To understand the capacity of growth hormone-releasing hormone (GHRH) to regulate expression of the GHRH receptor, we studied the effects of GHRH on GHRH receptor mRNA expression in immature and adult rats by use of pituitary cell culture and immunoneutralization approaches. Pituitary cell cultures from neonatal (2-day-old) and adult (70-day-old) rats were treated with GHRH for 4, 24, or 72 h. The effect of GHRH on GHRH receptor mRNA expression depended on the duration of GHRH exposure in both age groups; short-term (4 h) GHRH treatment significantly reduced GHRH receptor mRNA expression (P < 0.05), whereas intermediate treatment (24 h) restored GHRH receptor mRNA to basal levels, and long-term treatment (72 h) stimulated GHRH receptor mRNA expression (P < 0.02). The long-term stimulatory effect of GHRH on GHRH receptor mRNA expression required the presence of serum in the culture medium, and, in the absence of serum, the stimulatory effect was completely abolished. Moreover, the capacity of the pituitary to increase GHRH receptor mRNA expression in response to 72-h GHRH treatment was age dependent, with neonatal pituitaries exhibiting a much greater stimulatory effect than adult pituitaries (P < 0.025). Immunoneutralization of endogenous GHRH significantly reduced GHRH receptor mRNA expression in neonatal (P < 0.004), juvenile (P < 0.003), and mature (P < 0.004) pituitaries compared with age-matched controls. Taken together, these results indicate that GHRH is a potent regulator of GHRH receptor gene expression in immature and mature pituitaries; however, the nature and direction of GHRH regulation of its receptor depend significantly on several variables, including the duration of GHRH exposure, the presence of permissive components in serum, and the developmental stage of the pituitary.