Long-lasting alterations in 5-HT2A receptor after a binge regimen of methamphetamine in mice.
The repeated administration of methamphetamine (MA) to animals in a single-day 'binge' dosing regimen produces damage to dopamine and serotonin terminals and psychosis-like behaviours similar to those observed in MA abusers. The present study aimed to examine the effects of MA binge exposure on 5-HT2A receptors, the subtype of serotonin receptors putatively involved in psychosis. ICR male mice were treated with MA (4 × 5 mg/kg) or saline at 2 h intervals. Recognition memory and social behaviours were sequentially evaluated by a novel location recognition test, a novel object recognition test, a social interaction and a nest-building test to confirm the persistent cognitive and behavioural impairments after this dosing regimen. Subsequently, a hallucinogenic 5-HT2A/2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced head-twitch, molecular and electrophysiological responses were monitored. Finally, the levels of 5-HT2C, 5-HT1A, 5-HT2A and mGlu2 receptors in the medial prefrontal cortex were determined. MA binge exposure produced recognition memory impairment, reduced social behaviours, and increased DOI-induced head-twitch response, c-Fos and Egr-2 expression and field potentials in the medial prefrontal cortex. Furthermore, MA binge exposure increased 5-HT2A and decreased mGlu2 receptor expression in the medial frontal cortex, whereas 5-HT2C and 5-HT1A receptors were unaffected. These data reveal that the increased behavioural, molecular and electrophysiological responses to DOI might be associated with an up-regulation of 5-HT2A receptors in the medial prefrontal cortex after MA binge exposure. Identifying the biochemical alterations that parallel the behavioural changes in a mouse model of MA binge exposure may facilitate targeting therapies for treatment of MA-related psychiatric disorders.
Institute of Pharmacology and Toxicology, Tzu Chi University,701, Section 3, Chung-Yang Road, Hualien,Taiwan.
Hong-Yi
HY
Chiu
Institute of Neuroscience, National Chengchi University,Wenshan District, Taipei City,Taiwan.
Ming-Huan
MH
Chan
Institute of Pharmacology and Toxicology, Tzu Chi University,701, Section 3, Chung-Yang Road, Hualien,Taiwan.
Mei-Yi
MY
Lee
Institute of Pharmacology and Toxicology, Tzu Chi University,701, Section 3, Chung-Yang Road, Hualien,Taiwan.
Shao-Tsu
ST
Chen
Department of Life Science,Tzu Chi University,Hualien,Taiwan.
Zih-Yi
ZY
Zhan
Institute of Pharmacology and Toxicology, Tzu Chi University,701, Section 3, Chung-Yang Road, Hualien,Taiwan.
Hwei-Hsien
HH
Chen
D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D000697:Central Nervous System Stimulants / Q000008:administration & dosage*; D051767:Early Growth Response Protein 2 / Q000378:metabolism; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D005106:Exploratory Behavior / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D019416:Head Movements / Q000187:drug effects; D066298:In Vitro Techniques; D007398:Interpersonal Relations; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage*; D051379:Mice; D008813:Mice, Inbred ICR; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D021641:Recognition, Psychology / Q000187:drug effects; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D000662:Amphetamines; D000697:Central Nervous System Stimulants; D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D044402:Receptor, Serotonin, 5-HT2A; D017366:Serotonin Receptor Agonists; D008694:Methamphetamine; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine