Long-term imipramine effects are prevented by NMDA receptor blockade.

Long-term exposure to different antidepressant treatments induces increased motor response to central stimulants, due to a selective supersensitivity of dopamine D2 receptors in the limbic areas. Such an effect is accompanied by down-regulation of dopamine D1 receptor number, and by a decreased response of adenylyl cyclase to dopamine stimulation in the limbic system. Moreover, the number of beta-adrenergic receptors and the response of adenylyl cyclase to beta-adrenergic stimulation in the cortex result to be reduced. The present data confirms that imipramine (10 mg/kg twice a day for 3 weeks) produces such effects, and shows that the co-administration of imipramine with MK-801 (administered by a subcutaneously implanted osmotic minipump delivering 0.05 mg/kg/day of the compound) prevented the occurrence of both the behavioral supersensitivity to quinpirole, and the decrease of dopamine D1 and beta-adrenergic receptor function.