Following our behavioral studies demonstrating augmentation of
imipramine action by concomitant administration of
nicotine, we investigated the effects of one or 14 days of treatment (twice daily) with
imipramine and
nicotine on
dopamine metabolism in various brain areas of rat and
noradrenaline in the brain stem. In addition, we evaluated the responses of this metabolism to
apomorphine challenge in the rat. Generally, chronic treatment of
imipramine and
nicotine produced opposite effects to acute administration. As revealed by HPLC,
dopamine metabolism in the nucleus accumbens was slightly decreased after 14 days of treatment with
imipramine, and co-administration of
nicotine resulted in a significant and much more pronounced depression of
dopamine metabolism in all investigated dopaminergic structures. Such biochemical effects suggested the development of a compensatory mechanism related with
hypersensitivity of
dopamine D(2) receptors in the mesolimbic and nigrostriatal system. Chronic administration of
imipramine produced an opposite effect to the acute one in the brain stem noradrenergic system, like it was observed in dopaminergic structures. Significant inhibition of
noradrenaline metabolism after acute administration of
imipramine may be explained by its inhibitory effect on
noradrenaline reuptake process. In contrast, chronic
imipramine administration had no effect on
noradrenaline metabolism what indicated the development of subsensitivity of (2)-adrenoceptors in the brain stem responsible for the rate of
noradrenaline metabolism.
Apomorphine alone decreased metabolism of both
catecholamine,
dopamine and
noradrenaline through activation of
dopamine D(2) receptors which are located also on noradrenergic neurons. The biochemical response to
apomorphine in terms of
dopamine metabolism was not changed by chronic administration of the investigated drugs but
noradrenaline metabolism in the brain stem was strongly attenuated after a combined treatment of
imipramine and
nicotine. The present data demonstrate facilitation and potentiation of biochemical
antidepressant-like effects of
imipramine by
nicotine co-treatment. We suggest that
nicotine may potentiate the
antidepressant-like effects of
imipramine by promoting some
plastic changes in the brain within
dopamine and
noradrenaline system considerably more strongly than
imipramine alone.