The effects of acute and chronic cocaine (40 mg/Kg i.p.) in vivo administration, on 125I-Tyr11-somatostatin binding and somatostatin-like immunoreactivity (SLI) in the rat frontoparietal cortex, hippocampus and olfactory bulb were explored. Acute and chronic cocaine administration did not affect the levels of SLI in the three brain areas studied. Acute cocaine administration resulted in an 55% and 32% decrease in the total number of specific somatostatin receptors in the hippocampus and olfactory bulb respectively, but not in the frontoparietal cortex. Somatostatin receptor affinity increased in the hippocampus and was unaltered in frontoparietal cortex and olfactory bulb. After two weeks of daily cocaine injections the somatostatin binding in the hippocampus and olfactory bulb returned to control values. The in vitro addition of cocaine to a brain membrane preparation obtained from untreated rats did not markedly affect somatostatin binding characteristics. These results are suggestive of a possible role for somatostatin in the limbic structures as a response to cocaine administration.