AbstractInsulin‐like growth factor‐I (IGF‐I) has protective effects against β‐amyloid (Aβ)‐induced neuronal cell death. Because alterations of the somatostatinergic system have been described in Alzheimer's disease, we investigated the effects of the Aβ peptide and the possible protective role of IGF‐I on the somatostatinergic system of the rat temporal cortex and on cell death and phosphorylated (p)‐Akt levels in this area. Aβ25–35 was administered intracerebroventricularly to male rats via an osmotic minipump over 14 days (300 pmol/day). Another group received a subcutaneous IGF‐I infusion (50 μg/kg/day), concomitant with Aβ25–35 administration, whereas a third group received IGF‐I alone. Aβ25–35 significantly decreased the somatostatin (SRIF)‐like immunoreactive content and the SRIF receptor density, as a result of a decrease in the levels of the SRIF receptor subtype 2. The inhibitory effect of SRIF on adenylyl cyclase activity was significantly lower after Aβ25–35 infusion, whereas the levels of the inhibitory G protein subunit Giα1, Giα2 or Giα3 were unaltered. Cell death was increased and p‐Akt levels decreased in Aβ25–35‐treated animals. IGF‐I administration increased immunoreactive IGF‐I levels in the temporal cortex and restored all parameters affected by Aβ25–35 to baseline values. These findings suggest that IGF‐I prevents the deleterious effect of Aβ25–35 on the somatostatinergic system.