title: N-acetylcysteine modulates hallucinogenic 5-HT(2A) receptor agonist-mediated responses: behavioral, molecular, and electrophysiological studies.
abstract: N-acetylcysteine (NAC) has been reported to reverse the psychotomimetic effects in the rodent phencyclidine model of psychosis and shown beneficial effects in treating patients with schizophrenia. The effect of NAC has been associated with facilitating the activity of cystine-glutamate antiporters on glial cells concomitant with the release of non-vesicular glutamate, which mainly stimulates the presynaptic metabotropic glutamate receptor subtype 2 receptors (mGluR2). Recent evidence demonstrated that functional interactions between serotonin 5-HT2A receptor (5-HT(2A)R) and mGluR2 are responsible to unique cellular responses when targeted by hallucinogenic drugs. The present study determined the effects of NAC on hallucinogenic 5-HT(2A)R agonist (±)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-elicited behavioral and molecular responses in mice and DOI-evoked field potentials in the mouse cortical slices. NAC significantly attenuated DOI-induced head twitch response and expression of c-Fos and Egr-2 in the infralimbic and motor cortex and suppressed the increase in the frequency of excitatory field potentials elicited by DOI in the medial prefrontal cortex. In addition, the cystine-glutamate antiporter inhibitor (S)-4-carboxyphenylglycine (CPG) and the mGluR2 antagonist LY341495 reversed the suppressing effects of NAC on DOI-induced head twitch and molecular responses and increased frequency of excitatory field potentials, supporting that NAC attenuates the 5-HT(2A)R-mediated hallucinogenic effects via increased activity of cystine-glutamate antiporter followed by activation of mGluR2 receptors. These findings implicate NAC as a potential therapeutic agent for hallucinations and psychosis associated with hallucinogen use and schizophrenia.
authors.affiliation: Department of Pharmacology and Toxicology, Tzu Chi University, 701, Section 3, Chung-Yang Road, Hualien 97004, Taiwan.
authors.forename: Mei-Yi
authors.initials: MY
authors.lastname: Lee
authors.affiliation: School of Medicine, Tzu Chi University, 701, Section 3, Chung-Yang Road, Hualien 97004, Taiwan.
authors.forename: Chun-Cheng
authors.initials: CC
authors.lastname: Chiang
authors.affiliation: Department of Pharmacy, Hualien, Tzu Chi General Hospital, 707, Section 3, Chung-Yang Road, Hualien 97004, Taiwan.
authors.forename: Hong-Yi
authors.initials: HY
authors.lastname: Chiu
authors.affiliation: Institute of Neuroscience, National Changchi University, 64, Sec. 2, ZhiNan Road, Wenshan District, Taipei City 11605, Taiwan; Research Center for Mind, Brain, and Learning, National Changchi University, 64, Sec. 2, ZhiNan Road, Wenshan District, Taipei City 11605, Taiwan.
authors.forename: Ming-Huan
authors.initials: MH
authors.lastname: Chan
authors.affiliation: Department of Pharmacology and Toxicology, Tzu Chi University, 701, Section 3, Chung-Yang Road, Hualien 97004, Taiwan; Center for Neuropsychiatric Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 35053, Taiwan. Electronic address: hwei5514@gmail.com.
authors.forename: Hwei-Hsien
authors.initials: HH
authors.lastname: Chen
mesh_terms: D000111:Acetylcysteine / Q000627:therapeutic use*; D000200:Action Potentials / Q000187:drug effects*; D000596:Amino Acids / Q000494:pharmacology; D000662:Amphetamines / Q000633:toxicity; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D051767:Early Growth Response Protein 2 / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006212:Hallucinations / Q000139:chemically induced / Q000188:drug therapy*; D006213:Hallucinogens / Q000633:toxicity; D008297:Male; D051379:Mice; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D014966:Xanthenes / Q000494:pharmacology
chemical_list: D000596:Amino Acids; D000662:Amphetamines; D001565:Benzoates; D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; D018691:Excitatory Amino Acid Antagonists; D016166:Free Radical Scavengers; D058787:GABA-A Receptor Antagonists; D006213:Hallucinogens; C114624:LY 341495; D016760:Proto-Oncogene Proteins c-fos; D018094:Receptors, Metabotropic Glutamate; D014966:Xanthenes; C108822:metabotropic glutamate receptor 2; C079693:4-carboxyphenylglycine; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; D005998:Glycine; D000111:Acetylcysteine; D001640:Bicuculline
keywords: 5-HT(2A) receptor; Head twitch; N-acetylcysteine; mGluR2 receptor