Chronic treatment with the vasopressin 1b receptor antagonist SSR149415 prevents the dysphoria associated with nicotine withdrawal in rats

- Nicotine withdrawal induces a negative mood state.
- Acute treatment with a V1b receptor antagonist partly prevents withdrawal.
- Chronic treatment with a V1b receptor antagonist completely prevents withdrawal.
- Blockade of V1b receptors does not affect reward function in control animals.
- Blockade of V1b receptors does not induce sedation or motor impairments.

Nicotine addiction is a chronic brain disorder that is characterized by dysphoria upon smoking cessation and relapse after brief periods of abstinence. It has been hypothesized that the negative mood state associated with nicotine withdrawal is partly mediated by a heightened activity of brain stress systems. Animal studies suggest that blockade of vasopressin 1b (V1b) receptors diminishes high levels of drug intake in dependent animals and attenuates the emotional response to stressors. The goal of the present studies was to investigate the effect of acute and chronic treatment with the V1b receptor antagonist SSR149415 on the negative mood state associated with nicotine withdrawal in rats. An intracranial self-stimulation (ICSS) procedure was used to assess mood states and nicotine dependence was induced using minipumps. The nicotinic receptor antagonist mecamylamine was used to precipitate withdrawal. Mecamylamine elevated the brain reward thresholds of the nicotine dependent rats, which reflects a negative mood state. Mecamylamine did not affect the brain reward thresholds of the saline-treated control rats. Chronic treatment with SSR149415 completely prevented the elevations in brain reward thresholds associated with nicotine withdrawal while acute treatment only partly prevented nicotine withdrawal. These data suggest that chronic treatment with V1b receptor antagonists may prevent the dysphoria associated with smoking cessation and thereby improve relapse rates.