The recent discovery of atypical antidepressants like iprindole and mianserine which are devoid of any significant inhibitory effect on monoamine oxidase (MAOI) or on monoamine reuptake indicates that the antidepressant action is not necessarily associated with these two pharmacological effects. Systematic studies on the interactions of various antidepressants with the receptors for neurotransmitters reveal that the therapeutic action of these drugs is not related to the possible blockade of muscarinic, histaminergic, serotoninergic and/or alpha-adrenergic receptors in the CNS. However, chronic treatments with antidepressants (MAOIs, uptake inhibitors or atypical antidepressants) regularly induce a significant reduction in the number of beta-adrenergic and serotoninergic receptors in brain (particularly in the cerebral cortex of rats). This down regulation is associated with an hyposensitivity to NE and 5-HT agonists. These data further support the "monoamine theory" of depression: since down regulation is generally due to a long lasting overstimulation of receptors, it can be proposed that antidepressants increase NE and 5-HT neurotransmission in the CNS, notably in some depressed patients.