Valproate blocks high-dose methamphetamine-induced behavioral cross-sensitization to locomotion-inducing effect of dizocilpine (MK-801), but not methamphetamine.
BACKGROUND
Our group has recently shown that methamphetamine (METH) (2.5 mg/kg) induced delayed increases in glutamate (Glu) levels in the rat nucleus accumbens (NAC), and that its repeated administration leads to behavioral cross-sensitization to a selective uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine (MK-801).


OBJECTIVE
The present study aims to examine whether valproate (VPA) would inhibit the delayed increases in Glu levels and prevent METH (2.5 mg/kg)-induced behavioral cross-sensitization to MK-801 (0.2 mg/kg).


METHODS
We examined the effects of post-treated VPA (50 mg/kg) on METH (2.5 mg/kg)-induced delayed increases in Glu levels. We injected VPA (50 mg/kg) at 120 min after each METH (2.5 mg/kg, once every other day, total of five times) administration and measured locomotor activity induced by challenge with MK-801 (0.2 mg/kg) or METH (0.15 mg/kg) after sufficient withdrawal period. Finally, we measured locomotion induced by MK-801 (0.2 mg/kg) after pretreatment of a competitive NMDA receptor antagonist, CPP (30 mg/kg). Effects of VPA on extracellular Glu levels were examined by using in vivo microdialysis. Locomotor activity was measured by using an infrared sensor.


RESULTS
VPA administered 120 min after METH injection had no effect on METH-induced hyperlocomotion, and inhibited METH-induced delayed increases in Glu levels. Repeated VPA administration prevented METH-induced behavioral cross-sensitization to MK-801, but not sensitization to METH. MK-801-induced hyperlocomotion was enhanced when pretreated with the competitive NMDA receptor antagonist, CPP.


CONCLUSIONS
These results suggest that VPA inhibits high-dose METH-induced delayed increases in Glu levels to prevent development of behavioral cross-sensitization to an NMDA antagonist, but not sensitization to METH.
Ito
K
K
Department of Psychiatry, Hokkaido University, Graduate School of Medicine, Kita 15, Nishi 7, Sapporo, 060-8638, Japan. itokoki@med.hokudai.ac.jp
Abekawa
T
T
Koyama
T
T
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D017551:Microdialysis; D009473:Neuronal Plasticity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D014635:Valproic Acid / Q000494:pharmacology*
D000927:Anticonvulsants; D000697:Central Nervous System Stimulants; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D008694:Methamphetamine; D014635:Valproic Acid; D016291:Dizocilpine Maleate