INTERACTION OF CENTRAL AND PERIPHERAL BENZODIAZEPINE SITES IN BENZODIAZEPINE TOLERANCE AND DISCONTINUATION

1. Chronic administration of benzodiazepines is associated with the de velopment of tolerance and discontinuation effects in humans and in a mouse model. 2. Co-administration of compounds active at the ''periphe ral'' benzodiazepine site my alter chronic benzodiazepine effects. 3. During chronic lorazepam administration, addition of the peripheral si te antagonist PK11195 attenuates behavioral tolerance and receptor dow nregulation. 4. In mice treated with both lorazepam and PK11195, disco ntinuation effects were also attenuated compared to lorazepam alone. 5 . Specificity of the action of PK11195 was confirmed by antagonism of its action by the peripheral-site agonist Ro5-4864.