The NMDA receptor antagonist MK-801 does not protect against serotonin depletions caused by high doses of DL-fenfluramine.
The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) has been shown to block methamphetamine (MA) induced damage to the dopamine (DA) and serotonin (5HT) systems of the brain. DL-Fenfluramine (FEN) is another potential neurotoxin but its long-term depletions are more selective to the 5HT system. To determine whether MK-801 protects against damage induced by FEN, we treated rats with FEN (4 injections of 12.5 mg/kg, at 1 h intervals) in conjunction with either saline or MK-801 (2 injections of 2.5 mg/kg, administered 15 min before and 90 min after the first FEN injection). Two weeks post-treatment, MK-801 alone caused a small but significant decrease in 5HT tissue concentrations in striatum and amygdala. FEN significantly reduced 5HT in all 8 brain regions studied. MK-801 + FEN did not protect against FEN-induced 5HT depletions in nucleus accumbens/olfactory tubercle, septum, frontal cortex, somatosensory cortex or hippocampus. MK-801 + FEN enhanced 5HT depletions in striatum, hypothalamus and amygdala. The differential protective effect of MK-801 between MA and FEN are discussed in terms of a possible dopaminergic mechanism.
Sabol
K E
KE
University of Chicago, Department of Pharmacological and Physiological Sciences, Chicago, IL 60637.
Richards
J B
JB
Seiden
L S
LS
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005277:Fenfluramine / Q000494:pharmacology*; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D009928:Organ Specificity; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012701:Serotonin / Q000378:metabolism*; D013997:Time Factors
D016194:Receptors, N-Methyl-D-Aspartate; D005277:Fenfluramine; D012701:Serotonin; D016291:Dizocilpine Maleate; D009638:Norepinephrine