In this study, the spontaneous dwarf rat (SDR) has been used to examine GHRH production and action in the selective absence of endogenous GH. This dwarf model is unique in that GH is not produced because of a point mutation in the GH gene. However, other pituitary hormones are not obviously compromised. Examination of the hypothalamic pituitary-axis of SDRs revealed that GHRH messenger RNA (mRNA) levels were increased, whereas somatostatin (SS) and neuropeptide Y (NPY) mRNA levels were decreased, compared with age- and sex-matched normal controls, as determined by Northern blot analysis (n = 5 animals/group; P < 0.05). The elevated levels of GHRH mRNA in the SDR hypothalamus were accompanied by a 56% increase in pituitary GHRH receptor (GHRH-R) mRNA, as determined by RT-PCR (P < 0.05). To investigate whether the up-regulation of GHRH-R mRNA resulted in an increase in GHRH-R function, SDR and control pituitary cell cultures were challenged with GHRH (0.001-10 nM; 15 min), and intracellular cAMP concentrations were measured by RIA. Interestingly, SDR pituitary cells were hyperresponsive to 1 and 10 nM GHRH, which induced a rise in intracellular cAMP concentrations 50% greater than that observed in control cultures (n = 3 separate experiments; P < 0.05 and P < 0.01, respectively). Replacement of GH, by osmotic minipump (10 microg/h for 72 h), resulted in the suppression of GHRH mRNA levels (P < 0.01), whereas SS and NPY mRNA levels were increased (P < 0.05), compared with vehicle-treated controls (n = 5 animals/treatment group). Consonant with the fall in hypothalamic GHRH mRNA was a decrease in pituitary GHRH-R mRNA levels. Although replacement of insulin-like growth factor-I (IGF-I), by osmotic pump (5 microg/h for 72 h), resulted in a rise in circulating IGF-I concentrations comparable with that observed after GH replacement, IGF-I treatment was ineffective in modulating GHRH, SS, or NPY mRNA levels. However, IGF-I treatment did reduce pituitary GHRH-R mRNA levels, compared with vehicle-treated controls (P < 0.05). These results further validate the role of GH as a negative regulator of hypothalamic GHRH expression, and they suggest that SS and NPY act as intermediaries in GH-induced suppression of hypothalamic GHRH synthesis. These data also demonstrate that increases in circulating IGF-I are not responsible for changes in hypothalamic function observed after GH treatment. Finally, this report establishes modulation of GHRH-R synthesis as a component of GH autofeedback regulation.