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The present study investigated the role of the GABAA-benzodiazepine (BDZ) receptor complex in mediating ethanol (ETOH)-induced increases in exploration (head-dipping) and locomotion of rats in a holeboard test. Male Sprague-Dawley rats were selected based on low basal exploratory rates to increase the likelihood that ETOH would increase these behaviors. The effects of the BDZ partial inverse agonist, Ro15-4513 (2.5 mg/kg), and the BDZ receptor antagonist, Ro15-1788 (flumazenil) (8.0 mg/kg), alone, and in combination with ETOH (0.25, 0.50 and 0.75 g/kg, IP) were investigated. The 0.25 and 0.50 g/kg doses of ETOH markedly increased both exploration and locomotion in low exploratory rats. The ETOH-induced increases were prevented by Ro15-4513 on both measures at a dose that produced no observable intrinsic action; however, this apparent lack of intrinsic activity on exploration may have been related to the low basal rates of responding in the subjects. The BDZ antagonist, flumazenil, completely reversed the antagonistic action produced by Ro15-4513 of the ETOH-induced stimulant effects on locomotion, however, flumazenil exerted only a marginal statistically significant effect on Ro15-4513's actions on head-dipping. When flumazenil was given alone, it increased head-dipping, but was without effect on locomotion. Flumazenil did not affect ETOH-induced increases in locomotion; however, ETOH and flumazenil appeared to show agonistic effects on exploration. The different effects exerted by flumazenil alone, and in combination with ETOH on head-dipping and locomotion suggest that the actions of flumazenil on these behaviors are mediated through separate mechanisms. The research further suggests that both the anxiolytic and locomotor activational effects of ETOH are mediated through the GABAA-BDZ receptor complex.

Previously, we reported that the GABA(A)receptor containing alpha(5)subunit played a significant role in the reinforcing actions of EtOH in rats selectively bred to consume alcohol. However, the role of the alpha(5) receptor in regulating the neurobehavioral effects of EtOH in outbred rats is not known.In the present study, RY024, a novel benzodiazepine (BDZ) inverse agonist with high affinity (K(d) approximately 0.40 nM) and selectivity (approximately 67.3-fold) for the alpha(5)receptor, was investigated for its capacity to antagonize EtOH's reinforcing, motor impairing, and sedative effects in Long-Evans rats.Rats were trained to lever press for EtOH under a fixed-ratio 1 schedule of reinforcement. Subsequent studies evaluated EtOH's motor-impairing effects in an oscillating bar task, while EtOH's sedative effects were measured in the open field.RY024 (0.125-3.5 mg/kg; IP) markedly reduced EtOH-maintained responding with no effects on water responding, except for the highest dose. RY024 (3.0-15 mg/kg; IP) also reversed the motor impairing effects of a moderate (0.75 g/kg), and intoxicating EtOH dose (1.25 g/kg) in the absence of intrinsic effects. Finally, RY024 (7.5 mg/kg) attenuated the sedation produced by the 1.25 g/kg EtOH dose; however, it failed to attenuate the sedation induced by the 0.75 g/kg EtOH dose. Given alone, RY024 exhibited intrinsic effects in the open field.The results suggest the GABA(A)receptor containing alpha(5)subtype plays an important role in regulating the reinforcing, motor-impairing, and sedative effects of alcohol in outbred rats.

Rationale: Given that alcoholics drink for different reasons, it is not likely that a single pharmacotherapeutic agent will be equally effective for all alcoholics. Hence, the development of new pharmacotherapeutic agents that are capable of reducing alcohol intake remains an important focus in the field of alcohol research. Objective: The objective of the present study was to examine the effects of the δ2 receptor antagonist naltriben (0.60–4.0 mg/kg) on operant responding maintained by the presentation of ethanol (EtOH) or saccharin in alcohol-preferring (P) rats. Methods: P rats were trained under a concurrent schedule [fixed ratio (FR)4–FR4] to press one lever for EtOH (10% v/v) and another for saccharin (0.0125–0.05% w/v) during a 60-min session. Naloxone, a non-specific opioid receptor antagonist, served as a reference antagonist. Results: When responding maintained by EtOH and saccharin were equated under baseline conditions, naloxone (0.003125–0.75 mg/kg) reduced levels of EtOH-maintained responding by 46–82%. None of the naloxone doses significantly reduced responding maintained by saccharin. Naltriben (0.9–4.0 mg/kg) reduced EtOH-maintained responding by 44–76%, while saccharin-maintained responding was reduced only by the highest dose of naltriben (4.0 mg/kg). Analysis of the EtOH within-session response pattern revealed that naloxone suppressed EtOH-maintained responding during the entire operant session and led to early termination of responding. Low doses of naltriben (0.90 mg/kg and 1.2 mg/kg) suppressed responding during the latter portion of the operant session, while higher doses (2.0, 3.0, 4.0 mg/kg) decreased responding during the entire session and led to early termination of responding. Conclusions: The results of the present study strengthen previous reports from our laboratory suggesting that naltriben, the selective δ2 opioid receptor antagonist, suppresses EtOH self-administration in rats selectively bred for high EtOH consumption. The results also suggest that naltriben may be a potential candidate for use as a pharmacotherapeutic agent in the treatment of EtOH dependence.

