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Reduced Contextual Discrimination following Alcohol Consumption or MDMA Administration in Mice.

Johansson EM, García-Gutiérrez MS, Moscoso-Castro M, Manzanares J, Valverde O - PLoS ONE (2015)

Bottom Line: We then introduced them to a contextual fear discrimination task and immune-related effects were examined by immunohistochemical and biochemical studies.Our results suggest that there is a relationship between the induction of immune activated pathways by voluntary alcohol consumption and a high-dose MDMA.This information will be helpful for discovering new selective drug targets, and to develop treatments and preventive approaches for patients with anxiety-related disorders.

View Article: PubMed Central - PubMed

Affiliation: Neurobiology of Behaviour Research Group (GReNeC), Department of Health and Experimental Sciences, Universitat Pompeu Fabra, IMIM, Hospital del Mar Medical Research Institute, Barcelona Biomedical Research Park C/Dr. Aiguader 88, 08003, Barcelona, Spain.

ABSTRACT
The recreational drugs, alcohol and 3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") have both been shown to cause immune activation in vivo, and they are linked to cognitive impairment and anxiety-like behaviors in rodents. The neuronal effects of these drugs in the hippocampal area, an area that has been a focus of studies aiming to explain the mechanisms underlying anxiety related-disorders, remains poorly understood. Therefore we investigated the specific inflammatory impact of alcohol and MDMA on this area of the brain and on a hippocampal-related behavioral task. We centered our study on two inflammatory factors linked to anxiety-related disorders, namely Interleukin-1β (IL-1β) and brain-derived neurotrophic factor (BDNF). We subjected drug-consuming mice to a battery of behavioral tests to evaluate general activity, anxiety-like and depressive-live behaviors. We then introduced them to a contextual fear discrimination task and immune-related effects were examined by immunohistochemical and biochemical studies. Our results suggest that there is a relationship between the induction of immune activated pathways by voluntary alcohol consumption and a high-dose MDMA. Furthermore, the ability of mice to perform a contextual fear discrimination task was impaired by drug consumption and we report long term inflammatory alterations in the hippocampus even several weeks after drug intake. This information will be helpful for discovering new selective drug targets, and to develop treatments and preventive approaches for patients with anxiety-related disorders.

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Experimental timeline and drinking behavior.(A) Each stage of the experiment is separated by a line and the day(s) of each stage is shown underneath. Mice were deprived of food but had free access to either water or EtOH (20%) for 2h per day or for 4h on days 4 and 11. On day 11, water and EtOH drinkers were injected (i.p.) with MDMA (20 mg/kg x 2) or saline, respectively, with 2h in between. Locomotor activity, anxiety-like and despair-like behaviors were evaluated 72 h and 4 days after the last MDMA or saline injection. The following morning 6 mice/group were euthanized and 6 mice/group continued to the CFD trial. Daily volume (ml) of (B) water or (C) EtOH intake registered, and (D) EtOH consumption, calculated as g/kg, (n = 12–24 mice/group) are shown. Statistically significant differences in EtOH intake between days 1–3 and 8–10 are indicated by brackets and are represented by C *p<0.0499 and D *p = 0.0241); Paired t-test. The mean ± SEM is shown at the sides. CFD, contextual fear discrimination; EPM, elevated plus maze; MDMA, 3,4-Methylenedioxymethamphetamine; TST, tail suspension test.
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pone.0142978.g001: Experimental timeline and drinking behavior.(A) Each stage of the experiment is separated by a line and the day(s) of each stage is shown underneath. Mice were deprived of food but had free access to either water or EtOH (20%) for 2h per day or for 4h on days 4 and 11. On day 11, water and EtOH drinkers were injected (i.p.) with MDMA (20 mg/kg x 2) or saline, respectively, with 2h in between. Locomotor activity, anxiety-like and despair-like behaviors were evaluated 72 h and 4 days after the last MDMA or saline injection. The following morning 6 mice/group were euthanized and 6 mice/group continued to the CFD trial. Daily volume (ml) of (B) water or (C) EtOH intake registered, and (D) EtOH consumption, calculated as g/kg, (n = 12–24 mice/group) are shown. Statistically significant differences in EtOH intake between days 1–3 and 8–10 are indicated by brackets and are represented by C *p<0.0499 and D *p = 0.0241); Paired t-test. The mean ± SEM is shown at the sides. CFD, contextual fear discrimination; EPM, elevated plus maze; MDMA, 3,4-Methylenedioxymethamphetamine; TST, tail suspension test.

Mentions: Drinking behavior was registered 4 days/week and on day 4 two saline injections were given to all mice. On day 11 two high-dose MDMA injections were given to mice drinking water, while mice drinking EtOH were given two saline injections. 72h after drug consumption, we conducted behavioral evaluation of locomotion, anxiety-like and despair-like responses, followed by either a contextual fear conditioning task or euthanasia for immunohistochemical and biochemical evaluation (Fig 1A and S1 Fig). Our results show an increased liking for EtOH throughout the DID-test. Furthermore, the capacity of the mice to perform a contextual fine discrimination task was not only obstructed by a high MDMA dose but also by voluntary alcohol intake during several consecutive days.


