CBD enhances the cognitive score of adolescent rats prenatally exposed to THC and fine-tunes relevant effectors of hippocampal plasticity

Abstract

Introduction: An altered neurodevelopmental trajectory associated with prenatal exposure to ∆-9-tetrahydrocannabinol (THC) leads to aberrant cognitive processing through a perturbation in the effectors of hippocampal plasticity in the juvenile offspring. As adolescence presents a unique window of opportunity for "brain reprogramming", we aimed at assessing the role of the non-psychoactive phytocannabinoid cannabidiol (CBD) as a rescue strategy to temper prenatal THC-induced harm. Methods: To this aim, Wistar rats prenatally exposed to THC (2 mg/kg s.c.) or vehicle (gestational days 5-20) were tested for specific indexes of spatial and configural memory in the reinforcement-motivated Can test and in the aversion-driven Barnes maze test during adolescence. Markers of hippocampal excitatory plasticity and endocannabinoid signaling-NMDAR subunits NR1 and 2A-, mGluR5-, and their respective scaffold proteins PSD95- and Homer 1-; CB1R- and the neuromodulatory protein HINT1 mRNA levels were evaluated. CBD (40 mg/kg i.p.) was administered to the adolescent offspring before the cognitive tasks. Results: The present results show that prenatal THC impairs hippocampal memory functions and the underlying synaptic plasticity; CBD is able to mitigate cognitive impairment in both reinforcement- and aversion-related tasks and the neuroadaptation of hippocampal excitatory synapses and CB1R-related signaling. Discussion: While this research shows CBD potential in dampening prenatal THC-induced consequences, we point out the urgency to curb cannabis use during pregnancy in order to avoid detrimental bio-behavioral outcomes in the offspring.

Keywords: CB1R; adolescent offspring; cannabidiol; hippocampal excitatory synapse; prenatal THC exposure; spatial memory.

FIGURE 1

Experimental design. Starting from PND 35, adolescent CTRL and pTHC (2 mg/kg, GD 5–20) rats underwent the spatial- and the simple visual tasks of the Can test or performed the probe- and reversal tasks of the Barnes maze test. CBD (40 mg/kg i.p.) was administered 24 h prior to each experimental session. Animals were sacrificed 24 h after the last experimental task and CBD administration. GD, gestational day; PND, postnatal day; s.c., subcutaneous; i.p., intraperitoneal; THC, Δ-9-tetrahydrocannabinol; CBD, cannabidiol; sac., sacrifice; NR1, ionotropic glutamate N-methyl-d-aspartate receptors (NMDARs) NR1 subunit; NR2A, NMDARs NR2A subunit; PSD95, scaffolding protein post-synaptic density-95; mGluR5, group I metabotropic glutamate receptor 5; CB1R, cannabinoid receptor type 1; HINT1, histidine triad nucleotide-binding protein 1. Created with BioRender.com, https://app.biorender.com (accessed on 15 July 2023).

FIGURE 2

The recovery effect of CBD on the impaired reinforcement-related cognitive score of pTHC-exposed adolescent rat offspring. Rats prenatally exposed to THC displayed a lower reinforcement-related cognitive integrated z-score than CTRL rats (A). CBD reversed pTHC-induced alteration in spatial and configural cognitive processing in the Can test of the adolescent offspring, by improving CR- and RE-related cognitive scores in pTHC-CBD rats tested in both spatial- (B,C) and simple visual (D,E) tasks. Each bar represents the mean of n = 10 rats; error bars indicate SEM. **p < 0.01, ****p < 0.0001. CTRL, male rat offspring prenatally exposed to Veh; pTHC, male rat offspring prenatally exposed to THC; pTHC-CBD, male rat offspring prenatally exposed to THC and exposed to CBD in adolescence; CR, correct responses; RE, reference memory errors.

FIGURE 3

The ability of CBD to counteract the impaired aversion-related cognitive score of pTHC-exposed adolescent rat offspring. pTHC decreased the aversion-related cognitive integrated z-score (A). CBD rescued pTHC-induced impairment in the retrieval of spatial memory and reversal learning, by improving primary latency- (B) and latency to escape-related cognitive scores (C) in pTHC-CBD rats. Each bar represents the mean of n = 12 rats; error bars indicate SEM. **p < 0.01, ***p < 0.001. CTRL, male rat offspring prenatally exposed to Veh; pTHC, male rat offspring prenatally exposed to THC; pTHC-CBD, male rat offspring prenatally exposed to THC and exposed to CBD in adolescence.

FIGURE 4

CBD (40 mg/kg) mitigates the abnormal mRNA relative expression levels of specific markers of excitatory plasticity and CB1R-related signaling in the hippocampus of pTHC-exposed (2 mg/kg, GD 5–20) adolescent rat offspring. Prenatal THC exposure increased the expression levels of the NMDAR NR1 subunit and decreased the levels of NR2A and PSD95, induced an increase in mGluR5, and its scaffolding partner Homer 1 isoform, and increased CB1R and HINT1 expression levels in the hippocampus of the adolescent male rat offspring. On the contrary, a decrease in NR1 subunit, mGluR5, Homer 1 and CB1R was detected in pTHC-CBD when compared to pTHC adolescent offspring. Each bar represents the mean of n = 6 rats; error bars indicate SEM.**pp < 0.01, ****pp < 0.0001, CTRL vs. pTHC; °°pp < 0.01, °°°pp < 0.001, °°°°pp < 0.0001, pTHC vs. pTHC-CBD; +pp < 0.05, ++pp < 0.01, +++pp < 0.001, ++++pp < 0.0001, pTHC-CBD vs. CTRL. CTRL, male rat offspring prenatally exposed to Veh; pTHC, male rat offspring prenatally exposed to THC; pTHC-CBD, male rat offspring prenatally exposed to THC and exposed to CBD in adolescence; NR1, ionotropic glutamate N-methyl-d-aspartate receptors (NMDARs) NR1 subunit; NR2A, NMDARs NR2A subunit; PSD95, scaffolding protein post-synaptic density-95; mGluR5, group I metabotropic glutamate receptor 5; CB1R, cannabinoid receptor type 1; HINT1, histidine triad nucleotide-binding protein 1.