Repeated tricyclics induce a progressive dopamine autoreceptor subsensitivity independent of daily drug treatment

Dopamine (DA) has largely been ignored in considering possible mechanisms underlying the therapeutic effects of tricyclic anti-depressants (TCA) 1–3 . Most previous work done has focused on the ability of some TCAs to block the in vitro re-uptake of DA 1 —an effect which unfortunately requires very high doses. Recently, however, Serra et al. 3 proposed that TCAs may exert their therapeutic effects by inducing a subsensitivity of presynaptic receptors located on the dendrites and soma of DA neurones (DA autoreceptors). This hypothesis was directly tested by examining the influence of TCAs on the demonstrated ability of the DA agonist, apomorphine, to depress selectively the spontaneous activity of single DA cells. We now report that repeated administration of both typical and atypical TCAs induces a progressive subsensitivity of DA autoreceptors, and that this gradual augmentation of DA autoreceptor subsensitivity depends on the passage of time rather than daily TCA administration. The latter finding suggests that daily drug administration may not be therapeutically necessary.