Effects of environmental enrichment upon ethanol-induced conditioned place preference and pre-frontal BDNF levels in adolescent and adult mice

Environmental enrichment (EE) provides a non-pharmacological tool to alter drug-induced reward, yet its effects on ethanol-induced reward remain controversial. We analyzed adolescent vs. adult (mice) differences in the influence of EE on ethanol-induced conditioned place preference (CPP). The effects of these treatments on brain-derived neurotrophic factor (BDNF) levels in the prefrontal cortex were examined in a separate group of animals. Ethanol-induced CPP was found in adults, and it was similar in EE and in animals reared under standard housing conditions (SC). Adolescents kept under EE, but not those in SC, exhibited CPP. Among SC, but not among EE, adolescents, BDNF levels were significantly lower in those treated with ethanol than in those given vehicle. These results indicate that, compared to adults, adolescent exhibited reduced sensitivity to ethanol's rewarding effects, yet the youth but not the adults exhibited sensitivity to the promoting effect of EE upon CPP by ethanol. Ethanol significantly reduced BDNF levels in adolescents reared under standard housing conditions, but not in adult mice nor in adolescents given EE housing conditions. The present results add to the plethora of adolescent-specific responses to ethanol or to environmental stimuli that may put the youth at risk for escalation of ethanol intake.Fil: Pautassi, Ricardo Marcos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina. Universidad Nacional de Córdoba. Facultad de Psicología; ArgentinaFil: Suarez, Andrea Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Hoffmann, Lucas Barbosa. Universidade de Sao Paulo; BrasilFil: Rueda, André Veloso. Universidade de Sao Paulo; BrasilFil: Rae, Mariana. Universidade de Sao Paulo; BrasilFil: Marianno, Priscila. Universidade de Sao Paulo; BrasilFil: Camarini, Rosana. Universidade de Sao Paulo; Brasi

Behavioral effects of short-term environmental enrichment in mice: microRNA expression and involvement of the BDNF - TrkB signaling pathway.

O enriquecimento ambiental (EA) reverte a sensibilização comportamental (SC) ao etanol em camundongos e diminui os níveis de BDNF no córtex pré-frontal (CPF). O objetivo deste trabalho foi estudar os efeitos do EA sobre parâmetros comportamentais, resposta de corticosterona ao estresse, expressão de microRNAS e a participação da via BDNF-TrkB no CPF frente à SC ao etanol. Camundongos mantidos em EA foram submetidos a testes comportamentais (ansiedade, depressão, anedonia e comportamentos repetitivos). Também foram tratados repetidamente com etanol e expostos ao EA para a avaliação da corticosterona plasmática e da expressão de microRNAs no CPF. A via BDNF-TrkB foi inibida no CPF de camundongos que desenvolveram a SC ao etanol. O EA diminuiu a atividade locomotora e exploratória, a ativação do eixo HPA após estresse agudo, aumentou o peso do baço e diminuiu a expressão de miR-132 e let-7d. Os resultados sugerem o envolvimento de microRNAs na reversão da SC ao etanol; contudo, a via BDNF-TrkB no CPF não parece estar diretamente envolvida neste processo.The environmental enrichment (EE) reverts the ethanol-induced behavioral sensitization (EIBS) in mice and decreases BDNF levels in the prefrontal cortex (PFC). The aim of this work was to evaluate the effects of EE on behavioral parameters, on the corticosterone response to stress and on microRNA expression and to assess the involvement of the BDNF-TrkB pathway in the PFC on the EIBS. Mice kept in EE were submitted to behavioral tests (anxiety, depression, anhedonia and repetitive behaviors). Mice were also treated repeatedly with ethanol and exposed to EE for the assessment of plasma corticosterone levels and microRNA expression in the PFC. The BDNF-TrkB pathway was blocked in the PFC of mice that developed EIBS. EE decreased locomotion, exploratory activity and HPA axis activation after acute stress, increased spleen weight and decreased miR-132 and let-7d expression. The results suggest the involvement of microRNAs in the reversal of EIBS promoted by EE; however, the BDNF-TrkB pathway in the PFC does not seem to be directly involved in this process

Environmental enrichment blocks the behavioral sensitization to ethanol in mice: effects on Egr-1 and the BDNF signalling.

