Estrogenic regulation of limbic cannabinoid receptor binding

doi:10.1016/j.psyneuen.2010.02.008

Psychoneuroendocrinology

Volume 35, Issue 8, September 2010, Pages 1265-1269

https://doi.org/10.1016/j.psyneuen.2010.02.008 Get rights and content

Summary

Sex differences have been identified in many of the behavioral and physiological effects of cannabinoids. While estrogen 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.

Introduction

The neuronal endocannabinoid system, which was first characterized as the neural system mediating the psychoactive effects of cannabis, is a neuromodulatory system which regulates a wide range of physiological and behavioral functions. The neuronal cannabinoid system is comprised of G-protein coupled receptors (CB₁ receptors) and the endogenous arachidonate-derived ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG).

A number of sex differences have been reported in the behavioral and physiological effects of cannabinoids. For example, CB₁ receptor agonists are more potent in females than males with respect to antinociception and reduced locomotor activity, but are more potent in males at stimulating food intake and increasing body weight (Diaz et al., 2009, Rubino et al., 2008, Tseng and Craft, 2001). Females have been found to self-administer cannabinoids at higher rates than males (Fattore et al., 2007). In both rodents and humans, females are more sensitive than males to the anxiogenic effects of cannabinoids (Marco et al., 2006, Willianson and Evans, 2000). Consistent with this, females are more sensitive than males to the adverse effects of escalating THC exposure during adolescence on emotional behavior and stress reactivity in adulthood (Rubino et al., 2008). Completely opposite effects have been seen in sexual behavior such that cannabinoids facilitate female but impair male sexual activity (Gorzalka et al., in press).

Differences in the profile of gonadal hormones in males and females could underlie sex differences in the effects of cannabinoids. In particular, the observed sex differences in potency and sensitivity to CB₁ receptor agonists could result if steroid hormones differentially regulate cannabinoid receptor expression or sensitivity to ligands. In support of this possibility, several responses to exogenously administered cannabinoids have been found to be dependent on levels of circulating estrogens (Anakari et al., 2008, Craft and Leiti, 2008). In addition, the higher rate of cannabinoid self-administration in females compared to males is reduced following ovariectomy (Fattore et al., 2007). Furthermore, cannabinoid influences on glutamatergic and GABAergic neuronal circuits are highly susceptible to modulation by estradiol (Nguyen and Wagner, 2006) and a recent report has demonstrated that protein levels of the CB₁ receptor are significantly lower in females relative to males (Reich et al., 2009).

With respect to the CB₁ receptor, CB₁ receptor mRNA transcript amounts fluctuate throughout the estrous cycle and respond to estradiol treatment in ovariectomized females (González et al., 2000) and the estradiol responsiveness of CB₁ receptor binding has been examined at the level of the forebrain (Rodríguez de Fonseca et al., 1994, Bonnin et al., 1993). However, the influences of sex and gonadal hormones on the density of cannabinoid receptors within distinct regions in the limbic system involved in emotionality and cognition has not been examined.

Section snippets

Subjects

Female and male Sprague–Dawley rats (Charles River, Montreal, Canada) weighing between 300 and 400 g were used in this study. All animals were pair housed in standard plastic maternity bins lined with contact bedding and had unrestricted access to tap water and Purina Rat Chow. The animals were kept in colony rooms with a constant temperature of 21 ± 1 °C and on a reverse 12:12 h light and dark cycle with lights turned off at 09:00 h. Following arrival, animals undergoing surgery were allowed to

Results

Within the hypothalamus there was a significant effect of treatment on the maximal binding (B_max) of ³H-CP55940 to the cannabinoid receptor [F(3, 18) = 7.18, p < 0.005: Fig. 1]. Post hoc analysis demonstrated that both males and OVX females exhibited higher levels of cannabinoid receptor binding than either intact females or OVX + E females (all p's < 0.05 for these comparisons). With respect to binding affinity (K_d) of ³H-CP55940 for the cannabinoid receptor, there was a main effect of treatment [F(3,

Discussion

Our goal in these studies was to test the global hypothesis that differences in cannabinoid receptor function contribute to sex differences in behavioral and physiological responses to exogenous cannabinoids. We tested the specific hypothesis that estradiol affects the expression and/or binding affinity of the cannabinoid receptor in three brain regions within the limbic circuit. Cannabinoid receptor binding parameters were compared in intact male and female rats; and in female rats following

Role of the funding sources

This research was supported by the Canadian Institutes of Health Research (CIHR) and Natural Sciences and Engineering Research Council of Canada (NSERC) grants to BBG and National Institute of Health (NIH) grants DA022439 and DA09155 to CJH. MNH is supported by a postdoctoral fellowship from CIHR and TTL is the recipient of a CIHR graduate fellowship. The CIHR, NSERC and NIH had no further role in study design nor in the collection, analysis and interpretation of data; in the writing of the

Conflict of interest

None declared.

