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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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Influence of voluntary EtOH intake and high-dose MDMA (20 mg/kg x 2) on contextual fine discrimination.(A, D) Learning acquisition during days 1–3 was measured as freezing during 3 minutes before shock in context A. (B, E) Generalization, demonstrated as no significant difference in freezing between contexts A (no fill) and B (stripes), is shown for the Control (white bars), EtOH (grey bars) and MDMA (red bars) groups. (C) The discrimination test followed a double alternation schedule from day 6–17 and, to show graphic overviews, each 2 days were averaged together to make six blocks. (F) While control animals discriminate between the two contexts by day 10 (observed in block 3) of the discrimination task, both the (G) EtOH and (H) MDMA groups had impaired discrimination capacity, shown as no significant difference in the percentage of freezing time between contexts A (shock) and B (safe context). Data shown are the mean ± SEM (n = 6 mice/group). Statistically significant differences over time within each group and context are indicated by brackets and * (p < 0.05) and ** (p < 0. 01), and between context A and context B by * (p < 0.05), *** (p < 0.001; Bonferroni’s post hoc test). MDMA, 3,4-Methylenedioxymethamphetamine.
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pone.0142978.g004: Influence of voluntary EtOH intake and high-dose MDMA (20 mg/kg x 2) on contextual fine discrimination.(A, D) Learning acquisition during days 1–3 was measured as freezing during 3 minutes before shock in context A. (B, E) Generalization, demonstrated as no significant difference in freezing between contexts A (no fill) and B (stripes), is shown for the Control (white bars), EtOH (grey bars) and MDMA (red bars) groups. (C) The discrimination test followed a double alternation schedule from day 6–17 and, to show graphic overviews, each 2 days were averaged together to make six blocks. (F) While control animals discriminate between the two contexts by day 10 (observed in block 3) of the discrimination task, both the (G) EtOH and (H) MDMA groups had impaired discrimination capacity, shown as no significant difference in the percentage of freezing time between contexts A (shock) and B (safe context). Data shown are the mean ± SEM (n = 6 mice/group). Statistically significant differences over time within each group and context are indicated by brackets and * (p < 0.05) and ** (p < 0. 01), and between context A and context B by * (p < 0.05), *** (p < 0.001; Bonferroni’s post hoc test). MDMA, 3,4-Methylenedioxymethamphetamine.

Mentions: Six mice per group were tested for contextual fine discrimination (Fig 4). On days 1 to 3, we measured contextual acquisition as freezing across 3 minutes in context A pre-shock (Fig 4A); we observed no difference between groups in the percentage of freezing time on day 2 nor on day 3, evaluated by one-way ANOVA followed by Bonferroni’s post hoc test (Fig 4D). We then evaluated generalization of contexts on day 4 and 5 (Fig 4B). This part of the test revealed similar freezing time in both contexts in all groups (two-way ANOVA: F(2,66) = 0.22, p = 0.8056), which confirms contextual generalization; again, we observed no difference between groups in context A or context B (Fig 4E) (one-way ANOVA: F(2,33) = 1.709, p = 0.1966 and F(2,33) = 2.828, p = 0.0735, respectively). Using the paired t-test within groups, we found a difference in freezing between the two contexts in the EtOH-group (p = 0.0092); however, as observed in block 1+2 (Fig 4G), generalization can be assigned to this group at a later stage of the test.


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)

Influence of voluntary EtOH intake and high-dose MDMA (20 mg/kg x 2) on contextual fine discrimination.(A, D) Learning acquisition during days 1–3 was measured as freezing during 3 minutes before shock in context A. (B, E) Generalization, demonstrated as no significant difference in freezing between contexts A (no fill) and B (stripes), is shown for the Control (white bars), EtOH (grey bars) and MDMA (red bars) groups. (C) The discrimination test followed a double alternation schedule from day 6–17 and, to show graphic overviews, each 2 days were averaged together to make six blocks. (F) While control animals discriminate between the two contexts by day 10 (observed in block 3) of the discrimination task, both the (G) EtOH and (H) MDMA groups had impaired discrimination capacity, shown as no significant difference in the percentage of freezing time between contexts A (shock) and B (safe context). Data shown are the mean ± SEM (n = 6 mice/group). Statistically significant differences over time within each group and context are indicated by brackets and * (p < 0.05) and ** (p < 0. 01), and between context A and context B by * (p < 0.05), *** (p < 0.001; Bonferroni’s post hoc test). MDMA, 3,4-Methylenedioxymethamphetamine.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4643963&req=5

pone.0142978.g004: Influence of voluntary EtOH intake and high-dose MDMA (20 mg/kg x 2) on contextual fine discrimination.(A, D) Learning acquisition during days 1–3 was measured as freezing during 3 minutes before shock in context A. (B, E) Generalization, demonstrated as no significant difference in freezing between contexts A (no fill) and B (stripes), is shown for the Control (white bars), EtOH (grey bars) and MDMA (red bars) groups. (C) The discrimination test followed a double alternation schedule from day 6–17 and, to show graphic overviews, each 2 days were averaged together to make six blocks. (F) While control animals discriminate between the two contexts by day 10 (observed in block 3) of the discrimination task, both the (G) EtOH and (H) MDMA groups had impaired discrimination capacity, shown as no significant difference in the percentage of freezing time between contexts A (shock) and B (safe context). Data shown are the mean ± SEM (n = 6 mice/group). Statistically significant differences over time within each group and context are indicated by brackets and * (p < 0.05) and ** (p < 0. 01), and between context A and context B by * (p < 0.05), *** (p < 0.001; Bonferroni’s post hoc test). MDMA, 3,4-Methylenedioxymethamphetamine.
Mentions: Six mice per group were tested for contextual fine discrimination (Fig 4). On days 1 to 3, we measured contextual acquisition as freezing across 3 minutes in context A pre-shock (Fig 4A); we observed no difference between groups in the percentage of freezing time on day 2 nor on day 3, evaluated by one-way ANOVA followed by Bonferroni’s post hoc test (Fig 4D). We then evaluated generalization of contexts on day 4 and 5 (Fig 4B). This part of the test revealed similar freezing time in both contexts in all groups (two-way ANOVA: F(2,66) = 0.22, p = 0.8056), which confirms contextual generalization; again, we observed no difference between groups in context A or context B (Fig 4E) (one-way ANOVA: F(2,33) = 1.709, p = 0.1966 and F(2,33) = 2.828, p = 0.0735, respectively). Using the paired t-test within groups, we found a difference in freezing between the two contexts in the EtOH-group (p = 0.0092); however, as observed in block 1+2 (Fig 4G), generalization can be assigned to this group at a later stage of the test.

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