Jerrold C. Winter - US grants

Nearly all drugs of abuse are able to assume stimulus control in animals. This fact provides a sensitive and informative approach to the study of the mechanism of action of a variety of drugs habitually chosen for non-medical use by humans. On a different organizational level, recent developments in radioligand binding techniques have made it possible to identify and characterize the receptors for many drugs and endogenous neurotransmitters. The proposed investigation combines drug-induced stimulus control with receptor binding in a study of hallucinogens of the indoleamine type; drugs which are, for a variety of reasons, thought to exert their actions via 5-hydroxytryptamine (5-HT). 5-HT is widely believed to function as a neurotransmitter and to play a significant role in a variety of behaviors including sleep, sexual activity, appetite, mood, and psychosis. It is the changes in mood and perception that are responsible for the primary reinforcing properties, hence the abuse liability, of indoleamine hallucinogens such as LSD. In the proposed investigation, a variety of drugs thought to act as 5-HT agonists or antagonists will be studied in animals trained to discriminate the effects of either LSD or 5-HTP, the amino acid precursor of 5-HT. Each drug will be characterized as either an agonist or an antagonist and, based on its dose-response curve, either the ED50 or the AD50 will be calculated. Concomitantly, the binding of each drug to the 5-HT1 receptor in rat hippocampal tissue ((3H)5-HT) and the 5-HT2 receptor in rat cortical tissue (3H)ketanserin) will be measured. The affinities of the drugs will be determined by analysis of competition curves. Finally, the behavioral and receptor-binding data will be combined in a series of correlations, e.t., between the ED50's of agonists substituting for LSD and their affinities for the 5-HT1 receptor. In this way, the relative role of the receptor subtypes in the behavioral effects of the drugs will be determined. It is expected that the direct comparison of behavioral activities with reference to LSD, an exogenous 5-HT agonist, and 5-HTP, precursor for the endogenous agonist, will be particularly informative in that the pharmacological effects of LSD and 5-HTP are markedly different in humans.

DESCRIPTION: (Applicant's Abstract) The discovery by Albert Hoffmann more than fifty years ago of the hallucinogenic effects of LSD irreversibly altered the course of both biological psychiatry and popular culture. Part of Hofmann's legacy is found in the August 1996 Advance Report of the National Household Survey on Drug Abuse which shows a dramatic increase in the use of hallucinogens among children 12-17 years of age; without question, the hallucinogens are drugs of abuse. But among the drugs of abuse, hallucinogens are perhaps unique in that an understanding of their mechanisms of action will not only ameliorate the burdens of illicit use but may also provide a key to solving the puzzle of psychosis, another major human affliction. The present investigations seek to characterize and to distinguish indoleamine hallucinogens such as LSD and phenethylamine hallucinogens as exemplified by DOM in combined behavioral [drug-induced stimulus control] and biochemical [radioligand binding and second messenger] studies. Specifically, the proposed experiments will identify the second messenger systems which mediate the discriminative stimulus effects of LSD and DOM and will, in addition, identify those serotonergic receptors which may modulate the effects of hallucinogens. These studies will also be extended to include the related indoleamine hallucinogens, 5-methoxy-DMT and ibogaine. Finally, the potentiation of LSD and other hallucinogens by fluoxetine and related selective serotonin reuptake inhibitors will be examined. Taken together, the use of powerful methods for the assessment of in vivo efficacy [drug discrimination], of in vitro efficacy [stimulation or suppression of second messenger formation], and of affinities for specific receptors [radioligand binding] will provide new understanding of the mode of action of hallucinogens.

6. Project Summary/Abstract Hallucinogens of all types are subject to widespread abuse especially by adolescents and young adults in this country. Perhaps equally important is the possibility that these drugs may offer clues to the etiology of the most serious forms of mental illness. The long-term objectives of the present proposal are to characterize hallucinogens behaviorally and pharmacologically with the ultimate goal of establishing their mechanisms of action. Although they are united by a common term, hallucinogen, these drugs represent distinct pharmacological entities. Lysergic acid diethylamide [LSD] is chemically and pharmacologically quite different from the simpler indoleamines represented by DMT and psilocybin. Indeed, in terms of a presumed receptor mechanism of hallucinogenic action, LSD more closely resembles a phenethylamine such as mescaline. Nonetheless, all of these drugs are joined by prominent activity via serotonergic [5- hydroxytryptaminergic] mechanisms. Until recently, the same could not be said for phencyclidine [PCP, Angel Dust]. However, a unifying serotonergic-glutamatergic mechanism is beginning to emerge with the hypothesis that glutamate release may represent a final common pathway for hallucinogens. Nonetheless, to say that all of these drugs are somehow serotonergic in nature obscures the fact that 14 distinct serotonergic receptors are known, each with a distinct neuroanatomic distribution and array of functions. The decision to focus in the present proposal on, 5-HT2c, 5-HT7, 5-HT2~a,n d 5-HTqAr eceptors is based upon suggestive pharmacological and behavioral evidence, which links these receptors to hallucinogenesis. The primary behavioral index will continue to be the stimulus effects of hallucinogens in rodents, effects widely believed to have significant subjective correlates in humans. In addition, hallucinogens will be characterized using in vivo microdialysis to correlate glutamate release with behavioral activity. It is expected that integration of the resulting data will provide new understanding of the mode of action of hallucinogens, especially those subject to abuse. In addition, these studies may contribute to our understanding of the most serious forms of mental illness including anxiety, depression, and psychosis. Finally, the role of the internet in expanding interest in these and other club drugs such as MDMA [Ecstasy] especially among youthful segments of society is inestimable but will almost certainly lead to increased illicit use. This likelihood coupled with continued interest in the therapeutic use of agents such as psilocybin makes a detailed pharmacological assessment of these drugs of utmost importance.