Prenatal THC exposure permanently disturbs kynurenic acid and glutamate levels and amplifies the responsivity to an acute kynurenine challenge in the rat prefrontal cortex

Throughout the world, cannabis remains one of the most widely used illicit drugs during pregnancy (Porath-Waller, 2015). The main psychoactive component of marijuana (delta9-tetrahydrocannabinol, THC) passes through the placenta, and its use is correlated with early physiological effects in the offspring. Neurobehavioural and cognitive impairments have been reported in several longitudinal studies on children and adolescents prenatally exposed to marijuana (Calvigioni et al., 2014), and a link to psychiatric disorders has been proposed (Jutras-Aswad et al., 2009; Mathews et al., 2014). Prenatal exposure to cannabinoids induces cognitive deficits in rat offspring (Ferraro et al., 2009) and is associated with alterations in cortical/hippocampal glutamate and GABA levels (Antonelli et al., 2005, Beggiato et al., 2017). Interestingly, the deleterious effects of cannabinoids on cognitive functions are similar to those observed in adult rats prenatally exposed to (L)-kynurenine (KYN), which is the direct bioprecursor of kynurenic acid (KYNA), a neuroactive metabolite of tryptophan degradation (Pocivavsek et al., 2014). We therefore investigated whether alterations in KYNA levels in the rat brain might play a role in the long-term consequences of prenatal cannabinoid exposure. Pregnant Wistar rats were treated daily with THC [5 mg/kg or vehicle (sesame oil) by oral gavage] from gestational day (GD) 5 through GD 20. One adolescent [postnatal day 35-45] and one adult male rat per litter was then used to determine the extracellular levels of KYNA and glutamate before and after a challenge with KYN (5 mg/kg i.p.) by in vivo microdialysis in the medial prefrontal cortex (mPFC). Compared to vehicle-treated controls, extracellular basal KYNA levels were higher in adolescent and adult rats that had been prenatally treated with THC (p<0.01; p<0.05, respectively). These rats also had lower extracellular glutamate levels than respective controls (p<0.01; p<0.05, respectively). Following a challenge with KYN, extracellular KYNA levels increased in both adolescent groups (i.e. vehicle- and THC-treated; p<0.05) Interestingly, this effect was more pronounced in adult rats which had been prenatally exposed to THC. KYN also caused a trend towards a reduction in extracellular glutamate levels in vehicle-treated adolescent and adult rats. We propose that these permanent alterations in KYNA and glutamate signalling in the mPFC of prenatally THC-exposed rats could be relevant for cognitive dysfunction. Our results are also in line with the hypothesis that a “double-hit” may precipitate psychiatric disorders such as schizophrenia later in life.