O uso de drogas de abuso pode levar a alterações neuroplásticas duradouras no encéfalo, entre elas a sensibilização comportamental (SC), um fenômeno relacionado à dependência. O enriquecimento ambiental (EA) permite estudar a influência do ambiente na resposta a diversas manipulações, entre elas o tratamento com drogas de abuso. O objetivo deste trabalho foi avaliar o efeito do EA sobre a SC ao etanol, e sobre a expressão de proteínas envolvidas nas respostas às drogas de abuso: BDNF, TrkB e Egr-1. Para tanto, camundongos foram expostos ao EA, e então tratados repetidamente com uma dose baixa (1,8 g/kg) de etanol. Outros grupos foram submetidos ao protocolo de SC e posteriormente expostos ao EA. O EA protegeu os animais de desenvolverem a SC ao etanol, bem como promoveu sua reversão. O EA diminuiu os níveis de BDNF no córtex pré-frontal e de TrkB no hipocampo, e aumentou a expressão de Egr-1 no córtex insular. O EA pode ser considerado uma estratégia útil para a reversão dos efeitos da SC, que está associada à fissura e a episódios de recaídas na dependência.The use of addiction drugs can lead to long-term neuroplastic changes on the brain, such as behavioral sensitization (BS), a phenomenon related to addiction. Environmental enrichment (EE) is a strategy used to study the environmental influence on the response to several manipulations, including the treatment with addiction drugs. The aim of this work was to evaluate the effects of EE on the BS to ethanol and on the expression of proteins related to the response to drugs of abuse, as BDNF, TrkB and Egr-1. Thus, mice were exposed to EE and then repeatedly treated with a low dose (1.8 g/kg) of ethanol. Other group of mice was first submitted to the BS protocol and then exposed to EE. EE protected the mice from developing the BS to ethanol, and promoted its reversion. EE decreased BDNF levels in the prefrontal cortex and TrkB in the hippocampus, and increased Egr-1 expression in the insular cortex. EE can be considered and useful strategy to block BS effects, a phenomenon related to craving and relapse

Environmental enrichment blocks ethanol-induced locomotor sensitization and decreases BDNF levels in the prefrontal cortex in mice

The use of addictive drugs can lead to long-term neuroplastic changes in the brain, including behavioral sensitization, a phenomenon related to addiction. Environmental enrichment (EE) is a strategy used to study the effect of environment on the response to several manipulations, including treatment with addictive drugs. Brain-derived neurotrophic factor (BDNF) has been associated with behaviors related to ethanol addiction. The aim of the present study was to evaluate the effects of EE on ethanol-induced behavioral sensitization and BDNF expression. Mice were exposed to EE and then repeatedly treated with a low dose (1.8 g/kg) of ethanol. Another group of mice was first subjected to repeated ethanol treatment according to the behavioral sensitization protocol and then exposed to EE. Environmental enrichment prevented the development of ethanol-induced behavioral sensitization and blocked behavioral sensitization in sensitized mice. Both repeated ethanol and EE decreased BDNF levels in the prefrontal cortex but not in the hippocampus. However, BDNF levels were lower in ethanol-treated mice exposed to EE. These findings suggest that EE can act on the mechanisms implicated in behavioral sensitization, a model for drug-induced neuroplasticity and relapse. Additionally, EE alters BDNF levels, which regulate addiction-related behaviors.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq

