Attenuation of Novelty-Induced Hyperactivity of Gria1-/- Mice by Cannabidiol and Hippocampal Inhibitory Chemogenetics

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.

Hippocampal Hyperactivity as a Druggable Circuit-Level Origin of Aberrant Salience in Schizophrenia

“…This is supported by the large body of evidence demonstrating the control of dopaminergic activity by the vHC and vSub in rodents, and the potential therapeutic effects achieved by local interventions in the vHC [ Tables 1 and 3 , ( Gilani et al, 2014 )]. However, salience-like signals in rodents have mostly been recorded in the dorsal hippocampus which receives predominantly sensory information, and more successful rescue approaches which reduce hippocampal hyperactivity in genetic mouse models of schizophrenia have been conducted in the dorsal subregion ( Marissal et al, 2018 ; Aitta-aho et al, 2019 ; Mukherjee et al, 2019 ) than in the vHC ( Gilani et al, 2014 ). Therefore, further elucidation of the different functional roles of the dorsal and ventral subregions in schizophrenia-related deficits remains a pressing need.…”

Blood Glutamate Scavenging With Pyruvate as a Novel Preventative and Therapeutic Approach for Depressive-Like Behavior Following Traumatic Brain Injury in a Rat Model

“…Gainetdinov et al (2001) showed that drugs that enhance glutamatergic transmission, such as positive modulators of L-α-amino-3-hydroxy-5-methylisoxazole-4-propionate glutamate receptors, suppress the hyperactivity of mice lacking the dopamine transporter (Gainetdinov et al, 2001). The involvement of the glutamate system in the development of attention-deficit disorder, hyperactivity, and other behavioral motor disorders has also been previously described (Procaccini et al, 2013;Maksimovic et al, 2014a,b;Miller, 2019;Aitta-Aho et al, 2019). Halberstadt et al (2011) demonstrated that loss of mGlu5 receptor activity either pharmacologically or through gene deletion leads to locomotor hyperactivity in mice.…”

The Relationship between Cannabis Use and Cognition in People with Bipolar Disorder: A Systematic Scoping Review

“…These mice exhibited mania-like hyperactivity when placed in a novel environment. This hyperactivity was blunted by both systemic and intra-hippocampal administration of CBD (Aitta-aho et al, 2019). Another study, however, failed to find any effect of CBD on locomotor activity in a different model of bipolar mania.…”