Buprenorphine is a partial opioid agonist derived from thebaine and has high affinity for mu and kappa opioid receptors. The present study investigated dose-response (0.03, 0.15, 0.3, 3 mg/kg) and time-dependent effects of buprenorphine (1.5 or 4 h post-treatment) on EtOH self-administration in outbred Sprague-Dawley rats. Freely feeding and drinking rats were trained to initiate EtOH self-administration for 1 h daily using the ascending concentration procedure, wherein they were provided with increasing concentrations of EtOH at 2, 5, 7, 9 and 11% (v/v), respectively. Water was concurrently available with each concentration. Animals were maintained on a given concentration of EtOH for 5 days. By day 21, animals began their stabilization on the 11% regimen and remained on this concentration throughout the remainder of the study. EtOH and water consumption were recorded daily at both 10- and 60-min intervals. At 1.5 h post-buprenorphine, all test doses greatly suppressed both EtOH and water intake at the 10-min interval. At the 60-min interval, all but the lowest dose (0.03 mg/kg) significantly suppressed EtOH intake, while only the highest dose (3 mg/kg) suppressed water intake. In contrast to the suppressant profile observed at 1.5 h post-buprenorphine, at 4 h post-buprenorphine the lower doses (0.03 and 0.15 mg/kg) significantly increased EtOH intake while the higher doses (0.3 and 3 mg/kg) continued to suppress intake. None of the doses of buprenorphine altered water intake 4 h post-buprenorphine. The results support previous research demonstrating the utility of low doses of buprenorphine in suppressing behavior rewarded by a non-opioid drug.

Buprenorphine, a partial mu opioid agonist, is an experimental medication under development for the treatment of opioid dependence as an alternative to methadone maintenance. The present study examined the relationship between level of opioid physical dependence and response to buprenorphine administration as part of a program to develop procedures for transferring patients from methadone to buprenorphine treatment. This laboratory study characterized the agonist and antagonist effects of acute doses of buprenorphine and methadone in subjects maintained on either 30 (n = 7) or 60 (n = 6) mg/day oral methadone. Test doses of placebo [sl. and PO), methadone (15, 30, and 60 mg PO) and buprenorphine (2, 4, and 8 mg sl.) were administered to volunteers residing on a closed residential unit. Subjective, physiological, observer-rated, and cognitive/psychomotor measures were collected for 6.5 h after test doses. Test doses of methadone, but not buprenorphine, constricted pupils and produced dose-related increases on subjective report measures reflecting opioid agonist drug effects. Agonist effects of methadone were more prominent in the 30 mg than in the 60 mg methadone maintenance condition. Buprenorphine, but not methadone, precipitated opioid withdrawal signs and symptoms that were more prominent in the 60 mg than in the 30 mg methadone maintenance condition. These findings suggest that abrupt transition from methadone to buprenorphine may produce patient discomfort that is positively related to both methadone maintenance dose and buprenorphine transition dose.

The time course of the benzodiazepine (BDZ) inverse agonist RO19-4603 in antagonizing ethanol (EtOH) intake was investigated in alcohol-preferring (P) rats (n=7) maintained on 24-h continuous free-choice access to EtOH (10% v/v), water, and food. After fluid intakes had stabilized over several weeks, animals were injected with Tween-80 vehicle solution or RO19-4603 (0.075, 0.150, and 0.30 mg/kg). EtOH and water intakes were determined at 8- and 24-h intervals. RO19-4603 caused a marked attenuation of EtOH drinking with each of the doses tested. EtOH intake during the 8-h following 0.075, 0.150, and 0.30 mg/kg RO19-4603 was decreased by approximately 36, 74, and 57%, respectively. Intakes during the 24-h interval were similar to the vehicle control condition. However, 32 h post-drug administration, EtOH intakes were reduced to approximately 27, 31, and 29% following the 0.075, 0.150 and 0.30 mg/kg doses, respectively. To further confirm the reliability of the RO19-4603 dose-response effect, and its selectivity for EtOH, the highest dose condition (0.30 mg/kg) was tested twice. The second 0.30 mg/kg dose condition exerted a profile of effects similar to the initial treatment; 8 h following administration, intake was decreased to 60% of the control level, and 32 h post-drug administration intake was decreased to approximately 46% of the controls. These decreases were evidently selective in comparison with water, since water drinking showed compensatory increases which paralleled the decreased EtOH consumption. Dose-response comparisons indicated that 0.150 mg/kg approaches the maximum effective dose, since the 0.30 mg/kg dose of RO19-4603 did not produce an additional decrease in EtOH intake. Furthermore, unlike the lower doses, the 0.30 mg/kg dose failed to yield reliable compensatory increases in water drinking. The results demonstrated that a single acute administration of RO19-4603 produces prolonged and selective suppression of EtOH intake in P rats maintained on 24-h continuous free access to EtOH. While it is not clear at present what properties of the ligand might explain the observed effects on EtOH intake, these findings along with our previous work, clearly suggest that RO19-4603 may modify neuronal processes that promote EtOH self-administration. Neural transmission at the GABAA-BDZ receptor complex may play an important role in mediating EtOH reinforcement.

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 GABAA 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.