Sexually-dimorphic alterations in cannabinoid receptor density depend upon prenatal/early postnatal history

Abstract

Recent research has demonstrated that the endogenous cannabinoid system is central to the brain’s response to stress. As part of an ongoing collaboration, we sought to examine the effects of prenatal and early postnatal rearing and housing conditions on developing endocannabinoid systems. We compare brain cannabinoid receptors (CBR) in offspring of either prenatal vehicle intubated or non-treated dams (Experiment 1) or in rats derived from a vendor and shipped at weaning to a collaborating lab (Experiment 2). From postnatal day (PND) 23, all rats were either housed in isolated conditions or enriched conditions with 3 rats/cage and a variety of stimulus objects changed twice a week. All rats underwent 5 days of handling as controls for a behavior study and all rats were sacrificed at approximately PND48-50 within 2 hours of the last behavioral test. All brains were processed together for CB1 receptor binding using 3H CP55,940 in prefrontal cortex, striatum, amygdala and hippocampus. Conditions in the two labs were as similar as possible since the two studies were intentionally designed to be comparable and contemporary. Results show that 1) comparing offspring of non-treated dams to offspring of dams receiving daily vehicle intubations, males show decreased CB1 binding in most brain regions while females only showed alterations in the hippocampus and these were increases in the offspring of the vehicle-intubated dams. 2) When comparing offspring of non-treated dams in NY with those derived from a vendor, shipped and maintained in the collaborating lab, this latter group showed reduced CB1 binding in prefrontal cortex in males and increased binding in all four brain regions in females. Therefore, overall, both prenatal handling (intubations) and being vendor-derived, shipped and maintained in a collaborating facility reduced CB1 receptors in males and increased them in females in key limbic brain regions. Effects of environmental enrichment or isolation were minor with only the prefrontal cortex showing an increase in binding in the isolated animals that were offspring of the vehicle-intubated dams. These results support the ideas that prenatal/early postnatal conditions produce different effects in males and females and override the effects of enrichment/isolation on cannabinoid receptors. Behavioral responses to cannabinoid challenges would therefore be expected to vary depending on sex, prenatal/early postnatal history and postweaning conditions of the rats. Since exogenous cannabinoids act through the CBR, the present data may provide a molecular basis for discrepant behavioral effects reported across various labs in the literature as well as sex differences seen following stress and/or manipulation of the cannabinoid system.

Ontogeny and programming of the fetal temporal cortical endocannabinoid system by moderate maternal nutrient reduction in baboons ( Papio spp.)

“…Sex‐dependent changes in CB1R have been observed in rodent models similar to results in our study (Dow‐Edwards et al. ). In our study, the CB1R and CB2R protein expression levels were lower at 140 dGA than at 120 dGA and then returned to the 120 dGA level at 165 dGA.…”

Sex difference in brain CB1 receptor availability in man

“…Our results are in good agreement with previous animal studies. The binding of CB1R agonist [ 3 H]CP55,940 is consistently higher in male rats [12][13][14] . Also, higher anterior pituitary CB1R mRNA and hippocampal CB1R protein levels have been measured in male rats using in situ hybridization and western blot experiments 10,11 .…”

“…Converging lines of evidence from pre-clinical studies show gender differences in ECS function. Relative to female rodents, male rodents show greater levels of CB1R protein 10 , mRNA 11 , receptor density 12,13 and agonist binding 14 . However, in vivo studies investigating CB1R availability in humans have yielded discrepant findings, reporting decreased and increased CB1R availability in males relative to females [15][16][17] .…”

Long-term aberrations to cerebellar endocannabinoids induced by early-life stress

“…These sex differences in the cannabinoid system may be important for key sex differences observed in behavior following stressors. Early-life stress affects the endocannabinoid system by (a) decreasing CB1Rs in adulthood in males 27 across various cortical regions as concluded through [ 3 H]CP55,940 binding and mRNA expression, though findings in females have been mixed 28 , and (b) increasing gene expression for endocannabinoid degradation enzymes 29 , though surprisingly these effects have not been studied in the cerebellum. Although endocannabinoids have not been thoroughly investigated in the cerebellum, males have been shown to exhibit increased cerebellar 2-AG compared to females 30 .…”