Acute Ultra Low Dose THC Attenuates Anxiety-Like Behavior in a Mouse Model for Major-Depressive Disorder

Major depressive disorder (MDD) is a prevalent psychiatric disorder, and is a leading cause of disability worldwide. Current treatments for MDD entail many side effects, and include a lag until the onset of therapeutic effects. The current hypotheses as for the etiology of MDD revolve around the monoamine hypothesis and the plasticity and neurodegeneration hypothesis. According to the latter, employing a neuroprotective treatment may help ameliorate depressive symptoms. Δ⁹-Tetrahydrocannabinol (THC) is the primary psychoactive component of the cannabis sativa plant. THC interacts with the endocannabinoid system, which was shown to be involved in the regulation of emotional states (e.g. anxiety) and stress through modulation of synaptic plasticity. Here, we show the potential of acute, ultra-low dose (0.002 mg/kg) THC in ameliorating anxious behavior in a chronic mild stress mouse model for MDD. We utilize next generation sequencing techniques to show the treatment's effect on neuronal differentiation and synaptic plasticity-related mRNAs, and specify Elmo domain containing 1 (Elmod1) as a molecular mediator of the observed anxiolytic effects. Moreover, we show the involvement of glucocorticoids-related mRNAs in the observed anxiolytic effect of acute, ultra-low dose THC.