THE N-METHYL-D-ASPARTATE ANTAGONIST MK-801 PROTECTS AGAINST SEROTONIN DEPLETIONS INDUCED BY METHAMPHETAMINE, 3,4-METHYLENEDIOXYMETHAMPHETAMINE AND P-CHLORAMPHETAMINE

The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 blocks the ability of D-methamphetamine (MA) to deplete striatal dopamine (DA). We now report that MK-801 attenuates decreases in serotonin (5-HT) concentration induced by MA and two other amphetamine analogues, 3,4-methylenedioxymethamphetamine (MDMA) and p-chloroamphetamine (PCA). Rats were injected with saline (1.0 ml/kg) or MK-801 (0.5, 1.0 or 2.5 mg/kg) followed by either saline (1.0 ml/kg), MA (4, 2 or 1 injection(s); 10.0, 20.0 or 40.0 mg/kg), MDMA (20.0 or 40.0 mg/kg) or PCA (5.0 or 10.0 mg/kg). In some experiments, two injections of MK-801 or saline were used. Seventy-two hours after the last injection rats were sacrificed and concentrations of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) and DA were determined in hippocampus and striatum. MA caused a depletion of 5-HT to 33% of control in hippocampus and to 50% of control in striatum after the 4 x 10.0 mg/kg dose regimen. When MK-801 (2.5 mg/kg) was co-administered with MA, concentrations of 5-HT did not differ from control levels in either brain region. MDMA depleted 5-HT to approximately 58% of control in hippocampus and 66% of control in striatum at the 40 mg/kg dose. Co-administration of 0.5, 1.0 or 2.5 mg/kg MK-801 with MDMA caused a dose-related attenuation of the 5-HT depletions. PCA caused dose-dependent depletions of 5-HT to approximately 20% of control levels in both hippocampus and striatum at the highest dose. Co-administration of one or two injections of MK-801 (2.5 mg/kg) caused small attenuations of 5-HT depletions in all groups, although statistical significance was reached only when experiments were pooled to increase the sample size. Changes in 5-HIAA concentration were similar to changes in 5-HT concentration in all experiments. Striatal DA was depleted by MA but not MDMA or PCA, and co-administration of MK-801 attenuated the MA-induced DA depletion. These results are discussed in terms of possible mechanisms of serotonergic neurotoxicity.