Acknowledgements

The authors would like to thank Amy Sasman for her technical assistance with these experiments.

Contributors: Ms. Riebe conducted the surgical procedures and ran the receptor binding assays for this study and wrote the initial draft of the manuscript. Dr. Hill proposed the rationale for this study, performed the tissue dissections, assisted with statistical analysis and interpretation and edited manuscript. Ms. Lee assisted with the surgical procedures, assisted with the receptor binding assay

References (19)

R.M. Craft et al.
Gonadal hormone modulation of the behavioral effects of Δ⁹-tetrahydrocannabinol in male and female rats
Eur. J. Pharmacol.
(2008)
S. González et al.
Sex steroid influences on cannabinoid CB1 receptor mRNA and endocannabinoid levels in the anterior pituitary
Biochem. Biophys. Res. Co.
(2000)
M.N. Hill et al.
Estrogen recruits the endocannabinoid system to modulate emotionality
Psychoneuroendocrinology
(2007)
E.M. Marco et al.
Adolescent exposure to nicotine modifies acute functional responses to cannabinoid agonists in rats
Behav. Brain Res.
(2006)
A.L. Mize et al.
Acute and long-term effects of 17β-estradiol on G_i/o coupled neurotransmitter receptor function in the female rat brain as assessed by agonist-stimulated [³⁵S] GTPγS-binding
Brain Res.
(2000)
C.G. Reich et al.
Differential effects of chronic unpredictable stress on hippocampal CB1 receptors in male and female rats
Behav. Brain Res.
(2009)
A.H. Tseng et al.
Sex differences in antonociceptive and motoric effects of cannabinoids
Eur. J. Pharmacol.
(2001)
S.E. Alves et al.
Estrogen-regulated progestin receptors are found in the midbrain raphe but not hippocampus of estrogen receptor alpha (ER alpha) gene-disrupted mice
J. Comp. Neurol.
(2000)
D. Anakari et al.
Modulation by female sex hormones of the cannabinoid-induced catalepsy and analgesia in ovariectomized rats
Eur. J. Pharmacol.
(2008)

There are more references available in the full text version of this article.

Cited by (106)

