Lewis Stanford Seiden - US grants

The ultimate goal of this proposed research is to understand the role of brain neurotransmitter systems in the actions of psychotropic drugs and in the maintenance of behavior. The research will focus on the behavioral involvement of dopamine, norepinephrine, and 5-hydroxytryptamine. Behavior will be measured using a computer-controlled real-time data application system. The research will employ two closely related parallel approaches. In the first approach, a sensitive and specific operant behavioral screen that detects drugs with antidepressant action will be used to determine the catecholaminergic and serotonergic components of antidepressant drugs effects. Also, studies will be done to determine whether norepinephrine, dopamine and 5-hydroxytryptamine systems interact to produce antidepressant effects. The goal of this research is to elucidate the neurochemical changes that mediate antidepressant drug effects on operant behavior. Knowledge of these neurochemical changes could provide insight into the pathophysiology of depression. For the second approach, studies will be done to determine the neurochemical mechanisms that mediate interactions between drugs, behavior and the environment. Drug effects on behavior depend not only on the specific drug and dose of the drug, but also depend on the environment in which the drug is administered and on the ongoing behavior. Therefore, neurochemical change will be measured as a function of systematically varied environmental and behavioral parameters. Knowledge of environmental and behavioral parameters as independent variables that alter brain chemistry would provide additional insight into the pathophysiology of mental illness.

The first long-range aim of the proposed research is to understand the role central nervous system neurotransmitter systems play in the action of psychotropic drug effects and in the maintenance of behavior. We will focus on dopamine (DA), norepinephrine (NE) and 5-hydroxytryptamine (5HT), and their relationship to operant behavior. Feeding, drinking and locomotion will also be studied since they are important components of operant behavior. The actions of neurotransmitters will be modified by drugs and/or neurotoxins. Behavior will be measured using computer-oriented techniques. We will measure changes in neuro-transmitter systems that occur when operant behavior is modified by administration of antidepressant drugs. The goal of this research is to elucidate changes in central nervous system neurochemistry which lead to changes in behavior and which may be involved in the pathophysiology of depression. We will measure the changes in transmitter turnover as a function of behavior that may account for drug-behavior-environment interactions to further understand the relative roles of drugs and the environment in modifications of behavior. The second aim of the proposed research is to determine whether the long-term alternations in monoamine levels and morphological signs of degeneration demonstrated previously in our research on the neurotoxicity of methamphetamine, is also produced by other prescribed or abused anorectics and psychomotor stimulants. Benzphetamine, phenmetrazine, phendimetrazine, phentermine, chlortermine and cocaine will be examined for neurotoxicity. We will study long-term behavioral changes associated with monoaminergic toxicity produced by methamphetamine and hallucinogenic amphetamine analogs, including 3,4-methylenedioxyamphetamine (MDA) and 3,4- methylenedioxymethamphetamine (MDMA), and cocaine. The third aim is to examine in detail the mechanism by which methamphetamine and related drugs produce neurotoxic effects. Our results to date have indicated that 6-hydroxydopamine (6- OHDA) and 5,6-dihydroxytryptamine (5,6-DHT) are formed in brain after a large dose of methamphetamine. We propose to confirm that 6-OHDA and 5,6-DHT are formed in the brain from DA or 5HT using gas chromatography and mass spectrometry. We shall also study the conditions under which this reaction occurs in vitro, ex vivo, and in vivo.

The Drug Abuse Research Center: 1) provides a formal structure designed to encourage the cooperation of basic research scientists and clinical researchers in problem-oriented research 2) encourages communication among basic research scientists working in related fields 3) promotes the development and/or expansion of certain key areas in drug abuse research and 4) provides an interdisciplinary educational environment for students and faculty interested in various areas of drug abuse research. The philosophy of the Research Center is that drug abuse is a complex problem which needs to be studied on a variety of levels ranging from a drug's sub-cellular actions throuch its sociological impact. It is impossible for any single department, or individual, to possess the expertise to study drugs at all these levels. The Research Center has aimed to provide a formal structure for encouraging interaction between scientist and clinicians from several academic departments, all of whom are working in areas related to drug abuse. Current research includes studies on: 1) the reinforcing properties of diazepam 2) self-administration of sedative-hypnotics via the intragastric route 3) the effects of deprivation and punishment on drug self-administration 4) neuroleptic-stimulant interactions 5) drug tolerance and 6) the stimulus properties of a broad range of psychomotor stimulants.

