Progesterone receptor and dopamine receptors are required in Δ ⁹ -tetrahydrocannabinol modulation of sexual receptivity in female rats

Abstract

Ovarian steroids, estrogen and progesterone, influence the sensitivity of certain neural processes to cannabinoid treatment by modulation of brain dopaminergic activity. We examined the effects of the active ingredient of cannabis, ⌬ 9 -tetrahydrocannabinol (THC), on sexual behavior in female rats and its influence on steroid hormone receptors and neurotransmitters in the facilitation of sexual receptivity. Our results revealed that the facilitatory effect of THC was inhibited by antagonists to both progesterone and dopamine D 1 receptors. To test further the idea that progesterone receptors (PR) and͞or dopamine receptors (D1R) in the hypothalamus are required for THCfacilitated sexual behavior in rodents, antisense and sense oligonucleotides to PR and D 1R were administered intracerebroventricularly (ICV) into the third cerebral ventricle of ovariectomized, estradiol benzoate-primed rats. Progesterone-and THC-facilitated sexual behavior was inhibited in animals treated with antisense oligonucleotides to PR or to D 1R. Antagonists to cannabinoid receptor-1 subtype (CB 1), but not to cannabinoid receptor-2 subtype (CB2) inhibited progesterone-and dopamine-facilitated sexual receptivity in female rats. Our studies indicate that THC acts on the CB 1 cannabinoid receptor to initiate a signal transduction response that requires both membrane dopamine and intracellular progesterone receptors for effective induction of sexual behavior.transcription factors ͉ cannabinoids ͉ signal transduction cross talk T he major psychoactive cannabinoid in marijuana, ⌬ 9 -tetrahydrocannabinol (THC), alters many reproductive parameters in both male and female laboratory animals and humans (1). In males, THC has been reported to reduce testosterone concentrations in the plasma (2, 3), suppress spermatogenesis, reduce the weight of testes and accessory reproductive organs (4), and decrease components of male sexual behavior (5-7). In the females, THC has been demonstrated to prolong estrous cycle of rats (8), decrease proestrous luteinizing hormone (LH) surge leading to inhibition of ovulation (9, 10), and stimulate sexual behavior (11,12). THCmediated effects on central dopaminergic systems lead to increased extracellular dopamine concentration (13). These effects on brain dopaminergic activity vary as a function of the gonadal status of the animal (14). Furthermore, ovarian sex steroid hormones also alter the density and affinity of cannabinoid (CB) receptors in steroidsensitive brain areas, suggesting that ovarian steroid hormones could alter the sensitivity of certain neuronal processes to THC treatment.Ovarian steroid hormones, estrogen (E) and progesterone (P), regulate cellular functions in the brain that control sexual behavior in the female rat (15, 16). Estrogen priming causes an increase in progesterone receptor (PR) levels in the hypothalamus and preoptic areas of the rat brain (17). We and others previously have demonstrated a critical role for hypothalamic PRs in the induction of sexual behavior by using PR antagonists and...

N-Acylethanolamines in human reproductive fluids

“…These factors may account, in part, for the effects of marijuana and THC on secretion of gonadotrophic hormones and gonadal steroids, sperm production, ovulation, mating behavior, sperm capacitation, fertilization, early embryonic development; implantation of blastocysts into the uterine endometrium, placental functions, fetal growth, number of pregnancies carried to term, postnatal development, tumor growth, etc. (Powell and Fuller, 1983;Maykut, 1985;Smith and Asch, 1987;Astley and Little, 1990;Murphy et al, 1994;Maccarrone et al, 2000;Fried and Smith, 2001;Paria and Dey, 2000;Mani et al, 2001;Paria et al, 2001;Schuel et al, 2002). Collectively, these observations suggest that endocannabinoids may be normal physiological constituents of human reproductive fluids.…”

Evidence that anandamide‐signaling regulates human sperm functions required for fertilization

“…Similarly, our results imply that addition of exogenous cannabinoids from marijuana smoke may flood endogenous AEA-signal systems in female reproductive tracts, thereby impacting fertility in women who abuse marijuana. Consequently, our study has potential ramifications for clinical medicine and public policy because of marijuana abuse in our society (Turner et al, 1998), known effects of cannabinoids on reproductive functions (Powell and Fuller, 1983;Smith and Asch, 1987;Murphy et al, 1994;Schuel et al, 1999;Paria and Dey, 2000;Mani et al, 2001;Paria et al, 2001), and ongoing debates about medicinal use of marijuana.…”

“…THC and/or AEA affect all reproductive functions studied thus far, including: secretion of pituitary gonadotrophic hormones and gonadal steroids; sperm production; ovulation; mating behavior; early embryonic development; implantation of blastocysts into the uterine endometrium; fetal growth; number of pregnancies carried to term, etc. (Powell and Fuller, 1983;Maykut, 1985;Smith and Asch, 1987;Murphy et al, 1994;Schuel et al, 1999;Maccarrone et al, 2000;Paria and Dey, 2000;Mani et al, 2001;Paria et al, 2001).…”

Reproductive tissue selective actions of progesterone receptors

“…Studies using tissue culture systems have revealed that PRs as well as some other nuclear receptors can be activated in a ligand-independent manner by stimuli that modulate intracellular kinase activity (Denner et al 1990, Aronica & Katzenellenbogen 1991, Beck et al 1993, Sartorius et al 1993. The physiological relevance of a progesterone-independent mechanism of receptor activation has been substantiated in vivo: PR-mediated lordosis behavior exhibited by rats (Mani et al 2001) and mice (Mani et al 1996) can be stimulated either in response to progesterone or in the absence of progesterone by dopamine-activated intracellular signaling pathways.…”