Distinguishing Roles for Norepinephrine and Serotonin in the Behavioral Effects of Antidepressant Drugs

Antidepressant drugs have typically been classified into sets of compounds with actions targeted atserotonin (selective serotonin reuptake inhibitors [SSRIs]), norepinephrine (norepinephrine reuptakeinhibitors [NRIs]), or both neurotransmitters (serotonin-norepinephrine reuptake inhibitors). Theirclassification has been based predominantly on their acute pharmacologic effects, usually determinedby in vitro radioligand binding assays. The pharmacologic selectivity of antidepressants can be alteredafter their systemic administration, however, by dose, drug metabolism, physiologic interactions betweenneurotransmitters, and adaptive effects that emerge after chronic administration. This reviewexamines whether pharmacologic selectivity is maintained by different types of antidepressants invivo and whether pharmacologic selectivity matters for the production of their behavioral effects.Antidepressants increase extracellular levels of neurotransmitters according to their ability to inhibitpresynaptic transporters, although physiologic interactions among neurotransmitters can influenceantidepressants’ selectivity in certain brain regions. Chronic administration of many antidepressantsalso causes down-regulation of postsynaptic and presynaptic receptors. The pattern of responses ofpresynaptic markers suggests that pharmacologic selectivity is maintained after chronic administrationof many antidepressants. Behavioral tests indicate that depletion of serotonin (5-HT) is capable ofpreventing the effects produced by SSRIs but not NRIs. The depletion of catecholamines also inhibitsthe effects of NRIs, although test results can be complicated by inhibition of motor activity. Depletionof norepinephrine may also inhibit the effects of some SSRIs, but not highly selective SSRIs like citalopram.Although the pattern of results from in vivo tests supports the concept that parallel neurotransmittermechanisms lead to antidepressant activity, norepinephrine may participate in the effectsof some SSRIs. It is also possible that compounds with dual actions at 5-HT and norepinephrine systemsmay be effective under circumstances in which selective antidepressants are ineffective.