Implication of activated astrocytes in the development of drug dependence: differences between methamphetamine and morphine.
Astrocytes are a subpopulation of glial cells that directly affect neuronal function. This review focuses on the potential functional roles of astrocytes in the development of behavioral sensitization and rewarding effects induced by chronic treatment with drugs of abuse. In vitro treatment of cortical neuron/glia cocultures with either methamphetamine or morphine caused activation of astrocytes via protein kinase C (PKC). Purified cortical astrocytes were markedly activated by methamphetamine, whereas morphine had no such effect. Methamphetamine, but not morphine, caused a long-lasting astrocytic activation in cortical neuron/glia cocultures. Morphine-induced behavioral sensitization, assessed as hyperlocomotion, was reversed by 2 months of withdrawal from intermittent morphine administration, whereas behavioral sensitization to methamphetamine-induced hyperlocomotion was maintained even after 2 months of withdrawal. In vivo treatment with methamphetamine, which was associated with behavioral sensitization, caused PKC-dependent astrocytic activation in the mouse cingulate cortex and nucleus accumbens. Furthermore, the glial modulator propentofylline dramatically diminished the activation of astrocytes and the rewarding effect induced by methamphetamine and morphine. On the other hand, intra-nucleus accumbens and intra-cingulate cortex administration of astrocyte-conditioned medium aggravated the development of rewarding effects induced by methamphetamine and morphine. Furthermore, astrocyte-conditioned medium, but not methamphetamine itself, clearly induced differentiation of neural stem cells into astrocytes. These findings provide direct evidence that astrocytes may, at least in part, contribute to the development of the rewarding effects induced by drugs of abuse in the nucleus accumbens and cingulate cortex.
Narita
Minoru
M
Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan. narita@hoshi.ac.jp
Suzuki
Masami
M
Kuzumaki
Naoko
N
Miyatake
Mayumi
M
Suzuki
Tsutomu
T
D019969:Amphetamine-Related Disorders / Q000473:pathology*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D006179:Gyrus Cinguli / Q000187:drug effects / Q000502:physiology; D006801:Humans; D053612:Janus Kinases / Q000502:physiology; D008694:Methamphetamine / Q000494:pharmacology* / Q000633:toxicity; D051379:Mice; D009020:Morphine / Q000494:pharmacology* / Q000633:toxicity; D009021:Morphine Dependence / Q000473:pathology*; D009043:Motor Activity / Q000187:drug effects; D039902:Multipotent Stem Cells / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D012201:Reward; D050791:STAT Transcription Factors / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D017077:Culture Media, Conditioned; D016207:Cytokines; D009419:Nerve Tissue Proteins; D050791:STAT Transcription Factors; D008694:Methamphetamine; D009020:Morphine; D053612:Janus Kinases; D011493:Protein Kinase C