Morphine sensitized rats appear protected from the sequelae of an unavoidable stress: when exposed to stress (after a 7-day morphine wash-out) and then tested for escape, they perform like naive animals. This protection appears similar to that induced by chronic imipramine treatment, as it is antagonized by the inhibition of D(1)-dopamine receptors before exposure to unavoidable stress. Repeated unavoidable stress induces in rats a condition characterized by hyporeactivity to noxious stimuli and reverted by long-term antidepressant treatments, and this state is regarded as an experimental model of depression. The resistance to stress in morphine sensitized rats could be considered as the behavioral counterpart of the sensitivity to stress in control rats, i.e. as a model of mania. The aim of the present study was to validate such a putative model by studying whether the resistance to stress induced by morphine sensitization would respond to a long-term administration of lithium, the reference antimanic drug. Long-term lithium treatment induces in rats a condition of hyporeactivity to noxious stimuli, accompanied by decreased levels of dopamine in the nucleus accumbens shell. In morphine sensitized rats chronic lithium abolished the resistance to stress, but it did not modify the D(1)-dopamine receptor mediated response to morphine, nor did it modify the levels of extraneuronal dopamine in the nucleus accumbens shell. Thus, lithium treatment abolished the resistance to stress in morphine sensitized rats, conferring predictive validity to the paradigm. Moreover, it did so through a mechanism which appeared to be independent of D(1)-dopamine receptor activity.