Systemic administration of the phenethylamine hallucinogen 2,5-dimethoxy-4-methylamphetamine (DOM) has previously been shown to decrease spontaneous activity but increase the response to peripheral nerve stimulation of locus coeruleus (LC) neurons in anesthetized rats. Five antipsychotic drugs (spiperone, chlorpromazine, clozapine, haloperidol, and sulpiride) were tested for their ability to antagonize these effects of DOM in the LC. Spiperone, chlorpromazine, clozapine, and haloperidol were able to completely reverse the effects of a standard dose of DOM, while sulpiride was ineffective. The ED100s for reversing the effects of DOM showed a significant correlation only with the previously shown binding affinity for 5-HT2 receptors. These results suggest that certain types of antipsychotic drugs have activity as 5-HT2 antagonists in vivo.