NMDA receptor involvement in imipramine withdrawal-associated effects on swim stress, GABA levels and NMDA receptor binding in rat hippocampus

Abrupt antidepressant withdrawal after chronic treatment is associated with a stress response that may negatively affect the long-term outcome of depression, the neurochemical correlates, of which, remain undetermined. Prolonged depression involves the stress-related release of glucocorticoids and glutamate, while response to antidepressants involves γ-amino butyric acid (GABA) and the glutamate N-methyl-D-aspartate (NMDA) receptor. Here, imipramine (IMI) was administered to rats for three weeks followed by acute withdrawal for seven days. Levels of GABA in the hippocampus (HC), and effects on swim stress immobility (SSI), were determined. Furthermore, glutamate/NMDA receptor binding properties were determined using [³H]-CGP-39653. Finally, the ability of dizocilpine (MK801), a glutamate NMDA antagonist, to reverse IMI withdrawal was determined. Chronic IMI (15 mg/kg ip) significantly reduced SSI together with a slight but insignificant decrease in HC GABA levels. However, IMI significantly reduced specific binding (B_max) of [³H]-CGP-39653. Withdrawal of IMI for 7 days resulted in a loss of efficacy on SSI, a slight increase in GABA and a significant reversal of IMI effects on [³H]-CGP-39653 binding. MK801 (0.2 mg/kg ip) alone for seven days caused a significant decrease in SSI, a significant suppression of HC GABA, and significantly decreased [³H]-CGP-39653 B_max. MK801 during IMI-withdrawal significantly decreased GABA, prompted recovery on SSI, though not significantly, but significantly reversed withdrawal effects on [³H]-CGP-39653 B_max. In conclusion, acute antidepressant discontinuation is associated with subtle changes on HC GABA, a resurgence of NMDA receptor density and a loss of its anti-immobility response. These responses are reversed by a NMDA antagonist suggesting that abrubt antidepressant discontinuation mobilises glutamate activity.