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 alpha-2 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 (I g/kg). Naloxone (1 mg/kg) was injected to precipitate withdrawal jumping 72 hours after morphine injection. Go-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.