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The response to i.v. administration of bicuculline and its interaction with the benzodiazepine agonist diazepam and antagonist flumazenil were studied in male and female handling stressed and swim stressed rats. Both handling stressed and swim stressed male rats needed less bicuculline to produce myoclonic twitch and running/bouncing (RB) clonus than females. Besides, a lower dose of bicuculline produced tonic hindlimb extensor convulsion (THE) in male than in female swim stressed rats. Flumazenil failed to affect seizure thresholds for bicuculline either in handling stressed or in swim stressed animals. Sex differences remained present after diazepam pre-treatment as well. While diazepam enhanced doses of bicuculline producing all three convulsive signs similarly in both handling and swim stressed rats (141-162%), swim stress had the lowest anticonvulsive effect for the onset of myoclonic twitch (110% in males and 117% in females) and the highest for THE (148% in males and 188% in females). The anticonvulsive effect of diazepam was not sex-dependent, while the anticonvulsive effect of swim stress was greater in female than in male rats. The results suggest that greater sensitivity of male rats to bicuculline and the anticonvulsive effect of swim stress do not result from the release of endogenous modulators of benzodiazepine binding sites.

The present study investigated dose dependence and time course effects of the benzodiazepine (BDZ) partial inverse agonist, RO19-4603 (0.005-0.30 mg/kg) alone, and in combination with the BDZ receptor antagonists flumazenil, ZK 93426, and CGS 8216 (20 mg/kg) in selectively bred alcohol-preferring (P) rats provided a two-bottle choice test between ethanol (EtOH) (10% v/v), and a palatable saccharin (0.0125% g/v) solution. A single dose of RO19-4603 as low as 0.009 mg/kg selectively reduced EtOH drinking during the initial 15 min of a 4 h access to 19-0% of control levels on day 1. The 0.08, 0.15 and 0.30 mg/kg doses of RO19-4603 significantly reduced total EtOH intake in the 4 h access period to 57-45% of controls on day 1. On day 2, no RO19-4603 injections were given; however, six of the seven doses of RO19-4603 (0.009, 0.02, 0.04, 0.08, 0.15, and 0.30 mg/kg) continued to reduce EtOH intake to 42-3% of control levels at the initial 15 min interval, while the 0.005, 0.009, 0.08, and 0.30 mg/kg doses reduced total 4 h EtOH intake to 60-42% of controls. Saccharin intake was either not altered by RO19-4603 or showed increases during the initial 15 min intervals and the total 4 h sessions on days 1 and 2. Food intake was also unaffected by RO19-4603. The CGS 8216, but neither flumazenil nor ZK 93426, reliably reversed the RO19-4603-induced suppression of EtOH intake on days 1 and 2. That certain BDZ inverse agonists can attenuate motivated behavior for EtOH reinforcement over a prolonged time course may provide a possible therapeutic approach to reducing EtOH consumption associated with alcoholism.

Media conditioned by cultured neonatal cerebral cortex microexplants (CCM) or astrocytes (ACM) contain low molecular weight (< 1,000 Da) substance(s) which inhibits the gamma aminobutyric acid (GABA)-induced inward current recorded in cerebellar granule cells and hippocampal neurons in culture using the whole-cell patch-clamp technique. This effect is specific for CCM and ACM, as medium conditioned by PC12 cells (PC12CM) does not affect the GABA response of these cells. It is also specific for GABA-induced currents because glutamate-induced currents do not change either in amplitude or in shape in the presence of CCM or ACM. The inhibitory effect on the GABA response in cerebellar granule cells of both ACM and CCM could be suppressed by flumazenil, a specific benzodiazepine (BZD) antagonist and could be mimicked by two BZD inverse agonists. These data thus demonstrate the presence of a BZD inverse agonist-like activity in CCM and ACM. This effect of ACM on different neuronal cell types was heterogenous since no detectable effect could be observed on the GABA-induced current in GABA-responsive dorsal root ganglion (DRG) neurons, presumably reflecting a functional heterogeneity of the GABAA receptors present in these different neuronal subsets. By the release of such an endogenous BZD inverse agonist-like activity, glia cells could possibly modulate GABAA receptor-mediated responses.