Alterations in rat prefrontal cortex kynurenic acid levels are involved in the enduring cognitive dysfunctions induced by tetrahydrocannabinol exposure during the adolescence.
Sarah Beggiato, Alessandro Ieraci, Mariachiara Zuccarini, Patrizia Di Iorio, Robert Schwarcz, Luca Ferraro
Frontiers in Psychiatry 2022 DOI: 10.3389/fpsyt.2022.996406 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational animal study (in vivo experiment in rats) Peer reviewed |
|---|---|
| Population | Male Wistar rats, treated from postnatal day 35 to 45 and assessed in adulthood (postnatal day 75) |
| Interventions | THC PF-04859989 |
| Dose | Ascending intraperitoneal doses of THC; kynurenine 5 mg/kg i.p.; PF-04859989 30 mg/kg i.p. |
| Duration | THC treatment from postnatal day 35 to 45; assessment in adulthood at postnatal day 75 |
| Measures | Y-maze (spontaneous alternation), in vivo microdialysis |
| Topics | Cannabis |
| Keywords | Kat ii inhibitor Glutamate Kynurenine pathway Schizophrenia |
| Key findings | Adult rats exposed to chronic THC in adolescence showed higher basal prefrontal KYNA levels and impaired short-term memory (reduced spontaneous alternation) compared with vehicle-treated controls, with no change in extracellular glutamate. The KAT II inhibitor PF-04859989 (30 mg/kg) restored the cognitive impairment. The authors propose that altered prefrontal KYNA signaling may be involved in THC-induced cognitive dysfunction. |
Abstract
Cannabis 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. Male 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. Compared 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). We 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.
Comparable studies
Other preclinical and animal studies on cannabis, most cited first.
Citations in the library
Cites 14
- Use of Marijuana: Effect on Brain Health: A Scientific Statement From the American Heart Association Stroke February 10, 2022
- Cannabis exposure during adolescence: A uniquely sensitive period for neurobiological effects. International review of neurobiology 2022
- Cannabis and synaptic reprogramming of the developing brain. Nature Reviews Neuroscience July 2021
- Cannabis and the Developing Adolescent Brain Current Treatment Options in Psychiatry April 18, 2020
- Characterizing psychosis-relevant phenomena and cognitive function in a unique population with isolated, chronic and very heavy cannabis exposure Psychological Medicine October 16, 2019
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