Slow-wave sleep, wakefulness, locomotor activity and learning and memory are regulated in similar ways by somatostatin (SS) and histamine. To clarify the possible role of endogenous histamine on the somatostatinergic system of the rat frontoparietal cortex, we studied the effect of 50 μg of α-fluoromethylhistidine (α-FMH), a specific inhibitor of histidine decar☐ylase, administered intracerebroventricularly (i.c.v.) at 1, 4 and 6 h, on somatostatin-like immunoreactivity (SSLI) content and the SS receptor/effector system. The histamine content in the frontoparietal cortex decreased to about 67, 60 and 72% of control values at 1, 4 and 6 h after α-FMH administration, respectively. At 6 h after α-FMH injection, there was an increase in SSLI content and a decrease in the number of SS receptors, with no change in the apparent affinity. No significant differences were seen for the basal and forskolin (FK)-stimulated adenylyl cyclase (AC) activities in the frontoparietal cortex of α-FMH-treated rats when compared to the control group at all times studied. At 6 h after α-FMH administration, however, the capacity of SS to inhibit basal and FK-stimulated AC activity in the frontoparietal cortex was significantly lower than in the control group. The ability of the stable GTP analogue 5′-guanylylimidodiphosphate (Gpp(NH)p) to inhibit FK-stimulated AC activity in frontoparietal cortex membranes was the same in the α-FMH-treated (6 h) and control animals. Therefore, the decreased SS-mediated inhibition of AC activity observed in the α-FMH-treated rats is not due to an alteration at the guanine nucleotide-binding inhibitory protein (G i ) level but rather may be due to the decrease in the number of SS receptors. Taken together, these data suggest that α-FMH influences the sensitivity to SS in the rat frontoparietal cortex.