Augmentation of serotonin release by sustained exposure to MDMA and methamphetamine in rat organotypic mesencephalic slice cultures containing raphe serotonergic neurons.
Several lines of evidence suggest the involvement of the raphe-serotonergic neurons in addiction to psychostimulants and some recreational drugs. In this study, we established rat organotypic mesencephalic slice cultures containing the raphe nuclei and examined the effects of sustained exposure to 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine (METH). Immunostaining for tryptophan hydroxylase (TPH) studies revealed that serotonergic neurons were abundant in the slice cultures. Sustained exposure to MDMA and METH (1-1000 microM) for 4 days had little effect on the serotonin tissue content, [(3)H]citalopram binding, or expression/phosphorylation of TPH. Treatment with MDMA or METH for 30 min increased serotonin release in a concentration-dependent manner. Slice cultures were exposed to MDMA for 4 days following a 1-day withdrawal period and then challenged with MDMA (10 microM). Sustained MDMA exposure augmented MDMA-induced serotonin release in a concentration-dependent manner, indicating serotonergic sensitization. Similar serotonergic sensitization was observed for METH. The development of MDMA-induced serotonergic sensitization was attenuated by the NMDA receptor antagonist, MK-801 (10 microM). These results suggest that in mesencephalic slice cultures sustained MDMA or METH exposure induces serotonergic sensitization through activation of NMDA receptors without serotonergic neurotoxicity. The in vitro model system could help to elucidate the mechanisms underlying drug addiction.
Higuchi
Megumi
M
Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Suzuki
Yuichi
Y
Yatani
Yumi
Y
Kitagawa
Yutaka
Y
Nagayasu
Kazuki
K
Shirakawa
Hisashi
H
Nakagawa
Takayuki
T
Kaneko
Shuji
S
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D019969:Amphetamine-Related Disorders / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D000831:Animals, Newborn; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000187:drug effects / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D008636:Mesencephalon / Q000187:drug effects* / Q000378:metabolism; D008694:Methamphetamine / Q000494:pharmacology*; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009924:Organ Culture Techniques; D011903:Raphe Nuclei / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D018759:Adrenergic Uptake Inhibitors; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D012701:Serotonin; D008694:Methamphetamine; D018817:N-Methyl-3,4-methylenedioxyamphetamine