Sex-specific alterations in hippocampal cannabinoid 1 receptor expression following adolescent delta-9-tetrahydrocannabinol treatment in the rat

Abstract

Marijuana use by adolescents has been on the rise since the early 1990s. With recent legalization and decriminalization acts passed, cannabinoid exposure in adolescents will undoubtedly increase. Human studies are limited in their ability to examine underlying changes in brain biochemistry making rodent models valuable. Studies in adult and adolescent animals show region and sex specific downregulation of the cannabinoid 1 (CB1) receptor following chronic cannabinoid treatment. However, although sex-dependent changes in behavior have been observed during the drug abstinence period following adolescent cannabinoid exposure, little is known about CB1 receptor expression during this critical time. In order to characterize CB1 receptor expression following chronic adolescent Δ-9-tetrahydrocannabinol (THC) exposure, we used [(3)H] CP55,940 binding to assess CB1 receptor expression in the dentate gyrus and areas CA1, CA2, and CA3 of the hippocampus in both male and female adolescent rats at both 24h and 2 weeks post chronic THC treatment. Consistent with other reported findings, we found downregulation of the CB1 receptor in the hippocampal formation at 24h post treatment. While this downregulation persisted in both sexes following two weeks of abstinence in the CA2 region, in females, this downregulation also persisted in areas CA1 and CA3. Expression in the dentate gyrus returned to the normal range by two weeks. These data suggest that selective regions of the hippocampus show persistent reductions in CB1 receptor expression and that these reductions are more widespread in female compared to male adolescents.

Keywords: Adolescence; CB1 receptor expression; Delta-9-Tetrahydrocannabinol; Hippocampus; Sex differences.

Figure 1

Representative autoradiograms for day 42 showing [³H] CP55,940 binding. (A) Outline of sections analyzed for autoradiography (Plate 35, −3.8 mm from Bregma, from Paxinos and Watson, Fourth Edition, 1998). (B) Male Control. (C) Male 15 THC. (D) Female Control. (E) Female 15 THC.

Figure 2

Average CB1R Density in Hippocampal Sub-Regions 24 hours after final THC (15mg/kg/day) exposure. * indicates significantly (ANOVA, p<0.05) lower than vehicle group. (n=3–6/group). Values expressed as mean ± SEM.

Figure 3

Average CB1R Density in Hippocampal Sub-Regions 2 weeks after final THC (15mg/kg/day) exposure. (a.) Data for all sex and treatment groups * indicates significantly lower than vehicle group (ANOVA, p<0.05). $ indicates a significant sex by treatment interaction (n=3–6/group). Data for males (b.) and females (c.). * indicates significantly less than same sex vehicle treated group (Tukey, p<0.05). Values expressed as mean ± SEM.