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 1990’s. 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 [3H]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 24 hours and 2 weeks post chronic THC treatment. Consistent with other reported findings, we found downregulation of the CB1 receptor in the hippocampal formation at 24 hours 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.

Mechanisms Underlying Sex Differences in Cannabis Use

“…Preclinical cannabinoid exposure in adolescence largely induces a sex-independent, widespread reduction in CB1-R density [41, 61–63], although enhancement in hippocampus in female animals [64–66], and striatum in both sexes [64], has been observed. Chronic THC exposure during adolescence led to a reduction in CB1-R density in the amygdala [61], caudate, putamen, nucleus accumbens, and substantia nigra [41] of adult male rats.…”

“…In THC-exposed female rats, reductions were also observed in these regions, as well as ventral tegmental area [41, 61] prefrontal cortex, globus pallidus, and hypothalamus [41]. CB1-R reduction was observed in hippocampus in females and males, though in more hippocampal sub-regions in females [63]. Additionally, THC exposure reduces striatal CB1-R density in female rats, independent of ovarian hormone status [67].…”

Vaporized cannabis extracts have reinforcing properties and support conditioned drug-seeking behavior in rats

“…Rats were trained to nosepoke for CANTHC, CANCBD, or VEH vapor puffs under a fixed ratio-1 (FR-1) reinforcement schedule during daily one-hour sessions on 11 consecutive days (see Supplement for a description of the vapor delivery system). Rats then progressed to an FR-2 schedule (days 12-16) and then to an FR-4 schedule (day [17][18][19][20][21]. Nosepoke responses made on one (active) operandum resulted demand increased after each vapor delivery according to the following schedule: 1, 1, 2, 2, 3, 3, 4, 4, 5, 5, 7, 7, 9, 9, 11, 11, 13, 13, 15, 15, 18, 18, 21, 21, 24, 24, etc.…”

“…We used this procedure to examine whether vaporized cannabis extracts that are high in THC or CBD have reinforcing properties that support stable drug-taking behavior. We characterized the metabolic phenotype of cannabis-trained rats and since human cannabis users and rodents chronically treated with THC exhibit reduced CB1R availability [19] and decreased CB1R expression [20][21][22][23], respectively, we also measured hippocampal CB1 receptor binding in rats from each treatment group. Furthermore, given that acute abstinence can unmask withdrawal-related affective symptoms for other drugs of abuse [24], we examined whether acute forced abstinence from cannabis vapor increases anxiety-like behavior.…”

Marijuana Use Is Associated with Behavioral Approach and Depressive Symptoms in Adolescents and Emerging Adults

“…One reason for the potential additional susceptibility to the neurotoxic effects of marijuana may be due to altered signaling in the CB1 receptor in females, but not males [61, 62]. More widespread effects of THC in adolescent female rats than in male rats have also been observed [63]. Therefore, when examining consequences of marijuana exposure, it is important to examine potential gender differences.…”