothermic and convulsant action of the different ligands are unknown and warrant further investigation.     

Antagonizing the anticonvulsant effect of ethanol using drugs acting at the benzodiazepine/GABA receptor complex

The ability of various benzodiazepine receptor ligands to antagonize the anticonvulsant action of ethanol was investigated using intravenous infusion of the GABA antagonist bicuculline. The partial inverse agonists FG 7142, RO 15-4513 and RO 15-3505 produced dose-related reductions in seizure threshold. These compounds also partially reversed the anticonvulsant action of ethanol. However, the magnitude of the effects in each case was only equivalent to the reduction in seizure threshold caused by each compound when administered alone. This is the proconvulsant effect of each compound merely subtracted from the anticonvulsant effect of ethanol. ZK 93426, a benzodiazepine receptor antagonist which alone failed to alter seizure threshold, did not affect the anticonvulsant action of ethanol. Both RO 15-4513 and RO 15-3505 also lowered the seizure threshold of barbiturate-treated mice, again in a subtractive fashion. The ability of RO 15-4513 and other inverse agonists to antagonize the anticonvulsant effect of ethanol appears to result from their intrinsic proconvulsant properties.     

Effects of RO 15-4513 and FG 7142 alone and in combination with ethanol on avoidance in the rat

Rats were trained on a complex avoidance schedule in which responses on one lever postponed shock and responses on another lever occasionally (variable-interval 45 sec schedule) produced 2 min periods of timeout from avoidance. As shown in previous experiments, ethanol (1.5 or 2.0 g/kg) produced an increase in timeout responding relative to avoidance lever rates. These effects were attenuated in five of the six rats by 6 mg/kg RO 15-4513, a dose that did not produce consistent intrinsic effects. In contrast, FG 7142 (10 mg/kg) reliably reversed ethanol effects in only one of the six rats tested. These results support the notion that RO 15-4513 possesses specific ethanol antagonist properties.     

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.     

Behavioral studies with the beta-carboline FG 7142 combined with related drugs in monkeys

The beta-carboline FG 7142 was studied alone and in combination with Ro 15-1788, CGS 8216 and lorazepam in squirrel monkeys trained to respond under a fixed-interval (FI) schedule of food presentation. FG 7142 (0.3-5.6 mg/kg i.v.) produced dose-related decreases in the rate of FI responding, effects opposite to those of moderate doses of lorazepam (0.03-0.3 mg/kg i.v.). Pretreatment with low doses of Ro 15-1788 (0.1 and 0.3 mg/kg i.v.) shifted the dose-response curve of FG 7142 progressively to the right indicating pharmacological antagonism at benzodiazepine recognition sites. In comparison, pretreatment with the pyrazoloquinoline CGS 8216 (0.1-1.0 mg/kg i.v.), which alone decreased responding, did not alter the effects of FG 7142 in a systematic manner. Combinations of behaviorally active doses of FG 7142 and lorazepam had primarily additive effects: the opposing actions of one drug tended to cancel the other's effect on responding. These results show that the reduction in behavior by FG 7142 is modified predictably by Ro 15-1788 but not by CGS 8216, and behaviorally active doses of both FG 7142 and lorazepam may be needed for their mutual antagonism.     

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.     

Loss of Inositol Phospholipids in Epididymal Sperm Following Exposure of Mice to Long-Term Feeding of Organophosphates

Abstract: The action of central and peripheral type benzodiazepine ligands on growth hormone, luteinizing hormone and follicle stimulating hormone levels in serum were studied in male rats. Graded doses of Ro 5-4864, that binds to the peripheral type benzodiazepine receptors, clonazepam, a fairly pure central type agonist and diazepam, a mixed-type agonist, were given intraperitoneally. Also a benzodiazepine partial inverse agonist, FG 7142, was investigated. Clonazepam increased growth hormone levels at 0.2 mg/kg while higher doses were not active. Diazepam (5-25 mg/kg) was not effective. FG 7142 (15 mg/kg) and Ro 5-4864 (25 mg/kg) decreased growth hormone levels. Flumazenil, a central-type antagonist, reversed at least partially the effects of clonazepam and FG 7142, suggesting an effect through GABA-benzodiazepine complex. Elevation of growth hormone could be associated with anxiolysis and decrease of growth hormone with enhanced anxiety. Clonazepam (0.2-5 mg/kg) and diazepam (5-25 mg/kg) increased luteinizing hormone concentrations, but only the effects of 1 mg/kg of clonazepam and 5 mg/kg of diazepam reached statistical significance. Even FG 7142 caused a modest increase of luteinizing hormone at 5 mg/kg, but Ro 5-4864 rather decreased luteinizing hormone, although not significantly. Flumazenil (25 mg/kg) antagonized partially the effects of diazepam and clonazepam. Effects of Ro 5-4864 and FG 7142 were not modified by flumazenil or PK 11195, a peripheral-type mixed antagonist/agonist. Luteinizing hormone stimulation by benzodiazepine ligands may be a pituitary action while inhibition could be caused by the activation of the central GABAergic system. Serum follicle stimulating hormone levels were not significantly altered by central or peripheral type benzodiazepine agonists or antagonists.     

