It was recently reported that acute cocaine pretreatment can reduce the (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced 5-hydroxytryptamine2 (5-HT2)-receptor mediated head-twitch response (HTR) in mice via indirect stimulation of adrenergic alpha 2- and serotonergic 5-HT1A-receptors. The aim of the present investigation was to determine whether cocaine can alter the DOI-induced HTR in 5-HT2-receptor supersensitive mice. Supersensitivity was induced by a single injection of DOI 48 h prior to experimentation. These supersensitive mice exhibited a greater frequency of HTR to a challenge dose of DOI 48 h after its initial administration. Cocaine pretreatment dose-dependently reduced the DOI-induced HTR in the supersensitive mice. The stimulant was approximately four times more potent in the 5-HT2-receptor supersensitive mice relative to its reported effects in normal mice. Receptor blockade studies with yohimbine and alprenolol revealed that both of the inhibitory components of cocaine's actions (i.e., adrenergic alpha 2- and serotonergic 5-HT1A-receptor effects, respectively) were more efficient in reducing the DOI-induced HTR in supersensitive mice compared to normosensitive animals. The present results further support the previously suggested hypothesis that acute cocaine administration inhibits the 5-HT2-receptor function by increasing the synaptic concentration of norepinephrine and serotonin via inhibition of their uptake and therefore indirectly stimulating the respective inhibitory adrenergic alpha 2- and serotonergic 5-HT1A-receptors.