Adolescent THC Treatment Does Not Potentiate the Behavioral Effects in Adulthood of Maternal Immune Activation

Abstract

Both in utero exposure to maternal immune activation and cannabis use during adolescence have been associated with increased risk for the development of schizophrenia; however, whether these exposures exert synergistic effects on brain function is not known. In the present study, mild maternal immune activation (MIA) was elicited in mice with prenatal exposure to polyinosinic-polycytidylic acid (poly(I:C)), and ∆9-tetrahydrocannabinol (THC) was provided throughout adolescence in cereal (3 mg/kg/day for 5 days). Neither THC nor MIA pretreatments altered activity in assays used to characterize hyperdopaminergic states in adulthood: amphetamine hyperlocomotion and prepulse inhibition of the acoustic startle reflex. Adolescent THC treatment elicited deficits in spatial memory and enhanced spatial reversal learning in adult female mice in the Morris water maze, while exposure to MIA elicited female-specific deficits in fear extinction learning in adulthood. There were no effects in these assays in adult males, nor were there interactions between THC and MIA in adult females. While doses of poly(I:C) and THC were sufficient to elicit behavioral effects, particularly relating to cognitive performance in females, there was no evidence that adolescent THC exposure synergized with the risk imposed by MIA to worsen behavioral outcomes in adult mice of either sex.

LACK OF INTERACTIONS BETWEEN PRENATAL IMMUNE ACTIVATION AND Δ9-TETRAHYDROCANNABINOL EXPOSURE DURING ADOLESCENCE IN BEHAVIOURS RELEVANT TO SYMPTOM DIMENSIONS OF SCHIZOPHRENIA IN RATS

“…Our results showed PPI reduction in both male and female MIA rats (Figure 2F), in accordance with previous studies (Wischhof et al, 2015); however, in agreement with previous literature, we found no detrimental effects of THC exposure on PPI. Importantly, we found no interaction between MIA and cannabinoid exposure during adolescence, suggesting that there are no summative or synergistic actions between both hits in this model, as reported with other two-hit models (Garcia-Mompo et al, 2020; Guma et al, 2023; Rodríguez et al, 2017; Stollenwerk and Hillard, 2021a).…”

“…In this work, we have shown that MIA and THC exposure during adolescence do not interact to precipitate schizophrenia-related symptoms in rats, at least not in the behavioural dimensions that we have examined. This adds to the growing number of studies that have experimentally tested the two-hit hypothesis and have found no evidence for synergy between the two hits (Guma et al, 2023; Lecca et al, 2019b; Stollenwerk and Hillard, 2021b). Clearly, we are still at an early stage of research using these two-hit models before we can unmistakably dismiss a precipitating role of cannabis consumption during adolescence in the onset of schizophrenia.…”

“…They obtained similar results with prepulse inhibition and cognitive tests such as the Morris water maze. One of the hits was enough to produce behavioural alterations but without evidence of any synergistic effects (Stollenwerk and Hillard, 2021a). All together, these results again highlight the complex and heterogeneous interaction between MIA and cannabinoid exposure.…”

Advantages and Limitations of Animal Schizophrenia Models

“…Prenatal exposure to viral pathogens, such as influenza, is related to an increased risk of developing schizophrenia in adulthood [ 225 ], and most research has shown increased schizophrenia cases after influenza pandemics [ 226 , 227 ]. The MIA model requires the administration of polyinosinic:polycytidylic acid (poly(I:C)) during the gestational stage to activate the innate immune system dependent on toll-like receptor 3 (TLR-3) signaling [ 225 ]. Some researchers also use LPS to induce an immune response, and this method also qualifies as MIA [ 228 ].…”