Somatic and anxiety-like behaviors in male and female rats during withdrawal from the non-selective cannabinoid agonist WIN 55,212–2
2024, Pharmacology Biochemistry and Behavior
Synthetic cannabinoids are associated with higher risk of dependence and more intense withdrawal symptoms than plant-derived Δ9-tetrahydrocannabinol (THC). Avoidance of withdrawal symptoms, including anxiogenic effects, can contribute to continued cannabinoid use. Adult male and female Long-Evans rats were given escalating doses of WIN 55,212–2 (WIN) via twice daily intrajugular infusions. Precipitated withdrawal was elicited with SR 141716 (rimonabant) 4 h after the final infusion. Global withdrawal scores (GWS) were compiled by summing z-scores of observed somatic behaviors over a 30-min period with locomotor activity simultaneously collected via beam breaks. Rimonabant precipitated withdrawal in female and male rats at 3 or 10 mg/kg, respectively, but the individual behaviors contributing to GWS were not identical. 3 mg/kg rimonabant did not impact locomotor behavior in females, but 10 mg/kg decreased locomotion in male controls. Spontaneous withdrawal observed between 6 and 96 h after the final infusion was quantifiable up to 24 h following WIN administration. Individual behaviors contributing to GWS varied by sex and time point. Males undergoing spontaneous withdrawal engaged in more locomotion than females undergoing withdrawal. Separate groups of rats were subjected to a battery of anxiety-like behavioral tests (elevated plus maze, open field test, and marble burying test) one or two weeks after WIN or vehicle infusions. At one week abstinence, sex-related effects were noted in marble burying and the open field test but were unrelated to drug treatment. At two weeks abstinence, females undergoing withdrawal spent more time grooming during marble burying and performed more marble manipulations than their male counterparts. WIN infusions did not impact estrous cycling, and GWS scores were not correlated with estrous at withdrawal. Collectively, these results show qualitative sex differences in behaviors contributing to the behavioral experience of cannabinoid withdrawal supporting clinical findings from THC.
Mechanisms of cannabinoid tolerance
2023, Biochemical Pharmacology
Cannabis has been used recreationally and medically for centuries, yet research into understanding the mechanisms of its therapeutic effects has only recently garnered more attention. There is evidence to support the use of cannabinoids for the treatment of chronic pain, muscle spasticity, nausea and vomiting due to chemotherapy, improving weight gain in HIV-related cachexia, emesis, sleep disorders, managing symptoms in Tourette syndrome, and patient-reported muscle spasticity from multiple sclerosis. However, tolerance and the risk for cannabis use disorder are two significant disadvantages for cannabinoid-based therapies in humans. Recent work has revealed prominent sex differences in the acute response and tolerance to cannabinoids in both humans and animal models. This review will discuss evidence demonstrating cannabinoid tolerance in rodents, non-human primates, and humans and our current understanding of the neuroadaptations occurring at the cannabinoid type 1 receptor (CB₁R) that are responsible tolerance. CB₁R expression is downregulated in tolerant animals and humans while there is strong evidence of CB₁R desensitization in cannabinoid tolerant rodent models. Throughout the review, critical knowledge gaps are indicated and discussed, such as the lack of a neuroimaging probe to assess CB₁R desensitization in humans. The review discusses the intracellular signaling pathways that are responsible for mediating CB₁R desensitization and downregulation including the action of G protein-coupled receptor kinases, β-arrestin2 recruitment, c-Jun N-terminal kinases, protein kinase A, and the intracellular trafficking of CB₁R. Finally, the review discusses approaches to reduce cannabinoid tolerance in humans based on our current understanding of the neuroadaptations and mechanisms responsible for this process.
Women are taking the hit: Examining the unique consequences of cannabis use across the female lifespan
2023, Frontiers in Neuroendocrinology
Cannabis use has risen dramatically in recent years due to global decriminalization and a resurgence in the interest of potential therapeutic benefits. While emerging research is shaping our understanding of the benefits and harms of cannabis, there remains a paucity of data specifically focused on how cannabis affects the female population. The female experience of cannabis use is unique, both in the societal context and because of the biological ramifications. This is increasingly important given the rise in cannabis potency, as well as the implications this has for the prevalence of Cannabis Use Disorder (CUD). Therefore, this scoping review aims to discuss the prevalence of cannabis use and CUD in women throughout their lifespan and provide a balanced prospective on the positive and negative consequences of cannabis use. In doing so, this review will highlight the necessity for continued research that goes beyond sex differences.
Impaired inhibition after delta-9-tetrahydrocannabinol in women not related to circulating estradiol levels
2023, Pharmacology Biochemistry and Behavior
