CB1 cannabinoid receptor-mediated aggressive behavior
- Marta Rodriguez-Ariasa, b,
, 
, - Francisco Navarreteb, c,
- Manuel Daza-Losadaa, b,
- Daniela Navarrod,
- María A. Aguilara, b,
- Pere Berbelb, d,
- José Miñarroa, b,
- Jorge Manzanaresb, c
- a Unidad de Investigación Psicobiología de las Drogodependencias, Departamento de Psicobiología, Facultad de Psicología, Universitat de València, Avda. Blasco Ibáñez 21, 46010 Valencia, Spain
- b Red Temática de Investigación Cooperativa en Salud (RETICS-Trastornos Adictivos), Instituto de Salud Carlos III, MICINN and FEDER, Madrid, Spain
- c Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Avda. Ramón y Cajal s/n, 03550 San Juan de Alicante, Alicante, Spain
- d Departamento de Histología, Universidad Miguel Hernández, 03550 San Juan de Alicante, Alicante, Spain
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Highlights
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CB1KO mice display higher levels of offensive aggression than WT mice.
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COMT, MAO-A, 5-HTT and 5HT1Br mRNA levels differ between WT and CB1KO mice.
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There is a co-localization of CB1r and COMT in the amygdaloid nuclei.
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The administration of ACEA decreases aggression levels in OF1 mice.
Abstract
This study examined the role of cannabinoid CB1 receptors (CB1r) in aggressive behavior. Social encounters took place in grouped and isolated mice lacking CB1r (CB1KO) and in wild-type (WT) littermates. Cognitive impulsivity was evaluated in the delayed reinforcement task (DRT). Gene expression analyses of monoaminooxidase-A (MAO-A), catechol-o-methyl-transferase (COMT), 5-hydroxytriptamine transporter (5-HTT) and 5-HT1B serotonergic receptor (5HT1Br) in the median and dorsal raphe nuclei (MnR and DR, respectively) and in the amygdala (AMY) were performed by real time-PCR. Double immunohistochemistry studies evaluated COMT and CB1r co-localization in the raphe nuclei and in the cortical (ACo), basomedian (BMA) and basolateral (BLA) amygdaloid nuclei. The behavioral effects of the CB1r agonist ACEA (1 and 2 mg/kg) on aggression were also evaluated in isolated OF1 mice. CB1KO mice housed in groups showed higher levels of offensive aggression. Isolation increased aggressive behavior only in WT. In grouped CB1KO mice COMT gene expression was significantly higher in the MnR and DR, while MAO-A gene expression was lower in the MnR. Gene expression of 5HT1Br, COMT and MAO-A was higher in the amygdala of CB1KO mice. CB1r double-immunohistochemistry revealed cytoplasmic-labeled COMT-ir cells in the raphe nuclei and in the ACo, BMA and BLA. CB1r immunolabeling was observed only in ACo, BMA and BLA, where it was localized in axons and buttons. The density of labeled processes increased in BLA. Acute administration of the CB1 agonist ACEA (2 mg/kg) significantly decreased the aggression levels of OF1 mice. These results suggest that CB1r plays an important role in social interaction and aggressive behavior.
Keywords
- Social encounters;
- Aggression;
- CB1KO mice;
- ACEA;
- Gene expression;
- Confocal microscopy
Figures and tables from this article:
- Fig. 1. Means of accumulated times (in seconds) with ±SEM for Social Investigation (dark gray), Threat (light gray) and Attack (white) behaviors of group- or single-housed CB1KO and WT adult mice during the social interaction test. Differences with respect to their corresponding WT group *p < 0.05; **p < 0.01, ***p < 0.001; Differences with respect to the grouped-housed WT group ++p < 0.01.
- Fig. 2. Delay discounting (cognitive impulsivity) evaluation in the delayed reinforcement task. Dots represent means and vertical lines ±SEM of % preference for delayed reinforcement. *, CB1KO mice values that are significantly different (p < 0.05) to those of WT mice.
