Effect of oral yohimbine on withdrawal jumping behaviour of morphine-dependent mice.

Acute administration of the alpha-2 adrenoceptor agonist clonidine and chronic administration of the alpha2 antagonist yohimbine both inhibit opioid withdrawal signs in experimental models of dependence and also in clinical studies with opiate abusers. There are exceptions to this general rule: restlessness or self-reported abstinence in humans and withdrawal-induced escape behaviour in rodents are resistant to inhibition by acute clonidine. We have explored the effect of the alpha-2 antagonist yohimbine on morphine withdrawal-induced escape behaviour in a mouse model that we have proposed to differentiate between the urge to escape (number of jumps) and non-specific sedative/motor actions (height of jumps). Morphine dependence was induced by s.c. administration of a sustained-release preparation (1 g/kg). Naloxone (1 mg/kg) was injected to precipitate withdrawal jumping 72 hours after morphine injection. Co-treatment with yohimbine dissolved in the tap water (70 mg/l) decreased the number of jumps upon naloxone challenge, an effect which did not seem to be related with a sedative or toxic effect of the drug. This result confirms previous data and suggests that yohimbine could prevent the development of opioid dependence being active to decrease withdrawal-induced escape behaviour. The mechanisms of this action are discussed.