Imipramine and phenelzine decrease glutamate overflow in the prefrontal cortex - A possible mechanism of neuroprotection in major depression?

Antidepressant drugs have been used for decades, but the neurobiological su bstrate of their efficacy is not completely understood. Although these drug s have well-established effects on monoamines, evidence is emerging that th ey may also affect other neurotransmitter systems. It has been shown that t reatment with a wide range of antidepressants changes the binding character istics of the N-methyl-D-aspartate type of glutamate receptor.(23) This cha nge is delayed and occurs only in the cortex. The mechanism that triggers i t is unknown. We hypothesized that N-methyl-D-aspartate receptor alteration s may be due to changes in the dynamics of cortical excitatory amino acid r elease. Such changes are of particular interest in areas such as the prefro ntal cortex, a region involved in stress responses and affected in major de pression.(6) We investigated the effects of two antidepressants with differ ent modes of action, imipramine and phenelzine, on glutamate and aspartate outflow in rat prefrontal cortex and striatum. We showed that antidepressan ts significantly decreased stimulated glutamate outflow. The effect had a r apid onset, was sustained during chronic administration and was only seen i n the prefrontal cortex. This change may initiate receptor alterations. Fur thermore, if antidepressants can dampen states of hyperglutamatergic activi ty and the subsequent excitotoxicity, their chronic use may have a consider able neuroprotective potential in major depression. (C) 2000 IBRO. Publishe d by Elsevier Science Ltd. All rights reserved.