Studies of the basic mechanisms of the effects of cocaine have utilized several behavioral procedures. The stimulant effects of cocaine are assessed in studies of locomotor activity in rodents, as well as studies of learned operant behavior. In addition, the subjective effects of cocaine are examined in studies of the discriminative stimulus effects, and reinforcing effects of cocaine. Additional studies are conducted assessing cocaine overdose toxicity in which the lethal and convulsive effects of cocaine are assessed. Initial studies have investigated the roles of dopamine receptor subtypes in the effects of cocaine. These studies have indicated that both D1 and D2 receptor systems appear to be involved in the discriminative effects of cocaine, however, agonist actions at only one of these receptors does not appear to be sufficient to fully reproduce the subjective effects of cocaine. Results of these studies are forming the basis for further studies that will examine the effects of several of these dopaminergic agents on cocaine self-administration. Previous studies from this laboratory have indicated that the toxic effects of cocaine may be primarily mediated by actions at D1 dopamine receptors. Recent further studies have indicated that these toxic effects of cocaine appear to principally involve peripheral rather than central nervous system mechanisms. The toxic effects of cocaine may be influenced by actions mediated by several other neurotransmitter systems besides the dopamine system. Studies have indicated that agonist actions at mu-opioid receptors can protect against the lethal effects of cocaine. This action may be the basis for the potential therapeutic effects of buprenorphine as a cocaine abuse treatment. In addition, the convulsive effects of cocaine can be attenuated by the administration of excitatory amino acid antagonists, as well as modulators of these systems. Other studies have investigated the behavioral and physiological effects of repeated administration of cocaine. The tolerance that develops to the effects of cocaine on learned operant behavior is relatively minor compared to that occurring with other drugs of abuse. It appears that learning plays a significant role in the development of tolerance to cocaine. Along with that tolerance there can be physiological changes. Repeated injections of cocaine can produce a hyper-prolactinemia, and increases neurotensin binding in the prefrontal cortex (where neurotensin is co-localized with dopamine). Preliminary results also indicate that binding to the dopamine transporter is decreased in the nucleus accumbens.