title: N-acetylcysteine treatment blocks the development of ethanol-induced behavioural sensitization and related ΔFosB alterations.
abstract: Ethanol addiction is a serious public health problem that still needs more effective pharmacological treatment. A key factor in the development and maintenance of this disease is the advent of neuroadaptations in the mesocorticolimbic brain pathway upon chronic ethanol abuse. In general, these neuroadaptations are maladaptive and affect numerous neurotransmitter systems and intracellular molecules. One of these molecules is ΔFosB, a transcription factor that is altered after chronic drug use. Behavioural sensitization is a useful model for the study of the neuroadaptations related to addiction. Recent works have shown a role for the imbalance of glutamatergic neurotransmission in the symptoms found in addicted people. In this sense, the treatment with N-acetylcysteine, a l-cysteine prodrug that acts by restoring extrasynaptic concentrations of glutamate through the activation of cystine-glutamate antiporter, has shown promising results in the treatment of addiction. Thus, an animal model of behavioural sensitization was used to evaluate the effects of N-acetylcysteine treatment in the behavioural and molecular alterations induced by chronic ethanol administration. Swiss mice were subject to 13 days of daily ethanol administration to induce behavioural sensitization. Two hours before each ethanol administration and locomotor activity evaluation, the animals received intraperitoneally N-acetylcysteine injections. Immediately after the last test session, their brains were removed for ΔFosB and cystine-glutamate antiporter quantification. It was found that N-acetylcysteine treatment blocked ethanol-induced behavioural sensitization, the increase of ΔFosB content in the prefrontal cortex, and its reduction in the nucleus accumbens. The results suggest a possible use of N-acetylcysteine in ethanol-related disorders.
authors.affiliation: Laboratory of Pharmacology, School of Pharmaceutical Sciences, Univ Estadual Paulista - UNESP, Araraquara, SP, Brazil; Joint Graduate Programme in Physiological Sciences, UFSCar/UNESP, São Carlos/Araraquara, SP, Brazil.
authors.forename: Gessynger
authors.initials: G
authors.lastname: Morais-Silva
authors.affiliation: Laboratory of Pharmacology, School of Pharmaceutical Sciences, Univ Estadual Paulista - UNESP, Araraquara, SP, Brazil.
authors.forename: Gabrielle Cunha
authors.initials: GC
authors.lastname: Alves
authors.affiliation: Laboratory of Pharmacology, School of Pharmaceutical Sciences, Univ Estadual Paulista - UNESP, Araraquara, SP, Brazil; Joint Graduate Programme in Physiological Sciences, UFSCar/UNESP, São Carlos/Araraquara, SP, Brazil. Electronic address: marcelo@fcfar.unesp.br.
authors.forename: Marcelo T
authors.initials: MT
authors.lastname: Marin
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D000431:Ethanol / Q000008:administration & dosage*; D007274:Injections, Intraperitoneal; D008124:Locomotion / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D011897:Random Allocation; D016896:Treatment Outcome
chemical_list: C483819:Fosb protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D000431:Ethanol; D000111:Acetylcysteine
keywords: Alcohol addiction; Glutamate; N-acetylcysteine; Nucleus accumbens; Prefrontal cortex; xCT antiporter