Alterations in rat prefrontal cortex kynurenic acid levels are involved in the enduring cognitive dysfunctions induced by tetrahydrocannabinol exposure during the adolescence

Abstract

IntroductionCannabis abuse during adolescence is a risk factor for cognitive impairments in psychiatric disorders later in life. To date, the possible causal relationship between cannabinoids, kynurenic acid (KYNA; i.e., a neuroactive metabolite of tryptophan degradation) and cognition has not been investigated in adolescence. Early exposure to delta 9-tetrahydrocannabinol (THC; i.e., the main psychotropic component of cannabis) causes enduring cognitive deficits, which critically involve impaired glutamatergic function in the prefrontal cortex (PFC). In addition, prenatal cannabis exposure results in enduring increases in PFC KYNA levels. Based on these findings, the effects of chronic THC exposure in rats, during another critical period of neurodevelopment particularly sensitive to perturbation by exogenous stimuli, such as adolescence, have been investigated.MethodsMale Wistar rats were chronically treated with vehicle or ascending intraperitoneal (i.p.) doses of THC starting on postnatal day (PND) 35 until PND 45. In adulthood (PND 75), cognitive assessment (Y-maze) and extracellular KYNA/glutamate levels were measured in the PFC by in vivo microdialysis, before and after a challenge with KYN (5 mg/kg i.p., the biological precursor of KYNA). By using the selective, brain-penetrable KAT II inhibitor PF-04859989, we then examined whether blockade of KYNA neosynthesis prevents the cognitive impairment.ResultsCompared to vehicle-treated controls, extracellular basal KYNA levels were higher in the PFC of adult rats chronically exposed to THC in adolescence (p < 0.01). No changes were observed in extracellular glutamate levels. Following a challenge with KYN, extracellular KYNA levels similarly increased in both groups (i.e., vehicle- and THC-treated; p < 0.001 and p < 0.01, respectively). Chronic adolescent THC exposure negatively affected short-term memory (reduced spontaneous alternation), in adult animals (p < 0.001), while PF-04859989 (30 mg/kg i.p.) restored the cognitive impairment (p < 0.05).DiscussionWe propose that the observed alterations in PFC KYNA signaling might be involved in the cognitive dysfunction induced by the exposure to THC during the adolescence. In the translational realm, these experiments raise the prospect of prevention of KYNA neosynthesis as a possible novel approach to counteract some of the detrimental long-term effects of adolescence cannabis use.

(Endo)Cannabinoids and Cognitive Functions in Animals: Healthy and Pathological Brain

“…It was also demonstrated that exposure to THC in adolescent rats (35-45 days) can cause deficits in short-term memory in adult animals tested in the Y-maze [74]. Interestingly, in this study, exposure of juvenile rats to THC induced a malfunction of the kynurenine pathway in the adult brain, specifically increasing the level of kynurenic acid in the medial prefrontal cortex.…”

“…Interestingly, the effects of cannabinoids on cognitive performance in animals change with age, with stronger negative effects being observed in the pubertal phase compared to the adult [72][73][74]. In view of this, Verrico and colleagues carried out a research of the effect of THC on working spatial memory and object recognition memory in adolescent monkeys.…”

Gut—brain barrier dysfunction bridge autistic‐like behavior in mouse model of maternal separation stress: A behavioral, histopathological, and molecular study

“…Mice were euthanized under deep anesthesia by pentobarbital (60 mg/kg, i.p.) (Amiri et al, 2017), brains were rapidly removed, the PFC dissected out from one brain's hemisphere on the ice-cold surface and directly placed into liquid nitrogen and then stored at À80 C for molecular evaluations (Beggiato et al, 2022). Another hemisphere was immersed in 10% formalin for evaluation of histological changes in the pyramidal area of the hippocampus (Anjomshoa et al, 2020).…”

The Tryptophan and Kynurenine Pathway Involved in the Development of Immune-Related Diseases

“…Notably, increased levels of cerebral kynurenic acid have been detected in the aged brain and in several major neurological and psychiatric diseases [ 85 ]. Kynurenic acid has been also suggested to be related to cognitive impairments [ 86 ], which have been frequently discussed as possible markers of perioperative neurocognitive disorders [ 87 ]. A lower level of kynurenic acid has been associated with worse cognitive functioning in a bipolar depression group [ 88 ] ( Figure 2 ).…”