A novel allosteric modulator of the cannabinoid CB1 receptor ameliorates hyperdopaminergia endophenotypes in rodent models

Catharine A Mielnik,Sean Harrington,Kim S Sugamori,Nirunthan Sivananthan,Laurent A Trembleau,David B Finlay,W Mcintyre Burnham,Ruth A Ross,Ali Salahpour,Jibran Y Khokhar,Amy J Ramsey,Matthieu Schapira,Iain R Greig,Chun Kit Li,Michelle Glass,Vincent M Lam,Mostafa H Abdelrahman,Hayley H A Thorpe

doi:10.1038/s41386-020-00876-5

Abstract

The endocannabinoid system (eCBs) encompasses the endocannabinoids, their synthetic and degradative enzymes, and cannabinoid (CB) receptors. The eCBs mediates inhibition of neurotransmitter release and acts as a major homeostatic system. Many aspects of the eCBs are altered in a number of psychiatric disorders including schizophrenia, which is characterized by dysregulation of dopaminergic signaling. The GluN1-Knockdown (GluN1KD) and Dopamine Transporter Knockout (DATKO) mice are models of hyperdopaminergia, which display abnormal psychosis-related behaviors, including hyperlocomotion and changes in pre-pulse inhibition (PPI). Here, we investigate the ability of a novel CB1 receptor (CB1R) allosteric modulator, ABM300, to ameliorate these dysregulated behaviors. ABM300 was characterized in vitro (receptor binding, β-arrestin2 recruitment, ERK1/2 phosphorylation, cAMP inhibition) and in vivo (anxiety-like behaviors, cannabimimetic effects, novel environment exploratory behavior, pre-pulse inhibition, conditioned avoidance response) to assess the effects of the compound in dysregulated behaviors within the transgenic models. In vitro, ABM300 increased CB1R agonist binding but acted as an inhibitor of CB1R agonist induced signaling, including β-arrestin2 translocation, ERK phosphorylation and cAMP inhibition. In vivo, ABM300 did not elicit anxiogenic-like or cannabimimetic effects, but it decreased novelty-induced hyperactivity, exaggerated stereotypy, and vertical exploration in both transgenic models of hyperdopaminergia, as well as normalizing PPI in DATKO mice. The data demonstrate for the first time that a CB1R allosteric modulator ameliorates the behavioral deficits in two models of increased dopamine, warranting further investigation as a potential therapeutic target in psychiatry.

Highlights

Dysregulation of dopaminergic and glutamatergic signaling are thought to underpin the development of psychosis and schizophrenia [1]
Pharmacological treatment of schizophrenia and psychosis includes the use of antipsychotics, which act as orthosteric receptor antagonists/partial agonists of various GPCR targets, including dopamine receptor D2 and serotonin receptor 5HT1A
Docking model of ABM300 bound to CB1 receptor (CB1R) A model of ABM300 bound to CB1R was derived from the CB1CP55940-Org275 ternary complex [16] (Fig. 1)

Summary

Introduction

Dysregulation of dopaminergic and glutamatergic signaling are thought to underpin the development of psychosis and schizophrenia [1]. Pharmacological treatment of schizophrenia and psychosis includes the use of antipsychotics, which act as orthosteric receptor antagonists/partial agonists of various GPCR targets, including dopamine receptor D2 and serotonin receptor 5HT1A. While not directly expressed on dopaminergic neurons, the endocannabinoid system acts as a crucial filter that integrates both inhibitory and excitatory signaling that modulates dopamine neuron signaling [4]. In combination with the complex dysregulation and circuit-based mechanisms for brain regiondependent alterations in dopaminergic signaling in psychiatry, this suggests that the CB1R may be a more attractive, alternative therapeutic target to the classical D2 receptor antagonism approaches of antipsychotics [4]

Methods

Results

Conclusion