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. 2012;7(4):e34129.
doi: 10.1371/journal.pone.0034129. Epub 2012 Apr 3.

Distinct Neurobehavioural Effects of Cannabidiol in Transmembrane Domain Neuregulin 1 Mutant Mice

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Free PMC article

Distinct Neurobehavioural Effects of Cannabidiol in Transmembrane Domain Neuregulin 1 Mutant Mice

Leonora E Long et al. PLoS One. .
Free PMC article

Abstract

The cannabis constituent cannabidiol (CBD) possesses anxiolytic and antipsychotic properties. We have previously shown that transmembrane domain neuregulin 1 mutant (Nrg1 TM HET) mice display altered neurobehavioural responses to the main psychoactive constituent of cannabis, Δ(9)-tetrahydrocannabinol. Here we investigated whether Nrg1 TM HET mice respond differently to CBD and whether CBD reverses schizophrenia-related phenotypes expressed by these mice. Adult male Nrg1 TM HET and wild type-like littermates (WT) received vehicle or CBD (1, 50 or 100 mg/kg i.p.) for 21 days. During treatment and 48 h after withdrawal we measured behaviour, whole blood CBD concentrations and autoradiographic receptor binding. Nrg1 HET mice displayed locomotor hyperactivity, PPI deficits and reduced 5-HT(2A) receptor binding density in the substantia nigra, but these phenotypes were not reversed by CBD. However, long-term CBD (50 and 100 mg/kg) selectively enhanced social interaction in Nrg1 TM HET mice. Furthermore, acute CBD (100 mg/kg) selectively increased PPI in Nrg1 TM HET mice, although tolerance to this effect was manifest upon repeated CBD administration. Long-term CBD (50 mg/kg) also selectively increased GABA(A) receptor binding in the granular retrosplenial cortex in Nrg1 TM HET mice and reduced 5-HT(2A) binding in the substantia nigra in WT mice. Nrg1 appears necessary for CBD-induced anxiolysis since only WT mice developed decreased anxiety-related behaviour with repeated CBD treatment. Altered pharmacokinetics in mutant mice could not explain our findings since no genotype differences existed in CBD blood concentrations. Here we demonstrate that Nrg1 modulates acute and long-term neurobehavioural effects of CBD, which does not reverse the schizophrenia-relevant phenotypes.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Horizontal locomotor and vertical activity (i.e. rearing) in the open field test (10 min) after injection of CBD.
A–C: Overall distance travelled and D–F: Rearing on days 1, 13 and treatment withheld (WH) day. Data represent mean+S.E.M. Significant one-way ANOVA (split by ‘treatment’) results are shown: * P<0.05, ** P<0.01 (vs. WT receiving corresponding treatment).
Figure 2
Figure 2. Anxiety-related measures in the open field test (10 min) after injection of CBD.
A–C: Time spent in the central area and D–F: Distance ratio on days 1, 13 and treatment withheld (WH) day. Data represent mean+S.E.M. Significant one-way ANOVA (split by corresponding factor) results are shown: # P<0.05 (vs. vehicle of corresponding genotype). ** P<0.01 (vs. WT receiving corresponding treatment).
Figure 3
Figure 3. Anxiety-related measures in the light-dark test (10 min) after injection of CBD.
A–C: Time spent in the light compartment and D–F: Distance ratio on days 1, 15 and treatment withheld (WH) day. Data represent means+S.E.M. Significant one-way ANOVA (split by ‘treatment’) results are shown: * P<0.05, ** P<0.01 (vs. WT receiving corresponding treatment).
Figure 4
Figure 4. Sensorimotor gating after injection of CBD.
A–C: % PPI on days 1, 21 and treatment withheld (WH) day. Data represent means+S.E.M. Significant one-way ANOVA (split by corresponding factor) results are shown: ## P<0.01 (vs. vehicle of corresponding genotype), * P<0.05, ** P<0.01 (vs. WT receiving corresponding treatment).
Figure 5
Figure 5. Concentration (ng/ml) of CBD in whole blood 2 days after the last treatment.
Data represent means+S.E.M.
Figure 6
Figure 6. Representative autoradiograms showing [3H]ketanserin (5-HT2A receptors) and [3H]muscimol (GABAA receptors) binding in specific brain regions.
Abbreviations: Cg: anterior cingulate cortex; CPu: caudate putamen; HPC: hippocampus; LSD: dorsolateral septum; PrL: prelimbic cortex; RSG: granular retrosplenial cortex; SN: substantia nigra; Thal: thalamus.

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