Reduced Contextual Discrimination following Alcohol Consumption or MDMA Administration in Mice.

Johansson EM, García-Gutiérrez MS, Moscoso-Castro M, Manzanares J, Valverde O - PLoS ONE (2015)

Experimental timeline and drinking behavior.(A) Each stage of the experiment is separated by a line and the day(s) of each stage is shown underneath. Mice were deprived of food but had free access to either water or EtOH (20%) for 2h per day or for 4h on days 4 and 11. On day 11, water and EtOH drinkers were injected (i.p.) with MDMA (20 mg/kg x 2) or saline, respectively, with 2h in between. Locomotor activity, anxiety-like and despair-like behaviors were evaluated 72 h and 4 days after the last MDMA or saline injection. The following morning 6 mice/group were euthanized and 6 mice/group continued to the CFD trial. Daily volume (ml) of (B) water or (C) EtOH intake registered, and (D) EtOH consumption, calculated as g/kg, (n = 12–24 mice/group) are shown. Statistically significant differences in EtOH intake between days 1–3 and 8–10 are indicated by brackets and are represented by C *p<0.0499 and D *p = 0.0241); Paired t-test. The mean ± SEM is shown at the sides. CFD, contextual fear discrimination; EPM, elevated plus maze; MDMA, 3,4-Methylenedioxymethamphetamine; TST, tail suspension test.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4643963&req=5

pone.0142978.g001: Experimental timeline and drinking behavior.(A) Each stage of the experiment is separated by a line and the day(s) of each stage is shown underneath. Mice were deprived of food but had free access to either water or EtOH (20%) for 2h per day or for 4h on days 4 and 11. On day 11, water and EtOH drinkers were injected (i.p.) with MDMA (20 mg/kg x 2) or saline, respectively, with 2h in between. Locomotor activity, anxiety-like and despair-like behaviors were evaluated 72 h and 4 days after the last MDMA or saline injection. The following morning 6 mice/group were euthanized and 6 mice/group continued to the CFD trial. Daily volume (ml) of (B) water or (C) EtOH intake registered, and (D) EtOH consumption, calculated as g/kg, (n = 12–24 mice/group) are shown. Statistically significant differences in EtOH intake between days 1–3 and 8–10 are indicated by brackets and are represented by C *p<0.0499 and D *p = 0.0241); Paired t-test. The mean ± SEM is shown at the sides. CFD, contextual fear discrimination; EPM, elevated plus maze; MDMA, 3,4-Methylenedioxymethamphetamine; TST, tail suspension test.
Mentions: Drinking behavior was registered 4 days/week and on day 4 two saline injections were given to all mice. On day 11 two high-dose MDMA injections were given to mice drinking water, while mice drinking EtOH were given two saline injections. 72h after drug consumption, we conducted behavioral evaluation of locomotion, anxiety-like and despair-like responses, followed by either a contextual fear conditioning task or euthanasia for immunohistochemical and biochemical evaluation (Fig 1A and S1 Fig). Our results show an increased liking for EtOH throughout the DID-test. Furthermore, the capacity of the mice to perform a contextual fine discrimination task was not only obstructed by a high MDMA dose but also by voluntary alcohol intake during several consecutive days.

Bottom Line: We then introduced them to a contextual fear discrimination task and immune-related effects were examined by immunohistochemical and biochemical studies.Our results suggest that there is a relationship between the induction of immune activated pathways by voluntary alcohol consumption and a high-dose MDMA.This information will be helpful for discovering new selective drug targets, and to develop treatments and preventive approaches for patients with anxiety-related disorders.

View Article: PubMed Central - PubMed

Affiliation: Neurobiology of Behaviour Research Group (GReNeC), Department of Health and Experimental Sciences, Universitat Pompeu Fabra, IMIM, Hospital del Mar Medical Research Institute, Barcelona Biomedical Research Park C/Dr. Aiguader 88, 08003, Barcelona, Spain.

ABSTRACT
The recreational drugs, alcohol and 3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") have both been shown to cause immune activation in vivo, and they are linked to cognitive impairment and anxiety-like behaviors in rodents. The neuronal effects of these drugs in the hippocampal area, an area that has been a focus of studies aiming to explain the mechanisms underlying anxiety related-disorders, remains poorly understood. Therefore we investigated the specific inflammatory impact of alcohol and MDMA on this area of the brain and on a hippocampal-related behavioral task. We centered our study on two inflammatory factors linked to anxiety-related disorders, namely Interleukin-1β (IL-1β) and brain-derived neurotrophic factor (BDNF). We subjected drug-consuming mice to a battery of behavioral tests to evaluate general activity, anxiety-like and depressive-live behaviors. We then introduced them to a contextual fear discrimination task and immune-related effects were examined by immunohistochemical and biochemical studies. Our results suggest that there is a relationship between the induction of immune activated pathways by voluntary alcohol consumption and a high-dose MDMA. Furthermore, the ability of mice to perform a contextual fear discrimination task was impaired by drug consumption and we report long term inflammatory alterations in the hippocampus even several weeks after drug intake. This information will be helpful for discovering new selective drug targets, and to develop treatments and preventive approaches for patients with anxiety-related disorders.

Show MeSH
Related in: MedlinePlus