Sex, THC, and hormones: Effects on density and sensitivity of CB1 cannabinoid receptors in rats.
Charlotte E Farquhar, Christopher S Breivogel, Thomas F Gamage, Elaine A Gay, Brian F Thomas, Rebecca M Craft, Jenny L Wiley
Drug and Alcohol Dependence January 1, 2019 DOI: 10.1016/j.drugalcdep.2018.09.018 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Controlled experimental animal study Peer reviewed |
|---|---|
| Population | Adult Sprague-Dawley rats of both sexes, including gonadectomized and sham-gonadectomized animals with or without estradiol or testosterone replacement |
| Interventions | Tetrahydrocannabinol (THC) Gonadectomy Testosterone replacement |
| Dose | 30 mg/kg THC twice daily |
| Duration | 1 week of THC treatment |
| Measures | CP55,940-stimulated [35S]GTPγS binding assay, [3H]SR141716A saturation binding assay |
| Topics | Cannabis |
| Keywords | Cb1 cannabinoid receptor Gonadal hormones Sex differences |
| Key findings | Vehicle-treated rats showed minimal sex differences in CB1 receptor density or G-protein coupling, except for greater receptor activation in female hippocampus. Repeated THC caused pronounced CB1 receptor desensitization and downregulation in all four brain regions in both sexes, with greater magnitude in females across intact, gonadectomized, and hormone-replaced groups. The authors suggest this is consistent with women progressing to tolerance and dependence faster than men after starting cannabis use. |
Abstract
The recent NIH mandate to consider sex as a biological variable in preclinical research has focused attention on delineation of sex differences in behavior. To investigate mechanisms underlying sex differences in Δ9-tetrahydrocannabinol (THC) effects, we examined the effects of sex and gonadal hormones on CB1 receptors in cerebellum, hippocampus, prefrontal cortex, and striatum. Adult Sprague-Dawley rats underwent gonadectomy (GDX) or sham-GDX. Half of the GDX females and males received estradiol or testosterone replacement (GDX+H), respectively. All rats were injected with vehicle or 30 mg/kg THC twice daily for 1 week before brain collection. CP55,940-stimulated [35S]GTPγS and [3H]SR141716A saturation binding assays were performed. With exception of enhanced receptor activation in the hippocampi of female rats compared to males, vehicle-treated rats exhibited minimal sex differences in CB1 receptor densities or G-protein coupling. Repeated treatment with THC resulted in pronounced CB1 receptor desensitization and downregulation in both sexes in all brain regions with a greater magnitude of change in females. These results suggest that sex differences in the density and G-protein coupling of brain CB1 receptors may play a limited role in sex differences in acute THC effects not mediated by the hippocampus. In contrast, sex differences after repeated THC were common, with females (intact, GDX, and GDX+H) showing greater downregulation or desensitization in all four brain regions compared to the respective male groups. This result is consistent with a finding that women tend to progress to tolerance and dependence quicker than men after initiation of cannabis use.
Comparable studies
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- Perinatal omega-3 sex-selectively mitigates neuropsychiatric impacts of prenatal THC in the cortico-striatal-hippocampal circuit. Molecular Psychiatry November 2025
- Brain Function Outcomes of Recent and Lifetime Cannabis Use JAMA Network Open 2025
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Cites 6
- Sex and age specific effects of delta-9-tetrahydrocannabinol during the periadolescent period in the rat: The unique susceptibility of the prepubescent animal. Neurotoxicology and Teratology 2016
- Sex-specific alterations in hippocampal cannabinoid 1 receptor expression following adolescent delta-9-tetrahydrocannabinol treatment in the rat. Neuroscience Letters August 18, 2015
- Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers Molecular Psychiatry July 12, 2011
- Long-term behavioral and pharmacodynamic effects of delta-9-tetrahydrocannabinol in female rats depend on ovarian hormone status. Addiction Biology January 2011
- Chronic delta 9-tetrahydrocannabinol during adolescence provokes sex-dependent changes in the emotional profile in adult rats: behavioral and biochemical correlates. Neuropsychopharmacology October 2008
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