Michael A. Taffe, PhD - US grants

Many neuropsychiatric and neurologic diseases including, schizophrenia, alcoholism, drug abuse, Alzheimer's, Parkinson's and HIV infection are associated with significant cognitive symptoms which substantially impact illness outcome. Rather than global cognitive deficits, studies that have used measures of selective cognitive tasks suggest that these patient groups exhibit impaired functioning in specific domains, implicating disruption in focal brain regions or systems. Animal models are valuable for investigating the role of particular neurochemical systems and neuroanatomical regions in the complex behavioral processes underlying cognition. A neuropsychological test battery employing a touch-sensitive computer screen has been developed to detect changes in cognitive performance in rhesus monkeys. The battery includes probes of memory, learning, attention, motor performance and reaction-time, as well as an estimate of relative reinforcement efficacy. The proposed studies offer a testable hypothesis for manipulating the dopamine, norepinephrine, acetylcholine and amino acid neurotransmitter systems with the goal of determining their respective contributions to cognitive function, focusing on domains that may be especially vulnerable to chronic drug abuse. Sensitive behavioral paradigms will be employed to test predictions about the likely functions of these neural systems and compare the functioning of these systems in a common behavioral context. The specific aims are: To identify the neuropharmacological substrates mediating the cognitive processes of I) learning (concurrent visual discrimination) and memory (pattern recognition, spatial working and visuo-spatial memory), II) vigilance, attention, motivation and, III) motor skill. Individual tasks within the battery permit comparisons between the effects of manipulations of different transmitter systems, while comparisons across tests allow a more comprehensive evaluation of the function of each system. The information gained will then offer 1) further evidence for behavioral homology among cognitive testing between human and nonhuman primates 2) knowledge on the relative contribution of distinct neurochemical systems, and more precisely the specific pharmacological substrates, for performance in different neurocognitive domains. These results will help to elucidate the deficits observed in various human diseases and animal models of these diseases, aiding in the interpretation of the clinical sequelae and pointing to potential pharmacotherapies that may be useful for treating specific aspects of neurocognitive dysfunction.

Neurocognitive complications are estimated to occur in 30-50 percent of all individuals infected with HIV and these behavioral pathologies can significantly impact quality of life. While early data suggest that highly active antiretroviral drug therapy (HAART) may have beneficial effects on cognitive dysfunction, the unknown duration of these actions and the fact that most HIV+ patients worldwide are not maintained on HAART emphasize the need for further study of the behavioral sequelae of HIV disease. A neuropsychological test battery employing a touch-sensitive computer screen has been developed to detect changes in cognitive performance of rhesus monkeys. The battery includes probes of memory, learning, attention, motor performance and reaction-time as well as an estimate of relative reinforcer efficacy. In monkeys, a neurovirulent form of simian immunodeficiency virus (SIV) produces a specific profile of deficits in this behavioral battery entirely consistent with those seen in humans with HIV disease. Performance in motor tasks, reinforcer efficacy and spatial working memory tasks are the most commonly disrupted. Evidence suggests that higher sustained viral loads are associated with rapid disease progression and an increase in the incidence and severity of neurobehavioral symptoms. This proposal will study the relationship between viral burden and behavior by employing experimental manipulations which result in the elevation or lowering of viral load during critical phases of infection. The concomitant measurement of body temperature and spontaneous locomotor activity with radiotelemetry, as well as recording of sensory evoked potentials will provide important adjuncts for charting the functional effects of disease progression. The Specific Aims are I) To investigate the effects of reducing CD8+ T cell populations with the CD8 specific antibody cM-T807 early in the course of infection on the incidence and severity of behavioral pathology; and II) To investigate the effect of rapid reduction of viral load with anti-retroviral combination-therapy on CNS functional outcome. Because we have shown that monkeys infected with SIV demonstrate behavioral deficits analogous to those observed in HIV infected humans, the use of this behavioral battery to study the role of viral burden is a valuable and productive approach towards a further understanding of NeuroAIDS.

