We investigated the ability of a moderately intoxicating dose of alcohol (3 g/kg, injected i.p. 3 h earlier) to up-regulate the genetic expression of CRF receptor type 1 (CRF-R1) and 2 (CRF-R2alpha) in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus as well as in the amygdala. The mRNA encoding CRF-R1 was not constitutively expressed in the PVN or the SON but was present in the amygdala. Alcohol selectively up-regulated CRF-R1 transcripts in the PVN. Basal levels of CRF-R2alpha transcripts were present in the limbic system and the ventromedial hypothalamic nucleus but were not altered by alcohol. We then determined whether the up-regulation of hypothalamic CRF-R1 mRNA levels was functionally connected to CRF-dependent pathways. We first showed that the i.c.v. injection of CRF significantly (P < 0.01) increased CRF-R1 but not CRF-R2alpha mRNA levels. We then injected the CRF antagonist, astressin, i.c.v. 30 min prior to alcohol, at a dose previously shown to completely block many CRF-dependent events in the brain, and found that it did not significantly interfere with-alcohol-induced gene expression of PVN CRF-R1. These results indicate that acute alcohol treatment selectively activates CRF-R1 in the endocrine hypothalamus and that this response does not appear to depend on the stimulation of CRF receptors. In contrast, no up-regulation of CRF-R1 or CRF-R2alpha gene expression was observed in extrahypothalamic regions thought to participate in the behavioral influence of alcohol.