Relationship between development of cross-sensitization to MK-801 and delayed increases in glutamate levels in the nucleus accumbens induced by a high dose of methamphetamine.
BACKGROUND
The present study hypothesized that delayed increases in extracellular glutamate (Glu) levels in the nucleus accumbens (NAC), induced by a high dose of methamphetamine (METH), can result in some functional changes of excitatory amino acid receptors, developing behavioral cross-sensitization to a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801.


OBJECTIVE
The present study aims to examine whether two different doses of METH (2.5 and 1.0 mg/kg) induce different effects on the development of cross-sensitization to MK-801. To clarify the mechanisms for development and expression of cross-sensitization to MK-801, we measured extracellular Glu and dopamine (DA) levels in the NAC at METH injections in a treatment period and at MK-801 injection after a 12-day withdrawal period.


METHODS
METH- or MK-801-induced changes in Glu and DA levels and in locomotion were measured using in vivo microdialysis and infrared sensor, respectively.


RESULTS
METH, at only 2.5 mg/kg, produced delayed increases in Glu levels and developed behavioral cross-sensitization to MK-801 (0.2 mg/kg). MK-801 (0.2 mg/kg) induced delayed increases in Glu levels in the NAC, but this time course was not completely consistent with MK-801-induced enhanced hyperlocomotion. During this time course, MK-801 (0.2 mg/kg) did not induce any changes in DA levels.


CONCLUSIONS
These results suggest that METH-induced, at 2.5 mg/kg, delayed increases in Glu levels are necessary for development of behavioral cross-sensitization to MK-801, but not METH. The enhanced locomotion-inducing effect of MK-801 might be related to some functional changes in excitatory amino acid receptors such as NMDA and DL-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid in the NAC.
Ito
K
K
Department of Psychiatry, Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Sapporo, 060-8638, Japan. itokoki@med.hokudai.ac.jp
Abekawa
T
T
Koyama
T
T
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004298:Dopamine / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000032:analysis*; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000737:chemistry / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D001552:Benzazepines; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D008694:Methamphetamine; D016291:Dizocilpine Maleate; D004298:Dopamine