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.