In recent years, considerable focus has been directed to understanding how drugs of abuse affect neuronal function at the molecular level. For example, repeated administration of stimulants or opiates can induce long-lasting alterations in gene expression, transcription factors, and signal transduction pathways. Our laboratory previously showed that intraaccumbens infusion of cholera toxin (CTX), which alters the Gs protein such that production of cyclic Adenosine Monophosphate (AMP) is upregulated, causes pronounced, long-lasting motor activation and sensitization to stimulants. In the present experiments, the effect of intraaccumbens infusion of cholera toxin on reward-related responding was investigated. The conditioned reinforcement (CR) paradigm was employed, which measures an animal's instrumental response to obtain presentation of a stimulus previously paired with a primary reward. When this stimulus supports acquisition of a new operant response (lever-pressing), it is termed a conditioned reinforcer (CR). In the first experiment, the effects of bilateral intraaccumbens infusion of CTX (100 ng/1 microliter) were examined on previously-established responding. CTX treatment resulted in enhanced responding for the CR. This enhancement developed over several days and reached its peak 3 days following infusion. In the second experiment, the influence of CTX was examined on acquisition of responding for the CR. The group treated with CTX (100 ng) discriminated between the CR and control (NCR) lever earlier than the vehicle-infused group, and showed greater levels of responding on the CR lever. In the third experiment, it was determined that infusion of CTX (300 ng bilaterally) into the anterior dorsal striatum did not affect levels of responding, although a later test with cocaine in these animals (25 mg/kg, intraperitoneally) (i.p.) indicated that they were capable of potentiated responding. These data are interpreted as evidence that the G(S) protein-cyclic AMP second messenger system within the nucleus accumbens is directly involved in reward-related behavior.