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.

Keywords: Morris water maze; amphetamine hyperlocomotion; fear conditioning; polyinosinic-polycytidylic acid; prepulse inhibition; schizophrenia.

Figure 1

Experimental design.

Figure 2

Amphetamine hyperlocomotion. (A,B) Distance traveled by male (A) and female (B) mice following saline (0–30 min) and d-amphetamine (AMPH, 2.5 mg/kg, 30–120 min) reported in 5 min bins. (C) Total distance traveled by mice during the 90 min following d-amphetamine injection. One female in the saline/THC group was removed from analysis as a statistical outlier (Rout, Q = 1%). Bar height represents the mean, vertical lines the SEM.

Figure 3

Prepulse inhibition (PPI) of the acoustic startle reflex in male (A) and female (B) adult offspring. The average percent PPI at five prepulse intensities was calculated. There were no effects of poly(I:C) or THC on PPI. All values are the mean ± SEM. n = 8–10 mice/sex/treatment.

Figure 4

Morris water maze (MWM). (A,B) The average time that it took male (A) and female (B) mice to reach the platform during the training phase. The average of the four trials from each day was reported. (C) The percent of total time that mice spent in the correct quadrant of the MWM during the probe trial when the platform was removed. (D) The average time that it took mice to find the new platform location when the platform was moved during the spatial reversal phase. The average of the last three trials was reported. One female mouse in the saline/THC group was excluded from analysis as a statistical outlier (ROUT, Q = 1%). (E) Correlation between time spent in the correct quadrant in the probe trial and the average time to platform in the spatial reversal trial for female mice treated with saline prenatally and adolescent THC. Except for panel E, all bars represent mean and vertical lines the SEM. ** p < 0.01, based on analysis with Šídák’s multiple comparisons post hoc test.

Figure 5

Fear conditioning and extinction. (A,B) The percent of time that male (A) and female (B) mice spent freezing during the tone in the training phase where mice received a foot shock at the end of the tone. (C,D). The percent of time that male (C) and female (D) mice spent freezing during the first five tones on each day the extinction phase. The data for four female mice on day two and two female mice on day five were lost due to technological failures. All values are the mean ± SEM. * p < 0.05, based on three-way repeated-measures ANOVA. n = 8–10 mice/sex/treatment.