The overall goal of this research is to continue to characterize the toxic effects of methamphetamine (MA) and related drugs on a biochemical, morphological, and behavioral basis. MA, amphetamine (AMPH), methylenedioxyamphetamine (MDMA) and a number of related drugs are widely abused and are neurotoxic when used in high and/or repeatedly administered doses. Cocaine is another drug of abuse which has long-lasting effects after repeated administration. The extent, duration, and consequences of this toxicity are important to understanding and treating the consequences of these drugs of abuse. The purpose of this research is to extend what is known about the relatively short-term toxicity of these drugs to an investigation of the long-term toxicity and consequences of this toxicity. To achieve the goals of this research, we will determine the magnitude of the long-lasting toxic effects of MA, AMPH, and MDMA upon dopamine (DA) and 5-hydroxytryptamine (5HT) systems as a function of dose and drug-free time period. We will measure the amine levels, the number of high affinity uptake sites, changes in local glucose utilization and alterations in morphology as lone as 64 weeks after the drug has been discontinued. We will also test MA analogues such as N-ethylamphetamine and dimethylamphetamine to determine whether these analogues have toxic potential. Further, we have recently found that a long-term effect of repeated exposure to COC is an alteration of dopamine receptors in the brain. We do not know the extent, duration or consequences of this alteration. We will examine these parameters by determining the effects on receptor subtypes of repeated administration of cocaine, MA and toxic analogues. The long-term consequence of receptor modifications may be correlated with neurotoxicity and/or with behavioral changes that may result from repeated administration of these compounds. We will also investigate the behavioral consequences of drug-induced neurotoxicity. If behavior is altered by neurotoxic drugs or by drug challenge, it will suggest that there are direct behavioral consequences, or that function of particular neuronal systems are compromised by this drug-induced damage. These experiments will be crucial in predicting and treating the consequences of the ingestion of neurotoxic drugs commonly abused by humans.

The Drug Abuse Research Center: 1) provides a formal structure designed to encourage the cooperation of basic research scientists and clinical researchers in problem-oriented research 2) encourages communication among basic research scientists working in related fields 3) promotes the development and/or expansion of certain key areas in drug abuse research and 4) provides an interdisciplinary educational environment for students and faculty interested in various areas of drug abuse research. The philosophy of the Research Center is that drug abuse is a complex problem which needs to be studied on a variety of levels ranging from a drug's sub-cellular actions throuch its sociological impact. It is impossible for any single department, or individual, to possess the expertise to study drugs at all these levels. The Research Center has aimed to provide a formal structure for encouraging interaction between scientist and clinicians from several academic departments, all of whom are working in areas related to drug abuse. Current research includes studies on: 1) the reinforcing properties of diazepam 2) self-administration of sedative-hypnotics via the intragastric route 3) the effects of deprivation and punishment on drug self-administration 4) neuroleptic-stimulant interactions 5) drug tolerance and 6) the stimulus properties of a broad range of psychomotor stimulants.

The major funding and core support for the Drug Abuse Research Center (DARC) are provided by the present grant. The objectives of the DARC have remained: 1) to provide a formal structure to encourage and facilitate communication and cooperation between basic research scientists with a common interest in drug abuse; 2) to promote the development and/or expansion of certain key areas in drug abuse research; and 3) to provide an inter-disciplinary educational environment for students and faculty interested in various areas of drug abuse research. The guiding philosophy of the Center is that drug abuse is a complex problem which must be studied at levels ranging from a drug's sub-cellular actions through its social impact. It is impossible for any individual investigator to possess the expertise to study drugs at all these levels. On the other hand, data, methods and concepts developed at one level may provide important leads for others working in another area. The key function of the Center has been to provide a formal structure for research and for encouraging interactions between scientists who, because of their different academic and professional affiliations, might never meet despite a common interest in the problems of drug abuse. In the present application, the components consist of a core grant, projects on the self-administration psychoactive drugs by animals and humans, a project on pharmacological modification of the effects of cocaine in animals and 2 projects on drug-induced neurotoxicity. The research will significantly expand our knowledge of the maintenance and consequences of drug abuse.

The overall goal of this research is to continue to characterize the toxic effects of methamphetamine (MA) and related drugs on a biochemical, morphological, and behavioral basis. MA, amphetamine (AMPH), methylenedioxyamphetamine (MDMA) and a number of related drugs are widely abused and are neurotoxic when used in high and/or repeatedly administered doses. Cocaine is another drug of abuse which has long-lasting effects after repeated administration. The extent, duration, and consequences of this toxicity are important to understanding and treating the consequences of these drugs of abuse. The purpose of this research is to extend what is known about the relatively short-term toxicity of these drugs to an investigation of the long-term toxicity and consequences of this toxicity. To achieve the goals of this research, we will determine the magnitude of the long-lasting toxic effects of MA, AMPH, and MDMA upon dopamine (DA) and 5-hydroxytryptamine (5HT) systems as a function of dose and drug-free time period. We will measure the amine levels, the number of high affinity uptake sites, changes in local glucose utilization and alterations in morphology as lone as 64 weeks after the drug has been discontinued. We will also test MA analogues such as N-ethylamphetamine and dimethylamphetamine to determine whether these analogues have toxic potential. Further, we have recently found that a long-term effect of repeated exposure to COC is an alteration of dopamine receptors in the brain. We do not know the extent, duration or consequences of this alteration. We will examine these parameters by determining the effects on receptor subtypes of repeated administration of cocaine, MA and toxic analogues. The long-term consequence of receptor modifications may be correlated with neurotoxicity and/or with behavioral changes that may result from repeated administration of these compounds. We will also investigate the behavioral consequences of drug-induced neurotoxicity. If behavior is altered by neurotoxic drugs or by drug challenge, it will suggest that there are direct behavioral consequences, or that function of particular neuronal systems are compromised by this drug-induced damage. These experiments will be crucial in predicting and treating the consequences of the ingestion of neurotoxic drugs commonly abused by humans.