254 ▪ PROGRESS IN CLINICAL NEUROSCIENCE Activation is Hallucinogenic and Antagonism is Therapeutic: Role of 5-HT 2A Receptors in Atypical Antipsychotic Drug Actions BRYAN L. ROTH, DAVID L. WILLINS, KURT KRISTIANSEN, and WESLEY K. KROEZE Departments of Psychiatry (BLR), Biochemistry (BLR, DLW, KK, WKK), and Neurosciences (BLR) Case Western Reserve University Medical School Cleveland, Ohio This review summarizes recent studies with 5-hydroxytryptamine 2A (5-HT 2A ) receptors, which represent the major site of action of hallucinogens and a likely site for atypical antipsychotic drug actions. We present evidence demonstrating that atypical antipsychotic drugs, as a group, have a preferentially high affinity for 5-HT 2A receptors, compared with their affinities for other neurotransmitter receptors. The 5-HT 2A receptor blockade seen with atypical antipsychotic drugs is probably an essential factor in explaining many of the unique features of atypical antipsychotic drugs. Atypical antipsychotic drugs have high affinities for several other 5-HT receptors (5-HT 2C , 5-HT 6 , and 5-HT 7 ), and the potential role of these novel 5-HT receptors in atypical antipsychotic drug action is also summarized. Hallucinogens are the second major class of drugs that exert their actions by binding to 5-HT 2A receptors. Studies are summarized that provide novel insights into the mechanism of action of hallucinogens at the molecular and atomic level. Two models of hallucinogen action, one atomic, the other thermodynamic, are advanced to explain various aspects of hallucinogen actions at 5-HT 2A receptors. Finally, a summary of studies demonstrating that 5-HT 2A receptors are regulated in a paradoxical manner is presented. Particular attention is paid to recent findings suggesting that both agonists and antagonists may induce receptor internalization. We propose that receptor redistribution may underlie many of the ther- apeutic actions of atypical antipsychotic drugs in vivo. NEUROSCIENTIST 5:254-262, 1999 KEY WORDS Atypical antipsychotic drugs, Clozapme, 5-HT 2A receptors, Serotonin Arguably, the birth of psychopharmacology occurred with the accidental discovery by a Swiss chemist that lysergic acid diethylamide (LSD) was a potent hallucin- ogen. The realization that the simple ergoline LSD al- tered the way in which people perceived reality led to the strikingly obvious hypothesis that consciousness might be chemically encoded. A clue to how this might occur came from the observations of Wooley and Shaw (1) that LSD and related hallucinogens had serotonin (5-hydroxytryptamine; 5-HT) embedded in their struc- tures. Wooley and Shaw proposed that because hallucinogens are structurally related to LSD, and be- cause schizophrenia is a disease exemplified by hallu- This work was supported by National Institutes of Health Grants ROI-MH57635, K02-MH01366, the Scottish Rite Schizophrema Re- search Foundation (all to B.L.R) and the National Alhance for Research m Schizophrema and Depression (to D.L.W.). D L.W. was supported by a National Alliance for Research m Schizophrema and Depression Young Investigator Award. Address reprint requests to: Bryan L. Roth, M.D., Ph.D., Room W438, Department of Biochemistry, Case Western Reserve Umversity Medical School, 10900 Euclid Avenue, Cleveland, OH 44106-4935 (E-mail: roth@biocserver.cwru edu). cinations, then schizophrenia must be a disease involv- ing serotonin. The ’serotonin hypothesis of schizophrenia’ was later discarded in favor of the ’dopamine hypothesis of schizophrenia’ because of several observations that im- plicated dopamine (DA) in antipsychotic drug actions. Additionally, clinical evidence suggested that the syn- drome elicited by hallucinogens was quite distinct from that seen in schizophrenia (2). The dopamine hypothesis of schizophrenia led to the development of a large num- ber of typical antipsychotic drugs. These drugs, although effective in treating certain core symptoms of schizo- phrenia, frequently induced serious side effects, includ- ing parkinsonism and other extrapyramidal symptoms, tardive dyskinesia, acute and tardive dystonias, and ak- athisia. Additionally, typical antipsychotic drugs, which are characterized by having potent D2 dopamine recep- tor antagonist activity, were ineffective in a significant number of patients. The recognition that clozapine was effective without having motor side effects or appreciable affinity for ei- ther the D 1 or D2 dopamine receptors has led to a reev- aluation of the dopamine hypothesis of schizophrenia