Learning theories of drug addiction propose that the disorder is, at least in part, attributable to drug effects on accumbal mechanisms that are normally involved in reward-related learning. The neurophysiological mechanisms that might transduce such a drug effect on accumbal mechanisms have yet to be identified. Previous studies showed that a population of accumbal neurons exhibit phasic excitatory responses time locked to cocaine-reinforced lever presses during intravenous cocaine self-administration sessions (neurons referred to as lever-press neurons). Most of the same neurons, like the majority of accumbal neurons, also show a decrease in average firing rate during the drug self-administration session. Evidence indicates that the phasic firing patterns transmit information related to drug-reward-related events. On the other hand, the decreases in average firing reflect a primary pharmacological effect of self-administered cocaine. In the present study, we tested the hypothesis that the phasic firing associated with drug seeking (i.e., signal) is less sensitive than other accumbal firing (i.e., background) to the inhibitory effect of cocaine. During intravenous cocaine self-administration sessions, 45 of 68 neurons showed a decrease in average firing during the self-administration session relative to a predrug baseline period. Fourteen neurons showed both an inhibition in average firing and an excitatory phasic response. For these 14 neurons, signal either remained equal to the average predrug firing rate or exceeded the predrug firing rate during the self-administration session. For the same neurons, background firing generally fell below average predrug firing. The differential changes in signal and background were associated with an increase in the ratio of signal-to-background for the individual neurons. Moreover, the relatively unique resistance of signal to inhibition was associated with an increase in the ratio of signal firing of all lever-press neurons relative to the background firing of all recorded neurons. This type of differential inhibition in signal and background firing might be expected to increase the relative influence of the drug-reward-related signals on accumbal-related neural circuits and differentially influence susceptibility of drug- and non-drug-reward-related synaptic and neural responses to neuroplasticity. It thus represents a mechanism by which inhibitory effects of self-administered drug might amplify the accumbal contribution to behavior and learning and potentially contribute to drug addiction.