Journal of pharmacological sciences
January 1, 2008
Takayuki Nakagawa, Shuji Kaneko
44 citations
Drugs of abuse such as amphetamines, cocaine, opioids, and recreational drugs cause dependence and addiction by converging on common neural pathways. Chronic treatment enhances mesocorticolimbic dopaminergic neurons from the ventral tegmental area to the nucleus accumbens and medial prefrontal cortex, and disrupts glutamatergic function between these regions. Serotonergic neurons from the raphe nuclei to limbic areas also modulate this system and contribute to neuropsychotoxicity. This review introduces the authors' in vitro studies on methamphetamine, MDMA (ecstasy), and 5-MeO-DiPT (foxy) using Xenopus oocytes and organotypic slice cultures to examine molecular targets and neural adaptation.
Journal of pharmacological sciences
March 1, 2024
Aimi Yamagishi, Yuiko Ikekubo, Masayoshi Mishina et al.
6 citations
The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) produces both immediate and lasting antidepressant-like effects in mice, while its stereoisomer (2S,6S)-HNK does not. The sustained effects depend on the GluN2D subunit of the NMDA receptor: they disappear in mice lacking this subunit, although the acute effects remain. In stressed wildtype mice, GluN2B protein expression decreases in the nucleus accumbens, but this decrease does not occur in GluN2D-knockout mice. These findings suggest that the GluN2D subunit, and possibly GluN2B, mediate the long-lasting antidepressant-like action of (2R,6R)-HNK.
Journal of pharmacological sciences
March 1, 2025
Mikio Yoshida, Hikari Katada, Yuya Isozumi et al.
4 citations
In mice exposed to social defeat stress as juveniles, social behavior impairments were linked to elevated levels of GluN2C and GluN2D proteins in the prefrontal cortex. Acute administration of PPDA, a GluN2C/GluN2D antagonist, or ketamine, a non-competitive NMDA receptor antagonist, reduced these impairments. The effect of ketamine was partially blocked by CIQ, a GluN2C/GluN2D potentiator. Activation of GluN2C- and/or GluN2D-containing NMDA receptors appears to contribute to social behavior deficits from juvenile stress, and these subunits may be involved in ketamine's therapeutic action. Targeting these subunits could offer new treatment strategies for stress-related psychiatric disorders in adolescents.
Journal of pharmacological sciences
December 1, 2022
Tomohiko Irie, Yuta Yanase, Yosuke Demizu et al.
2 citations
Methoxetamine and its derivatives deoxymethoxetamine and methoxisopropamine, sold online as designer drugs, block N-methyl-D-aspartate receptors (NMDARs) in the brain. Computer docking simulations suggested these compounds interact with NMDARs. Using patch-clamp recordings from mouse neurons expressing NMDARs, the half-maximal inhibitory concentrations (IC50s) were determined: methoxetamine 0.524 μM, deoxymethoxetamine 0.679 μM, methoxisopropamine 0.661 μM, and the methoxetamine metabolites N-desethyl methoxetamine 1.649 μM and O-desmethyl methoxetamine 0.227 μM. All acted as potent NMDAR blockers, indicating that deoxymethoxetamine and methoxisopropamine may cause harm by blocking these receptors, and the metabolites may contribute to adverse effects when methoxetamine is metabolized.
Journal of pharmacological sciences
August 1, 2026
Natsuko Hitora-Imamura, Yuki Nishida, Koki Kawazoe et al.
Mice exposed to three weeks of corticosterone showed increased conflict behavior in a three-compartment task, specifically by prolonging action initiation, without signs of anhedonia. Ketamine reduced conflict in control mice but not in corticosterone-treated mice, indicating that chronic stress abolishes ketamine's anticonflict effect. The findings suggest that chronic stress biases conflict-related decision-making and disrupts mechanisms that normally respond to ketamine.
Journal of pharmacological sciences
June 1, 2026
Daiki Masukawa, Rei Tajika, Yoshimi Ichimaru et al.
Hallucinogens like LSD act mainly through the 5-HT2A receptor, but how they are regulated is not fully understood. GPR143, a receptor for L-DOPA, modulates certain other receptors. In mice lacking GPR143, the hallucinogen DOI caused more hyperactivity and more c-Fos expression in the nucleus accumbens, indicating enhanced effects. In cells expressing the 5-HT2A receptor, adding GPR143 reduced DOI-induced signaling. These results suggest GPR143 dampens 5-HT2A receptor signaling and weakens behavioral responses to hallucinogens.