GABA(B) receptor agonist only reduces ethanol drinking in light-drinking mice

Baclofen, a GABA(B) agonist, reduces ethanol intake in animals and humans, but the contrary or no effect was also reported. Our previous study demonstrated that mice characterized as "loss of control over ethanol intake" had different Gabbr1 and Gabbr2 transcription levels, which express, respectively, the GABA(B1) and GABA(B2) subunits in brain areas related to addictive behavior. In the present study, we tested baclofen on ethanol intake in mice exposed to the free-choice paradigm. Adult male Swiss mice, individually housed, had free access to three bottles: ethanol (5% and 10%) and water. The protocol had four phases: acquisition (AC, 10 weeks), withdrawal (W, 4 cycles during 2 weeks of 2 day-free-choice and 2 day-only-water), reexposure (RE, 2 weeks), and adulteration of ethanol solutions with quinine (AD, 2 weeks). Mice characterized as "loss of control" (A, n = 11, preference for ethanol in AC and maintenance of ethanol intake levels in AD), heavy (H, n = 11, preference for ethanol in AC and reduction of ethanol intake levels in AD), and light (L n = 16, preference for water in all phases) drinkers were randomly distributed into two subgroups receiving either intraperitoneal injections of all doses of baclofen (1.25, 2.5, and 5.0 mg/kg, given each dose twice in consecutive days) or saline, being exposed to free-choice. Fluid consumption was measured 24 h later. Baclofen reduced ethanol intake in group L In group H a reduction compared to AC was observed. Group A maintained their high ethanol intake even after baclofen treatment. Activation of the GABA(B) receptor depends on the precise balance between the GABA(B1) and GABA(B2) subunits, so the disproportionate transcription levels, we reported in group A, could explain this lack of response to baclofen. These data highlight the importance to test baclofen in individuals with different ethanol drinking profiles, including humans. (C) 2012 Elsevier Inc. All rights reserved.Universidade Federal do ParanaUniversidade Federal do ParanaConselho de Auxilio do Pessoal de Ensino Superior (CAPES)Conselho de Auxilio do Pessoal de Ensino Superior (CAPES)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq

A transcriptional study in mice with different ethanol-drinking profiles: Possible involvement of the GABA(B) receptor

Previous studies have suggested that gamma-aminobutyric acid-B (GABA(B)) receptor agonists effectively reduce ethanol intake. The quantification using real-time polymerase chain reaction of Gabbr1 and Gabbr2 mRNA from the prefrontal cortex, hypothalamus, hippocampus, and striatum in mice exposed to an animal model of the addiction developed in our laboratory was performed to evaluate the involvement of the GABAB receptor in ethanol consumption. We used outbred, Swiss mice exposed to a three-bottle free-choice model (water, 5% v/v ethanol, and 10% v/v ethanol) that consisted of four phases: acquisition (AC), withdrawal (W), reexposure (RE), and quinine-adulteration (AD). Based on individual ethanol intake, the mice were classified into three groups: "addicted" (A group; preference for ethanol and persistent consumption during all phases), "heavy" (H group; preference for ethanol and a reduction in ethanol intake in the AD phase compared to AC phase), and "light" (L group; preference for water during all phases). In the prefrontal cortex in the A group, we found high Gabbr1 and Gabbr2 transcription levels, with significantly higher Gabbr1 transcription levels compared with the C (ethanol-naive control mice). L, and H groups. In the hippocampus in the A group, Gabbr2 mRNA levels were significantly lower compared with the C, L, and H groups. In the striatum, we found a significant increase in Gabbr1 transcription levels compared with the C, L, and H groups. No differences in Gabbr1 or Gabbr2 transcription levels were observed in the hypothalamus among groups. In summary, Gabbr1 and Gabbr2 transcription levels were altered in cerebral areas related to drug taking only in mice behaviorally classified as "addicted" drinkers, suggesting that these genes may contribute to high and persistent ethanol consumption. (C) 2012 Elsevier Inc. All rights reserved.Conselho Nacional de Pesquisa (CNPq)Conselho Nacional de Pesquisa (CNPq)Conselho de Auxilio do Pessoal de Ensino Superior (CAPES)Conselho de Auxilio do Pessoal de Ensino Superior (CAPES)Minas Gerais State Foundation (FAPEMIG: EDT Universal ) [01/2008 APQ-00179-08]Minas Gerais State Foundation (FAPEMIG: EDT Universal