Kynurenine amplifies tetrahydrocannabinol-induced sensorimotor impairment and classic “tetrad” effects in mice

Background: L-kynurenine (KYN), a kynurenine pathway (KP) metabolite, is the main precursor for the neuroactive metabolite kynurenic acid (KYNA). Several studies suggest a patho-physiologically relevant association between increased brain KYNA levels and cognitive dysfunctions in individuals with schizophrenia. Δ9 -tetrahydrocannabinol (Δ9 -THC; i.e. the main psychoactive compound of cannabis) can worse schizophrenia-related psychosis, often leads to the development of cannabis use disorder in individuals with schizophrenia, and increases the risk of earlier onset of schizophrenia symptoms in those with a genetic predisposition. A role of KP alterations and, specifically, increased brain KYNA levels in Δ9 -THC-induced psychotic symptoms has been previously proposed. The aim of the study was to investigate on the possible involvement of KP alterations in Δ9 - THC-induced sensorimotor and “tetrad” responses in mice. Methods: Adult male CD-1 mice were treated with Δ9 -THC (30 mg/ kg; i.p.) and KYN (20 mg/kg; i.p.), alone or in combination, and body temperature, acute mechanical and thermal analgesia, motor activity and sensorimotor responses were evaluated. Furthermore, brain KYNA levels as well as plasma Δ9 -THC and its metabolites concentrations after the treatments were also evaluated. Results: Brain KYNA levels were significantly increased 1 h, but not 4 h, after KYN and KYN + Δ9 -THC administration. KYN administration amplified the Δ9 -THC-induced impairment of sensorimotor responses (visual placing, acoustic and tactile responses). Furthermore, KYN significantly increased Δ9 -THC-induced motor activity impairment (bar test, drag test and rotarod test) and hypothermia (core and surface body temperature), but not Δ9 -THC-induced analgesia. Finally, 1 h after Δ9 -THC administration, Δ9 -THC and its psychoactive metabolite 11-OH-THC plasma levels were higher in mice pretreated with KYN than in control mice. Conclusions: The present data indicate for the first time that KYN amplifies the THC-induced sensorimotor impairment and classic “tetrad” response possibly through a pharmacokinetic interaction.