title: Direct evidence of astrocytic modulation in the development of rewarding effects induced by drugs of abuse.
abstract: Long-term exposure to pyschostimulants and opioids induced neuronal plasticity. Accumulating evidence suggests that astrocytes actively participate in synaptic plasticity. We show here that a glial modulator propentofylline (PPF) dramatically diminished the activation of astrocytes induced by drugs of abuse, such as methamphetamine (METH) and morphine (MRP). In vivo treatment with PPF also suppressed both METH- and MRP-induced rewarding effects. On the other hand, intra-nucleus accumbens (N.Acc.) administration of astrocyte-conditioned medium (ACM) aggravated the development of rewarding effects induced by METH and MRP via the Janus kinase/signal transducers and activators of transcription (Jak/STAT) pathway, which modulates astrogliosis and/or astrogliogenesis. Furthermore, ACM, but not METH itself, clearly induced the differentiation of multipotent neuronal stem cells into glial fibrillary acidic protein-positive astrocytes, and this effect was reversed by cotreatment with the Jak/STAT inhibitor AG490. Intra-cingulate cortex (CG) administration of ACM also enhanced the rewarding effect induced by METH and MRP. In contrast to ACM, intra-N.Acc. administration of microglia-conditioned medium failed to affect the rewarding effects of METH and MRP in mice. These findings suggest that astrocyte-, but not microglia-, related soluble factors could amplify the development of rewarding effect of METH and MRP in the N.Acc. and CG. The present study provides direct evidence that astrocytes may, at least in part, contribute to the synaptic plasticity induced by drugs of abuse during the development of rewarding effects induced by psychostimulants and opioids.
authors.affiliation: Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan. narita@hoshi.ac.jp
authors.forename: Minoru
authors.initials: M
authors.lastname: Narita
authors.forename: Mayumi
authors.initials: M
authors.lastname: Miyatake
authors.forename: Michiko
authors.initials: M
authors.lastname: Narita
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shibasaki
authors.forename: Keiko
authors.initials: K
authors.lastname: Shindo
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakamura
authors.forename: Naoko
authors.initials: N
authors.lastname: Kuzumaki
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Nagumo
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000737:chemistry*; D001522:Behavior, Animal / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003216:Conditioning, Operant / Q000187:drug effects*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D013287:Illicit Drugs / Q000494:pharmacology*; D007150:Immunohistochemistry / Q000379:methods; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000187:drug effects; D012201:Reward; D013234:Stem Cells / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D013287:Illicit Drugs; D020032:Tyrphostins; D014970:Xanthines; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D008694:Methamphetamine; C032114:propentofylline; D009020:Morphine