Role of Gonadal Steroids in the Corticotropin-Releasing Hormone and Proopiomelanocortin Gene Expression Response to Δ⁹-Tetrahydrocannabinol in the Hypothalamus of the Rat

Abstract

Chronic exposure to Δ⁹-tetrahydrocannabinol (Δ⁹-THC) increases corticotropin-releasing hormone (CRH) and proopiomelanocortin (POMC) gene expression in the rat hypothalamus. The levels of circulating gonadal steroids concurrently modulate both neuropeptides in male and female rats. However, it remains unknown whether gonadal steroids regulate Δ⁹-THC effects on CRH and POMC gene expression in the hypothalamus of male and female rats. To explore this hypothesis, experiments were conducted on intact, 2-week-gonadectomized, 1-week-gonadectomized, 1-week-dihydrotestosterone (DHT)- or estradiol-replaced male and female rats. One week after hormonal replacement, animals were treated with vehicle or Δ⁹-THC (5 mg/kg/day, i.p. for 7 days). Administration of Δ⁹-THC to intact male rats increased CRH gene expression. Castration abolished Δ⁹-THC effects of CRH gene expression in males but not in females. On the other hand, POMC mRNA levels were reduced as a result of castration, and DHT treatment did not prevent this decrease. Δ⁹-THC treatment similarly increases POMC gene expression of intact, orchidectomized and DHT-replaced males. In females, ovariectomy decreased CRH gene expression. Δ⁹-THC administration increased CRH gene expression to the same extent in castrated and estradiol-replaced rats. On the other hand, POMC gene expression was increased by ovariectomy, and Δ⁹-THC administration did only increase POMC transcript levels in the estradiol-replaced group. These data show that gonadal steroids differentially regulate the effects of Δ⁹-THC on both CRH and POMC gene expression in the hypothalamus of male and female rats, suggesting gender differences in the reaction to cannabinoids.

Sex differences in cannabinoid-regulated biology: A focus on energy homeostasis

“…It therefore stands to reason that cannabinoids acutely enhance inhibitory tone onto POMC neurons to a greater extent in males than they do in females. This would be consistent with the findings of Corchero and co-workers, who demonstrated that chronically administered THC increased POMC gene expression more robustly in male rats than in female rats (Corchero et al, 2001). …”

Estrogen Differentially Modulates the Cannabinoid- Induced Presynaptic Inhibition of Amino Acid Neurotransmission in Proopiomelanocortin Neurons of the Arcuate Nucleus

“…The ability of estrogen to both negatively modulate GABA B receptor/effector coupling and positively modulate the cannabinoid-induced presynaptic inhibition of GABA A receptor-mediated synaptic input effectively results in two ways in which the steroid can diminish GABAergic synaptic input onto POMC neurons. Moreover, estrogen upregulates AMPA receptors in the ARC [13] and facilitates alterations in POMC gene expression caused by chronic cannabinoid exposure [20]. Furthermore, the ability of estrogen to negatively modulate the cannabinoid-induced presynaptic inhibition of glutamate synaptic input observed in the results of the present study is consistent with the steroid’s potentiation of kainate currents in hippocampal neurons [56].…”

“…In addition, estrogen modulates N-methyl- D -aspartate (NMDA) and ĸ-opioid receptor-mediated regulation of A 12 dopamine neuronal activity [14, 15]. Furthermore, estrogen attenuates the coupling of metabotropic µ-opioid and γ-aminobutyric acid (GABA) B receptors to their effector K + channels in ARC POMC neurons [16, 17], which is instrumental in the negative feedback effects of the steroid on the reproductive axis [18, 19], and also exerts a permissive influence on the ability of cannabinoids to alter POMC gene expression [20]. …”

Sex Differences in the Cannabinoid Modulation of Appetite, Body Temperature and Neurotransmission at POMC Synapses

“…The fact that we also observed frank sexual disparities in the cannabinoid modulation of core body temperature is suggestive of an impressive capacity to influence a broader, more global array of sex differences in the hypothalamic control of homeostasis. Indeed, the cannabinoid regulation of preproCRH and POMC gene expression in the PVN and ARC, respectively, is sexually differentiated [39]. In addition, it is in accordance with broad-based inequities in the cannabinoid-induced antinociception [1, 2], locomotor effects [1,2,3], hemodynamic effects [4, 7], impairment of visuospatial memory [5], subjective ratings of intoxication [7] and interactions with other drugs of abuse [7, 40] that have been reported between males and females.…”