Effects of Prenatal Nicotine, THC, or Co-Exposure on Cognitive Behaviors in Adolescent Male and Female Rats

Abstract

Introduction: Although there has been a decrease in the prevalence of tobacco smoking, exposure to nicotine during pregnancy remains a substantial problem worldwide. Further, given the recent escalation in e-cigarette use and legalization of cannabis, it has become essential to understand the effects of nicotine and cannabinoid co-exposure during early developmental stages.

Aims and methods: We systematically examined the effects of nicotine and/or THC prenatal exposure on cognitive behaviors in male and female offspring. Dams were exposed to nicotine vape or vehicle, and oral edible THC or vehicle, throughout pregnancy. Adolescent offspring were then tested in the prepulse inhibition test, novel object recognition task, and novelty suppressed feeding task.

Results: At birth, pups from mothers exposed to nicotine vape or oral THC exhibited reduced body weight, compared to control pups. Prenatal nicotine vape exposure resulted in a decreased baseline startle reactivity in adolescent male and female rats, and in females, enhanced sensorimotor gating in the prepulse inhibition test. Prenatal nicotine and THC co-exposure resulted in significant deficits in the prepulse inhibition test in males. Deficits in short-term memory were also found in males prenatally exposed to THC, either alone or with nicotine co-exposure, and in females exposed to THC alone. Finally, in males, a modest increase in anxiety-associated behaviors was found with THC or nicotine exposure in the latency to approach a novel palatable food.

Conclusions: These studies demonstrate differential effects of prenatal exposure to e-cigarette nicotine vape and/or edible THC on cognitive function, with differing effects within male and female groups.

Implications: These studies demonstrate an impact of nicotine, THC, or co-exposure during early developmental stages in utero on behavioral outcomes in adolescence. These findings have important translational implications given the continued use of nicotine and THC containing products by pregnant women worldwide, which can be applied to support healthcare and policy efforts restricting nicotine and THC use during pregnancy.

Figure 1.

Altered sensorimotor gating in male and female adolescent offspring following prenatal nicotine and/or THC exposure. (a–b) Following prenatal exposure to THC, NIC, NIC/THC, or vehicle control, male offspring (n = 8–14/group) were examined for startle reactivity and prepulse inhibition (PPI) at PND22. (a) Prenatal NIC treatment resulted in a decrease in startle reactivity compared to the control. Similar effects were found in the NIC/THC co-exposure condition, but this did not reach statistical significance. (b) Following the 75 decibel (dB) prepulse, males exposed to NIC and THC exhibited a deficit in percent PPI compared to all other groups. The decreased response for the NIC/THC co-exposure group persisted at the 80 dB prepulse, when compared to the nicotine group. (c–d) Female offspring (n = 10–15/group) were examined for startle reactivity and PPI at PND22. (c) Adolescent females prenatally exposed to NIC exhibited a significant decrease in startle reactivity compared to the THC and control groups. (d) When specifically examined across the differing prepulse auditory levels, prenatal NIC treatment resulted in enhanced sensorimotor gating compared to the control group at 80 dB, and control and THC groups at 85 dBs, in females. *p < .05, **p < .01, and ***p < .001. Data represent mean ± SEM.

Figure 2.

Prenatal THC exposure results in deficits in short-term memory during adolescence in males and females. At PND35, males (n = 7–16/group) and females (n = 8–12/group) were tested in the novel object recognition (NOR) task following prenatal exposure to THC, NIC, NIC/THC, or vehicle control. (a) Males prenatally exposed to THC or NIC/THC co-exposed show a discrimination index < 0, indicating a deficit in recognition of a novel object. Both of these groups significantly differed from the control group. (b) Females prenatally exposed to THC exhibited no discrimination between the novel and familiar object, which was evidenced as a deficit in the behavioral expression of memory as compared to the control group. *p < .05, **p < .01. Data represent mean ± SEM.

Figure 3.

Longer approach latency in the novelty suppressed feeding task (NF) following prenatal THC or nicotine exposure in adolescent male, but not female, rats. At PND37, subjects were tested in the NF task following prenatal exposure to THC, NIC, NIC/THC, or vehicle control. Behaviors were examined after palatable food was placed in the center of an open field for food restricted male (n = 8–15/group) and female (n = 10–14/group) adolescent rats. (a) Males exposed prenatally to THC or NIC, but not NIC/THC co-exposure, exhibited a greater latency to approach the novel food than subjects in the control condition. (b) Female groups did not significantly differ in the latency to approach the novel food. s = seconds. *p < .05 and **p < .01. Data represent mean ± SEM.