Estrogenic regulation of limbic cannabinoid receptor binding

Abstract

Sex differences have been identified in many of the behavioral and physiological effects of cannabinoids. While estrogens has been linked to some of these variations, the effects of estrogen on cannabinoid receptor binding have not been characterized within regions of the brain specifically implicated in stress responsivity and emotional behavior. To examine sex differences, and the role of estradiol, in regulation of the cannabinoid receptor, we compared the binding site density of the cannabinoid receptor within the amygdala, hippocampus and hypothalamus in males, cycling females, ovariectomized (OVX) females and estradiol-treated OVX females (OVX + E). Our data reveal that males and OVX females have higher amounts of hypothalamic and lower amounts of amygdalar cannabinoid receptor binding relative to both cycling females and OVX + E females. Within the hippocampus, ovariectomy resulted in an upregulation of cannabinoid receptor binding. These data provide a putative biochemical mechanism mediating the observed behavioral and physiological sex differences in the effects of cannabinoids, particularly with respect to stress and emotional behavior.

Imaging the Cannabinoid CB1 Receptor in Humans with [11C] OMAR: Assessment of Kinetic Analysis Methods, Test–Retest Reproducibility, and Gender Differences

“…27 Although our present study and that of Van Laere et al both found elevated circulating tracer parent fraction and total brain uptake in men, opposite conclusions were drawn about the brain PET data because of differences in image analysis methods as described above. The discrepancy is not readily resolved by turning to the preclinical literature as studies in rodents using imaging and in vitro methods report elevated CB1 expression in male animals, 37 but results are frequently conflicting. 38 Moreover, such studies often did not account for the estrous cycle, but those that did typically show alterations attributable to menstrual phase and hormonal regulation.…”

Sex Differences in Cannabinoid 1 vs. Cannabinoid 2 Receptor-Selective Antagonism of Antinociception Produced by Δ9-Tetrahydrocannabinol and CP55,940 in the Rat

“…In addition, brain CB 1 receptor density and affinity may differ between female and male rats, although the direction of these differences seems to be brain site-specific. For example, cannabinoid receptor density is greater in females than males in the amygdala (Riebe et al, 2010) but lower in females than males in the hypothalamus (Riebe et al, 2010) and mesencephalon (Rodríguez de Fonseca et al, 1994). Higher binding affinity also has been observed in females in striatum, limbic forebrain, and mesencephalon (Rodríguez de Fonseca et al, 1994) and in males in hypothalamus (Riebe et al, 2010).…”

“…For example, cannabinoid receptor density is greater in females than males in the amygdala (Riebe et al, 2010) but lower in females than males in the hypothalamus (Riebe et al, 2010) and mesencephalon (Rodríguez de Fonseca et al, 1994). Higher binding affinity also has been observed in females in striatum, limbic forebrain, and mesencephalon (Rodríguez de Fonseca et al, 1994) and in males in hypothalamus (Riebe et al, 2010). One study in humans also reported greater peripheral cannabinoid receptor expression in women than men (Onaivi et al, 1999), although these were presumably CB 2 receptors given that they were on leukocytes.…”

Cannabis Abusers Show Hypofrontality and Blunted Brain Responses to a Stimulant Challenge in Females but not in Males

“…This could provide a neurobiological basis for differences in sensitivity to the effects of cannabis between the genders. Sex differences in cannabinoid action have been ascribed in part to menstrual phase and fluctuating hormonal levels (Fattore and Fratta, 2010;Riebe et al, 2010). In our study, we scanned women during the mid-follicular phase when levels of estrogen, FSH, LH, and progesterone are low, to minimize the effects of menstrual cycle.…”