- Fig. 3. MAO-A, COMT, 5HTT and 5-HT1Br relative gene expression evaluation in the MnR, DR and AMY of CB1KO and WT mice, as measured by real time-PCR. Columns represent means and vertical lines ±SEM of relative gene expression evaluation (2−ΔΔCt method) in the MnR (A), DR (B) and AMY (C). *, CB1KO mice values that are significantly different (p < 0.05) to those of WT mice.
- Fig. 4. Double immunolabeling for COMT and CB1r in the amygdaloid nuclei of WT mice. Confocal photomicrographs showing immunolabeling for COMT (green labeling in A1, B1, C1 and D1) and CB1r (red labeling in A2, B2, C2 and D2) in BLA (A1–B3), BMA (C1–C3) and ACo (D1–D3). Low power confocal A1–A3 images show the average overlay of 4 consecutive confocal images (2 μm-thick each). Double labeling (yellow labeling in A3, B3, C3 and D3) indicates that COMT does not co-localize with CB1r in the amygdaloid nuclei. COMT immunolabeling was seen in the cytoplasm of immunoreactive cells and less frequently in processes emerging from their soma (arrows in B1 and C1). In contrast, CB1r immunolabeling can only be seen in processes (mostly axons) and buttons that are COMT immunonegative. Note that the specificity of CB1r immunolabeling defines the BLA limits. Asterisks point to CB1r immunonegative adjacent neuropile to BLA. Note that COMT-ir cells are present (arrow in A3) in these CB1r immunonegative regions. The intensity of cytoplasmic COMT immunolabeling is weaker in BMA and ACo nuclei than in BLA (compare B1 with C1 and D1). Similarly, the density of CB1r-ir buttons and processes is also weaker in BMA and ACo nuclei (compare B2 with C2 and D2). Same scale for each set of confocal images. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
- Fig. 5. Immunolabeling for COMT in NLR of WT mice. Photomicrographs showing COMT immunolabeling in DR (A) and MnR (B). COMT immunolabeling can be seen mostly in the cytoplasm and in some processes emerging from it (arrow in B). The intensity of cytoplasmic immunolabeling in COMT-ir cells was stronger in MnR than in DR (compare immunolabeling in A and B). No immunoreactivity for CB1r was found in these raphe nuclei. Same scale for B.
- Fig. 6. Histograms showing mean density (A) and percentage of perisomatic (B) de-convoluted CB1r-ir buttons in BLA, BMA and ACo. Both mean density and percentage of perisomatic CB1r-ir buttons in amygdaloid nuclei was significantly higher in BLA. No differences were found between BMA and ACo nuclei. Error bars (±SD); no significant differences (n.s.); *p < 0.001 (n = 12 for each nuclei).
- Fig. 7. Means of accumulated times (in seconds) with ±SEM for Threat (black) and Attack (white) behaviors during the social interaction test in grouped and isolated adult OF1 mice treated with saline or ACEA (1 or 2 mg/kg). Differences with respect to saline-treated grouped mice *p < 0.05; ***p < 0.001. Differences with respect to saline-treated isolated mice +p < 0.05.
- Table 1. Means of accumulated times (s) with ±SEM allocated to different categories of spontaneous behavior of grouped and isolated CB1KO and WT adult mice during the social interaction test. Differences with respect to their corresponding WT group **p < 0.01, ***p < 0.001. Differences with respect to the group-housed WT group ++p < 0.01, +++p < 0.001.
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- Table 2. Means of accumulated times (s) with ±SEM allocated to different categories of spontaneous behavior of grouped and isolated adult mice treated with saline or ACEA (1 or 2 mg/kg) during the social interaction test. Differences with respect to saline-treated grouped mice **p < 0.01; ***p < 0.001. Differences with respect to saline-treated isolated mice ++p < 0.01. Differences with respect to ACEA 2-treated isolated mice ττ p < 0.01.
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- Corresponding author. Unidad de Investigación Psicobiología de las Drogodependencias, Departamento de Psicobiología, Facultad de Psicología, Universitat de València, Avda. Blasco Ibáñez 21, 46010 Valencia, Spain. Tel.: +34 963864637.
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