Rats were administered either continuous cocaine, daily injections of cocaine, continuous amphetamine, or no drug for 5 days and then given a 30 day drug-free recovery period. When subsequently tested in open field, the daily cocaine injection animals were the most hyperactive whereas the cocaine pellet animals were the most fearful. In vitro autoradiography was then utilized to examine persisting changes in receptor binding for D2 ([3H]spiperone), D1 ([3H]SCH23390), benzodiazepine ([3H]flunitrazepam), 5-HT1 ([3H]5-HT), 5-HT2 ([3H]ketanserin), and muscarinic acetylcholine (ACh) receptors ([3H]QNB; quinuclidinyl benzilate). In the amphetamine pellet animals, there were large increases in [3H]spiperone binding in several dopamine (DA)-rich regions; these were accompanied by conversely decreased [3H]SCH23390 binding. Cocaine pellet animals showed a completely different pattern, with appreciable increases in [3H]flunitrazepam binding in DA-rich areas, cortex, and amygdala but decreased [3H]QNB binding in DA-rich areas, hippocampus, and amygdala. While cocaine injection animals showed elevated [3H]spiperone binding in caudate and substantia nigra, they had generally smaller changes in most brain regions than the other drug groups. These findings replicate and extend previous reports that continuous drug administration induces long-lasting alterations in brain chemistry, but indicate that continuous cocaine has enduring effects on different neurochemical systems from continuous amphetamine.