Ethanol-induced locomotor stimulation in C57BL/6 mice following RO15-4513 administration

The purpose of this study was to examine the effects of two partial benzodiazepine inverse agonists, RO15-4513 and FG-7142, alone and in combination with ethanol on locomotor activity in C57BL/6 mice. When administered alone, 1.5 g/kg ethanol did not significantly influence activity, confirming previous reports indicating this mouse strain is relatively insensitive to the excitatory properties of ethanol. RO15-4513 treatment also did not significantly influence locomotor activity when administered alone. However, coadministration of RO15-4513 (1.5–6 mg/kg) and ethanol markedly increased locomotor activity. Moreover, the unmasking of ethanol's stimulant action by RO15-4513 (6 mg/kg) was completely reversed by pretreatment with the benzodiazepine receptor antagonist RO15-1788. In contrast, FG-7142 (10–20 mg/kg) increased activity to the same extent in both saline and ethanol-injected mice. This effect was blocked by RO15-1788 pretreatment as well. Neither RO15-4513, FG-7142, nor RO15-1788 significantly influenced blood ethanol concentrations. It is suggested that RO15-4513 unmasked the stimulant effects of ethanol by virtue of its ability to antagonize the depressant properties of ethanol in C57BL/6 mice.     

Effects of central and peripheral type benzodiazepine ligands on growth hormone and gonadotropin secretion in male rats.

The action of central and peripheral type benzodiazepine ligands on growth hormone, luteinizing hormone and follicle stimulating hormone levels in serum were studied in male rats. Graded doses of Ro 5-4864, that binds to the peripheral type benzodiazepine receptors, clonazepam, a fairly pure central type agonist and diazepam, a mixed-type agonist, were given intraperitoneally. Also a benzodiazepine partial inverse agonist, FG 7142, was investigated. Clonazepam increased growth hormone levels at 0.2 mg/kg while higher doses were not active. Diazepam (5-25 mg/kg) was not effective. FG 7142 (15 mg/kg) and Ro 5-4864 (25 mg/kg) decreased growth hormone levels. Flumazenil, a central-type antagonist, reversed at least partially the effects of clonazepam and FG 7142, suggesting an effect through GABA-benzodiazepine complex. Elevation of growth hormone could be associated with anxiolysis and decrease of growth hormone with enhanced anxiety. Clonazepam (0.2-5 mg/kg) and diazepam (5-25 mg/kg) increased luteinizing hormone concentrations, but only the effects of 1 mg/kg of clonazepam and 5 mg/kg of diazepam reached statistical significance. Even FG 7142 caused a modest increase of luteinizing hormone at 5 mg/kg, but Ro 5-4864 rather decreased luteinizing hormone, although not significantly. Flumazenil (25 mg/kg) antagonized partially the effects of diazepam and clonazepam. Effects of Ro 5-4864 and FG 7142 were not modified by flumazenil or PK 11195, a peripheral-type mixed antagonist/agonist. Luteinizing hormone stimulation by benzodiazepine ligands may be a pituitary action while inhibition could be caused by the activation of the central GABAergic system. Serum follicle stimulating hormone levels were not significantly altered by central or peripheral type benzodiazepine agonists or antagonists.     

Sodium phenobarbitone reverses the anxiogenic effects of compounds acting at three different central sites

Sodium phenobarbitone was tested for its ability to antagonise the anxiogenic effects of compounds acting at three different central sites. These compounds were: FG 7142, a beta-carboline which acts at the benzodiazepine binding site on the GABA-benzodiazepine receptor complex; pentylenetetrazole, which acts at the picrotoxinin site on the GABA-benzodiazepine receptor complex; and yohimbine which is an antagonist at the alpha 2-adrenoceptor. The experiments were carried out in two tests of anxiety using rats. In the social interaction test (the test arena was familiar and dimly lit), FG 7142 (5 mg/kg) and pentylenetetrazole (15 mg/kg) reduced the time spent in social interaction (indicating anxiogenic activity); these effects were reversed by sodium phenobarbitone (35 mg/kg). Sodium phenobarbitone (35 mg/kg) alone decreased locomotor activity as measured in the social interaction test, which was reversed by pentylenetetrazole (15 mg/kg). In the elevated plus-maze, FG 7142 (6.7 mg/kg) pentylenetetrazole (20 mg/kg) and yohimbine (4 mg/kg) reduced the percentage of open-arm entries and the percentage of time spent on the open arms (indicating anxiogenic activity); these effects were reversed by sodium phenobarbitone (35 mg/kg). Sodium phenobarbitone (35 mg/kg) alone significantly increased the percentage of open-arm entries and the percentage of time spent on the open arms (indicating anxiolytic activity). This study, together with previous studies using other clinically-effective anxiolytic drugs, suggests that the ability of a compound to antagonise the effects of anxiogenic agents may be a useful indirect means of predicting anxiolytic activity.     

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.