title: HIV antiretroviral drug Efavirenz induces anxiety-like and depression-like behavior in rats: evaluation of neurotransmitter alterations in the striatum.
abstract: Efavirenz (EFV) is an effective antiretroviral drug with a favorable pharmacokinetic profile and widely used in combination regimens to treat HIV infection. However, there are major concerns about the safety of this drug. Patients treated with EFV often experience neuropsychiatric adverse effects, which frequently lead to switching to alternative EFV-free regimens. The mechanisms involved in the central action of EFV are intrinsically unclear. Thus, this study aimed to investigate the effects of acute and subchronic (2 weeks) EFV administration in a series of behavioral tests for anxiety-like and depression-like behavior in healthy rats. We also evaluated the effect of EFV treatment in striatal concentrations of monoamine neurotransmitters (serotonin, dopamine and noradrenaline) and their metabolites and the amino acid neurotransmitters glutamate and GABA. Our results showed that acute treatment with EFV induced an anxiogenic-like effect, while sub-chronic treatment induced both anxiogenic-like and depressive-like behavior which was dose related.. Additionally, EFV treatment caused marked alterations in the striatal concentrations of monoamines and their metabolites (and turnover rates) and the amino acid neurotransmitters glutamate and GABA. These changes were influenced by treatment duration and dose. These findings add more evidence about the neuropsychiatric adverse effects of EFV and propose potential new mechanisms for the toxic action of this drug in the central nervous system.
authors.affiliation: Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: Giuliana Ignácio Teixeira
authors.initials: GI
authors.lastname: Cavalcante
authors.affiliation: Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: Adriano José Maia
authors.initials: AJ
authors.lastname: Chaves Filho
authors.affiliation: Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Linhares
authors.affiliation: Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: Camila Nayane
authors.initials: CN
authors.lastname: de Carvalho Lima
authors.affiliation: Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil; Pharmacy Department, Faculty of Dentistry, Nursing and Pharmacy, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: Edith Teles
authors.initials: ET
authors.lastname: Venâncio
authors.affiliation: Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil; Pharmacy Department, Faculty of Dentistry, Nursing and Pharmacy, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: Emiliano Ricardo Vasconcelos
authors.initials: ER
authors.lastname: Rios
authors.affiliation: Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: Francisca Cléa Florenço
authors.initials: FC
authors.lastname: de Souza
authors.affiliation: Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: Silvânia Maria Mendes
authors.initials: SM
authors.lastname: Vasconcelos
authors.affiliation: Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: Danielle
authors.initials: D
authors.lastname: Macêdo
authors.affiliation: Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil; Pharmacy Department, Faculty of Dentistry, Nursing and Pharmacy, Federal University of Ceará, Fortaleza, CE, Brazil. Electronic address: martafonteles@yahoo.com.br.
authors.forename: Marta Maria
authors.initials: MM
authors.lastname: de França Fonteles
mesh_terms: D000480:Alkynes; D000818:Animals; D019380:Anti-HIV Agents / Q000009:adverse effects*; D001007:Anxiety / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D048588:Benzoxazines / Q000009:adverse effects*; D003521:Cyclopropanes; D003863:Depression / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D018377:Neurotransmitter Agents; C098320:efavirenz
keywords: Antiretroviral drugs; Efavirenz; Monoamines; Neuropsychiatric adverse events; Neurotransmitters; Striatum