title: Cocaine-induced locomotor sensitization in rats correlates with nucleus accumbens activity on manganese-enhanced MRI.
abstract: A long-standing goal of substance abuse research has been to link drug-induced behavioral outcomes with the activity of specific brain regions to understand the neurobiology of addiction behaviors and to search for drug-able targets. Here, we tested the hypothesis that cocaine produces locomotor (behavioral) sensitization that correlates with increased calcium channel-mediated neuroactivity in brain regions linked with drug addiction, such as the nucleus accumbens (NAC), anterior striatum (AST) and hippocampus, as measured using manganese-enhanced MRI (MEMRI). Rats were treated with cocaine for 5 days, followed by a 2-day drug-free period. The following day, locomotor sensitization was quantified as a metric of cocaine-induced neuroplasticity in the presence of manganese. Immediately following behavioral testing, rats were examined for changes in calcium channel-mediated neuronal activity in the NAC, AST, hippocampus and temporalis muscle, which was associated with behavioral sensitization using MEMRI. Cocaine significantly increased locomotor activity and produced behavioral sensitization compared with saline treatment of control rats. A significant increase in MEMRI signal intensity was determined in the NAC, but not AST or hippocampus, of cocaine-treated rats compared with saline-treated control rats. Cocaine did not increase signal intensity in the temporalis muscle. Notably, in support of our hypothesis, behavior was significantly and positively correlated with MEMRI signal intensity in the NAC. As neuronal uptake of manganese is regulated by calcium channels, these results indicate that MEMRI is a powerful research tool to study neuronal activity in freely behaving animals and to guide new calcium channel-based therapies for the treatment of cocaine abuse and dependence.
authors.affiliation: Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Shane A
authors.initials: SA
authors.lastname: Perrine
authors.affiliation: Department of Anesthesiology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Farhad
authors.initials: F
authors.lastname: Ghoddoussi
authors.affiliation: Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Kirtan
authors.initials: K
authors.lastname: Desai
authors.affiliation: Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kohler
authors.affiliation: Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA.|Research and Development Service, John D. Dingell Veterans Affairs Medical Center, Detroit, MI, USA.
authors.forename: Ajay T
authors.initials: AT
authors.lastname: Eapen
authors.affiliation: Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lisieski
authors.affiliation: Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA.|Research and Development Service, John D. Dingell Veterans Affairs Medical Center, Detroit, MI, USA.
authors.forename: Mariana
authors.initials: M
authors.lastname: Angoa-Perez
authors.affiliation: Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA.|Research and Development Service, John D. Dingell Veterans Affairs Medical Center, Detroit, MI, USA.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Kuhn
authors.affiliation: Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA.|Research and Development Service, John D. Dingell Veterans Affairs Medical Center, Detroit, MI, USA.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Bosse
authors.affiliation: Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA.|Research and Development Service, John D. Dingell Veterans Affairs Medical Center, Detroit, MI, USA.
authors.forename: Alana C
authors.initials: AC
authors.lastname: Conti
authors.affiliation: Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: David
authors.initials: D
authors.lastname: Bissig
authors.affiliation: Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI, USA.|Department of Ophthalmology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Berkowitz
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D003042:Cocaine / Q000008:administration & dosage*; D003287:Contrast Media / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D008124:Locomotion / Q000187:drug effects / Q000502:physiology*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008345:Manganese / Q000493:pharmacokinetics; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013223:Statistics as Topic
chemical_list: D003287:Contrast Media; D008345:Manganese; D003042:Cocaine
keywords: behavioral sensitization; calcium; cocaine; dopamine transporter; magnetic resonance imaging; manganese; nucleus accumbens; striatum