Abstract
Gene-targeted mice with deficient AMPA receptor GluA1 subunits (Gria1-/- mice) show robust hyperlocomotion in a novel environment, suggesting them to constitute a model for hyperactivity disorders such as mania, schizophrenia and attention deficit hyperactivity disorder. This behavioral alteration has been associated with increased neuronal activation in the hippocampus, and it can be attenuated by chronic treatment with antimanic drugs, such as lithium, valproic acid, and lamotrigine. Now we found that systemic cannabidiol strongly blunted the hyperactivity and the hippocampal c-Fos expression of the Gria1-/- mice, while not affecting the wild-type littermate controls. Acute bilateral intra-dorsal hippocampal infusion of cannabidiol partially blocked the hyperactivity of the Gria1-/- mice, but had no effect on wild-types. The activation of the inhibitory DREADD receptor hM4Gi in the dorsal hippocampus by clozapine-N-oxide robustly inhibited the hyperactivity of the Gria1-/- mice, but had no effect on the locomotion of wild-type mice. Our results show that enhanced neuronal excitability in the hippocampus is associated with pronounced novelty-induced hyperactivity of GluA1 subunit-deficient mice. When this enhanced response of hippocampal neurons to novel stimuli is specifically reduced in the hippocampus by pharmacological treatment or by chemogenetic inhibition, Gria1-/- mice recover from behavioral hyperactivity, suggesting a hippocampal dysfunction in hyperactive behaviors that can be treated with cannabidiol.
Highlights
Neurological and psychiatric brain diseases cause vast harm and excessive costs to affected individuals and the society at large (DiLuca and Olesen, 2014)
CBD treatment dose-dependently attenuated the novelty-induced hyperlocomotion of Gria1−/− mice, while the locomotor activity of wild-type littermates (WT) mice remained unaltered
(15, 60, and 100 mg/kg), except for the lowest dose (5 mg/kg), brought the hyperactivity of Gria1−/− mice back to the level of WT mice (Figure 1C, locomotor activity analyzed from the beginning of the trial until 30 min, and Figure 1D, locomotor activity analyzed over the whole 2 h trial, Bonferroni post-test, P > 0.05 for the genotype difference within all doses, except for 5 mg/kg, when it was P < 0.001)
Summary
Neurological and psychiatric brain diseases cause vast harm and excessive costs to affected individuals and the society at large (DiLuca and Olesen, 2014). A mouse line with deficient AMPA-type glutamate receptor GluA1 subunits [the Gria1−/− mouse line (Zamanillo et al, 1999)] has been proposed as an animal model for hyperactive disorders, including schizoaffective disorder and bipolar disorder with mania (Fitzgerald et al, 2010; Barkus et al, 2011; Procaccini et al, 2011) This is based on (1) robust novelty-induced hyperactivity that is eventually habituated, leading to unaltered diurnal homecage activity in the Gria1−/− mice (Vekovischeva et al, 2001; Fitzgerald et al, 2010; Sanderson et al, 2010; Procaccini et al, 2011), (2) consistent attenuation of this behavior by chronic treatment with drugs having antimanic efficacy in patients (Maksimovic et al, 2014a,b), and (3) linkage equilibrium of GRIA1-gene polymorphisms in psychotic disorders (Ripke et al, 2013, 2014; Devor et al, 2017)
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