Cannabis and its main psychoactive constituent, delta-9-tetrahydrocannabinol (THC), impair cognitive processes, including the ability to inhibit inappropriate responses. However, responses to cannabinoid drugs vary widely, and little is known about the factors that influence the risk for adverse effects. One potential source of variation in response to cannabinoids in women is circulating ovarian hormones such as estradiol and progesterone. Whereas there is some evidence that estradiol affects responses to cannabinoids in rodents, little is known about such interactions in humans. Here, we investigate whether variations in estradiol levels across the follicular phase of the menstrual cycle modulate the effect of THC on inhibitory control in healthy women. Healthy female occasional cannabis users (N = 60) received THC (7.5 mg and 15 mg, oral) and placebo during either the early follicular phase, when estradiol levels are low, or the late follicular phase, when estradiol levels are higher. They completed a Go/No Go (GNG) task at the time of peak drug effect. We hypothesized that the effects of THC on GNG performance would be greater when estradiol levels were elevated. As expected, THC impaired GNG task performance: it increased response time and errors of commission/false alarms and decreased accuracy, relative to placebo. However, these impairments were not related to estradiol levels. These results suggest that THC-induced impairments in inhibitory control are not affected by cycle-related fluctuations in estradiol levels.
Age-dependent effects of estradiol on temporal memory: A role for the type 1 cannabinoid receptor?
2023, Psychoneuroendocrinology
Citation Excerpt :
Accordingly, the levels of CB1-R mRNA transcript fluctuate throughout the estrous cycle and respond to E2 treatment in ovariectomized females (González et al., 2000). Moreover, estrogens affect CB1-R binding capacities (Riebe et al., 2010; Rodríguez de Fonseca et al., 1994) and/or protein contents in several brain regions, including the hippocampus (Reich et al., 2009). These E2-ECS interactions are endowed with behavioral consequences, as shown for E2-CB1-R interactions in the nucleus accumbens and in the prefrontal cortex where they impact cocaine sensitization and reinstatement in female rats (Doncheck et al., 2018; Peterson et al., 2016).
This study investigated in male mice how age modulates the effects of acute 17β-estradiol (E2) on dorsal CA1 (dCA1)-dependent retention of temporal associations, which are critical for declarative memory. E2 was systemically injected to young (3–4 months old) and aged (22–24 months old) adult mice either (i) 1 h before the acquisition of an auditory trace fear conditioning (TFC) procedure allowing the assessment of temporal memory retention 24 h later or (ii) during in vivo electrophysiological recordings of CA3 to dCA1 synaptic efficacy under anesthesia. In young mice, E2 induced parallel dose-dependent reductions in memory and synaptic efficacy, i.e. an impairment in TFC retention and a long-term (NMDA receptor-dependent) depression of dCA1 synaptic efficacy as assessed by field excitatory postsynaptic potentials. In contrast, E2 tended to improved TFC retention whilst failing to change synaptic efficacy in aged mice. Age-dependent effects of E2 treatment were confirmed by immunohistochemical analyses of TFC acquisition-elicited dCA1 Fos activation. Thus, such an activation was respectively reduced and enhanced in young and aged E2-treated mice, compared to vehicle treatments. Hippocampal mRNA expression of estrogen receptors by RT-PCR analyses revealed an age-related increase in each receptor mRNA expression. In keeping with the key role of the endocannabinoid system in memory processes and CA3 to dCA1 synaptic plasticity, we next examined the role of cannabinoid type 1 receptors (CB₁-R) in the aforementioned age-dependent effects of E2. Having confirmed that mRNA expression of CB₁-R diminishes with age, we then observed that the deleterious effects of E2 on both memory and synaptic efficacy were both prevented by the CB₁-R antagonist Rimonabant whilst being absent in CB₁-R knock out mice. This study (i) reveals age-dependent effects of acute E2 on temporal memory and CA3 to dCA1 synaptic efficacy and (ii) suggests a key role of CB₁-R in mediating E2 deleterious effects in young adulthood. Aging-related reductions in CB₁-R might thus underlie E2 paradoxical effects across age.
Alterations of the endocannabinoid system by endocrine-disrupting chemicals: Effects on metabolism and reproduction
2023, Environmental Contaminants and Endocrine Health
The endocannabinoid system (ECS) is a lipid signaling system involved in a plethora of different physiological processes such as appetite control, mood, metabolism, immune response, or reproduction. The ECS is composed by the endocannabinoids, the receptors to which the endocannabinoids bind, and the enzymatic machinery that tightly regulates the tissue levels of the endocannabinoids. This system has been described in different organs, including brain, liver, and gonads in different mammalian and nonmammalian species. Recently, several studies have linked ECS disorders to the exposure to endocrine-disrupting chemicals (EDCs). According to the World Health Organization, EDCs are exogenous substances or mixtures that alter the functions of the endocrine system and, consequently, may cause adverse health outcomes in the organisms or their progeny. Here, we will overview the emerging evidence supporting the alteration of the ECS, specifically, in its capability to control the hepatic lipid metabolism and reproductive fitness, following EDC exposure in different animal models.

View all citing articles on Scopus

View full text

Short communicationEstrogenic regulation of limbic cannabinoid receptor binding

Summary

Introduction

Section snippets

Subjects

Results

Discussion

Role of the funding sources

Conflict of interest

Acknowledgements

Eur. J. Pharmacol.

Biochem. Biophys. Res. Co.

Psychoneuroendocrinology

Behav. Brain Res.

Brain Res.

Behav. Brain Res.

Eur. J. Pharmacol.

Estrogen-regulated progestin receptors are found in the midbrain raphe but not hippocampus of estrogen receptor alpha (ER alpha) gene-disrupted mice

J. Comp. Neurol.

Modulation by female sex hormones of the cannabinoid-induced catalepsy and analgesia in ovariectomized rats

Eur. J. Pharmacol.

Short communication
Estrogenic regulation of limbic cannabinoid receptor binding