Studies were conducted to identify neuroeffector systems involved in behavioral sensitization to cocaine-induced stereotypy in mice, and to compare the results with those from our previous amphetamine studies. The effects of eight relatively selective neuroeffector agonists and antagonists were measured in mice in order to identify specific functional changes associated with the sensitization. In contrast to amphetamine, the only neuroeffector response altered by cocaine sensitization was a decrease in convulsive threshold to kainate. The persistence of the change in convulsive threshold correlated with the persistence of behavioral sensitization. The induction of sensitization was blocked by pretreatment with four different classes of drugs, represented by haloperidol, dizocilpine, diltiazem and DNQX. These results suggest that the mechanism of induction to cocaine is similar to that of amphetamine; both the glutamate and dopaminergic systems appear to be involved in induction. The expression of the sensitized cocaine response was blocked by haloperidol, CPP and diltiazem. These results differed from those obtained previously insofar as CPP did not affect the expression of sensitization to amphetamine. Furthermore, DNQX, in contrast to its antagonism of the expression of amphetamine sensitization, did not affect the expression of cocaine sensitization. The pharmacological data suggest that the mechanism of induction differs from that of expression, and that the mechanism of expression for cocaine sensitization differs from that for amphetamine.