Behavioural evidence for supersensitivity of postsynaptic dopamine receptors in the mesolimbic system after chronic administration of desipramine.

The effects of acute and chronic administration of desipramine (DMI) on a number of behaviors thought to be dependent on central dopaminergic (DA) systems were examined in the rat. Chronic but not acute administration of DMI potentiated the locomotor response to d-amphetamine within a narrow dosage range. The potentiation of the amphetamine response was observed up to 5 days after cessation of chronic DMI but had nearly returned to baseline by 10 days. Neither amphetamine- nor apomorphine-induced stereotypy was affected by chronic DMI. Chronic administration of iprindole but not fluoxetine potentiated amphetamine-induced locomotor activity. Chronic DMI administration did not affect the concentration or distribution of [3H]d-amphetamine in the brain. Furthermore, residual anticholinergic effects of DMI did not appear to be responsible for the potentiated amphetamine response. Chronic administration of DMI did not significantly influence the hypomotility induced by low doses of apomorphine. The increased locomotor activity and rearing produced by moderate doses of apomorphine were significantly increased by chronic DMI administration. The results suggest that chronic DMI may produce supersensitivity of postsynaptic receptors in the mesolimbic DA projection, a system that has been associated with the mediation of amphetamine- and apomorphine-induced increases in locomotor activity. There was no evidence for subsensitivity of presynaptic DA receptors after DMI. The findings are discussed with reference to the possible role of central DA neurons in the antidepressant mechanism of action of the tricyclic compounds.