title: Methamphetamine compromises gap junctional communication in astrocytes and neurons.
abstract: Methamphetamine (meth) is a central nervous system (CNS) stimulant that results in psychological and physical dependency. The long-term effects of meth within the CNS include neuronal plasticity changes, blood-brain barrier compromise, inflammation, electrical dysfunction, neuronal/glial toxicity, and an increased risk to infectious diseases including HIV. Most of the reported meth effects in the CNS are related to dysregulation of chemical synapses by altering the release and uptake of neurotransmitters, especially dopamine, norepinephrine, and epinephrine. However, little is known about the effects of meth on connexin (Cx) containing channels, such as gap junctions (GJ) and hemichannels (HC). We examined the effects of meth on Cx expression, function, and its role in NeuroAIDS. We found that meth altered Cx expression and localization, decreased GJ communication between neurons and astrocytes, and induced the opening of Cx43/Cx36 HC. Furthermore, we found that these changes in GJ and HC induced by meth treatment were mediated by activation of dopamine receptors, suggesting that dysregulation of dopamine signaling induced by meth is essential for GJ and HC compromise. Meth-induced changes in GJ and HC contributed to amplified CNS toxicity by dysregulating glutamate metabolism and increasing the susceptibility of neurons and astrocytes to bystander apoptosis induced by HIV. Together, our results indicate that connexin containing channels, GJ and HC, are essential in the pathogenesis of meth and increase the sensitivity of the CNS to HIV CNS disease. Methamphetamine (meth) is an extremely addictive central nervous system stimulant. Meth reduced gap junctional (GJ) communication by inducing internalization of connexin-43 (Cx43) in astrocytes and reducing expression of Cx36 in neurons by a mechanism involving activation of dopamine receptors (see cartoon). Meth-induced changes in Cx containing channels increased extracellular levels of glutamate and resulted in higher sensitivity of neurons and astrocytes to apoptosis in response to HIV infection.
authors.affiliation: Public Health Research Institute (PHRI), New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.|Department of Microbiology and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Castellano
authors.affiliation: Public Health Research Institute (PHRI), New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.|Department of Microbiology and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.
authors.forename: Chisom
authors.initials: C
authors.lastname: Nwagbo
authors.affiliation: New York Institute of Technology College of Osteopathic Medicine, Old Westbury, New York, USA.
authors.forename: Luis R
authors.initials: LR
authors.lastname: Martinez
authors.affiliation: Public Health Research Institute (PHRI), New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.|Department of Microbiology and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.
authors.forename: Eliseo A
authors.initials: EA
authors.lastname: Eugenin
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002450:Cell Communication / Q000187:drug effects* / Q000502:physiology; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D017629:Gap Junctions / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats
chemical_list: D000697:Central Nervous System Stimulants; D008694:Methamphetamine
keywords: HIV; apoptosis; cocaine; connexin; drugs