title: Repeated cocaine administration decreases 5-HT(2A) receptor-mediated serotonergic enhancement of synaptic activity in rat medial prefrontal cortex.
abstract: Neural adaptations in the medial prefrontal cortex (mPFC) are thought to be crucial in the development and maintenance of addictive behaviors. The mPFC receives a dense serotonergic (5-hydroxytryptamine, 5-HT) innervation from raphe nuclei and 5-HT exerts complex actions on mPFC pyramidal neurons. The present study, using a rat model of behavioral sensitization to cocaine, was designed to determine whether repeated cocaine exposure in vivo is capable of altering 5-HT-induced regulation of glutamatergic transmission in the mPFC. In layer V pyramidal neurons of the mPFC, application of 5-HT, through activation of 5-HT(2A) receptors, induced a massive enhancement of spontaneous excitatory postsynaptic currents (sEPSCs). Repeated cocaine administration for 5 days resulted in an attenuation in the ability of 5-HT to enhance sEPSCs. This effect was prevented when cocaine was co-administered with the selective 5-HT(2A) receptor antagonist ketanserin and was mimicked by repeated 5-HT(2A) receptor agonist (-)4-iodo-2,5-dimethoxyphenylisopropylamine administration. Repeated cocaine administration is not associated with any changes in the levels of 5-HT(2A) receptors or regulator of GTP-binding protein signaling 4. These results suggest that cocaine-induced inhibition of 5-HT(2A) receptor-mediated enhancement of glutamatergic transmission in the mPFC may be caused, at least in part, by the impairment of coupling of 5-HT(2A) receptors with GTP-binding proteins during cocaine withdrawal. These alterations in 5-HT(2A) receptor responsiveness in the mPFC may be relevant to the development of behavioral sensitization and withdrawal effects following repeated cocaine administration.
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chiung-Chun
authors.initials: CC
authors.lastname: Huang
authors.forename: Ying-Ching
authors.initials: YC
authors.lastname: Liang
authors.forename: Cheng-Che
authors.initials: CC
authors.lastname: Lee
authors.forename: Mei-Ying
authors.initials: MY
authors.lastname: Wu
authors.forename: Kuei-Sen
authors.initials: KS
authors.lastname: Hsu
mesh_terms: D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004334:Drug Administration Schedule; D004347:Drug Interactions / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D013375:Substance Withdrawal Syndrome / Q000378:metabolism* / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: D018765:Dopamine Uptake Inhibitors; D044402:Receptor, Serotonin, 5-HT2A; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D012701:Serotonin; D018698:Glutamic Acid; D019204:GTP-Binding Proteins; D003042:Cocaine