Pre-natal benzodiazepine exposure. III. Lorazepam exposure is associated with a shift toward inverse agonist efficacy

Pre-natal exposure to benzodiazepines has been associated with neurobehavioral alterations in human and animal studies. To evaluate effects of pre-natal exposure on subsequent efficacy of benzodiazepine ligands, we exposed mice to lorazepam, 2 mg/kg/day, during days 14-20 of gestation and evaluated offspring at 6 weeks of age using pentylenetetrazol-induced convulsions. Mice exposed to lorazepam were similar to vehicle-exposed and untreated mice in pentylenetetrazol threshold. However, lorazepam-exposed mice had a reduced threshold after an acute dose of lorazepam compared to vehicle-exposed and untreated mice. For the proconvulsant inverse agonist compound FG 7142, threshold was also reduced after pre-natal lorazepam exposure compared to the other treatment groups. These data indicate that pre-natal lorazepam exposure is associated in mature mice with a shift in benzodiazepine efficacy toward the inverse agonist range of the benzodiazepine spectrum.