DESCRIPTION (provided by applicant): Recreational overuse of alcohol among adolescent populations remains a significant and growing public health concern. Surveys report that 10% of eighth graders and up to a third of high school seniors consume binge quantities of alcohol on at least a biweekly basis. Heavy drinking during this critical period of formal education and significant brain development may pose serious risk for later intellectual and cognitive function. The proposed studies will develop a novel nonhuman primate model to evaluate the consequences of heavy drinking during adolescence task acquisition and performance in a range of cognitive domains. The Aims under investigation are 1) To determine if chronic oral alcohol intake slows acquisition of a battery of cognitive and behavioral tests in peri-adolescent monkeys; 2) To determine the cognitive and behavioral effects of withdrawal from chronic alcohol exposure; and 3) To determine if a history of chronic oral alcohol intake alters monkeys' cognitive and behavioral sensitivity to challenge with specific psychoactive compounds. Peri-adolescent monkeys will be trained on a battery of tests which probe learning, memory, attention and motor functions. A flavorant-fade procedure will be used to generate consistent, high levels of alcohol drinking in the experimental group which will be allowed to orally self-administer alcohol (M-F) throughout the 18 month test acquisition period. Radiotelemetric measurement of circadian patterns of body temperature and locomotor activity, and cerebrospinal fluid monoamine / metabolite concentrations will be used as correlates for the behavioral measures. Access to alcohol will be discontinued following acquisition of all behavioral tests to evaluate possible effects of withdrawal on the behavioral and physiological measures. Acute doses of psychoactive compounds will be employed to probe possible persisting behavioral sensitivities to serotonergic, dopaminergic, GABAergic or glutamatergic challenge. This exploratory study will provide evidence regarding the risks posed to cognition by heavy alcohol drinking in the peri-adolescent period.

DESCRIPTION (provided by applicant): Recreational use of (+/-) 3,4 -methylenedioxymethamphetamine (MDMA, "Ecstasy") has become increasingly popular in recent decades. Major surveys in the US report steep increases in the rate of MDMA use while use of a number of other recreational drugs has been stable or in decline. College age adults have lifetime prevalence rates of 12-18% thus a substantial fraction of the population is exposed to MDMA. Numerous studies have shown that abstinent MDMA users exhibit deficits on a range of cognitive tasks. Work in nonhuman primate models over past decades has shown that high doses of MDMA (10 mg/kg);when administered at 12 hr intervals for 4 days, selectively reduce markers for serotonin (5-HT) axons and terminals in many brain regions. However, such MDMA-associated 5-HT neurotoxicity is not sufficient to produce cognitive or motor alterations in monkeys under unchallenged conditions. Prior monkey models have not employed repeated, intermittent dosing patterns similar to human users, however. To investigate the novel hypothesis that cognitive and motor disturbances in human users of MDMA result from repeated cycles of 5HT axon pruning/reinnervation, experiments will be conducted in rhesus macaques under the following Aims. Specific Aim I: To determine if repeated, intermittent exposure to a low dose of MDMA results in detectable neurochemical, behavioral or electrophysiological alterations. Specific Aim II: To determine if a short-interval, multi-dose exposure to low doses of MDMA ("MDMA stacking") results in a neurochemical, behavioral and electrophysiological profile similar to that produced by the repeated, high-dose, long interval regimen that produces serotonin neurotoxicity. Specific Aim III: To determine if repeated episodes of exposure to MDMA result in progressive electrophysiological, neurochemical or chronophysiological disturbance. Specific Aim IV: To determine if a history of MDMA exposure impairs acquisition and performance of a battery of neuropsychological tests.

DESCRIPTION (provided by applicant): Recreational overuse of alcohol among adolescent populations remains a significant and growing public health concern. Surveys report that 10% of eighth graders and up to a third of high school seniors consume binge quantities (5 drinks or more) of alcohol on a weekly basis. Heavy drinking during this critical period of formal education and significant brain development may pose serious risk for later intellectual and cognitive function. The proposed studies will use a nonhuman primate model to evaluate the consequences of heavy drinking during adolescence task acquisition and performance in a range of cognitive domains. The project seeks to determine the cognitive domains which are impaired by chronic oral alcohol intake; contributions of impulsivity, alcohol preference and serotonin transporter genotype to behavioral change; and the cognitive and behavioral effects of withdrawal from chronic alcohol exposure in periadolescent monkeys. These studies follow an Exploratory/Developmental project (R21 AA013972, 02/05/04-01/31/07) in which it was established that male monkeys consuming alcohol are impaired in acquiring a visuo-spatial paired-associates learning task and in performing the spatial delayed-response task of spatial working memory. Alcohol-exposed animals appeared unimpaired on discrimination learning and long-term memory tests suggesting an effect which may be selective for specific cognitive domains. The proposed studies will use an established procedure to generate consistent, high levels of alcohol drinking in the experimental groups which will be allowed to orally self-administer alcohol (M-F) for 24 months. The experimental groups and control group monkeys will be concurrently trained on a comprehensive battery of tests (derived in part from the human CANTAB) which probe multiple aspects of learning, memory, attention and motor functions. It is hypothesized that tasks which depend more on frontal-type executive function will be preferentially affected by chronic alcohol drinking. It is further predicted that cognitive differences attributable to alcohol will be maintained upon long-term removal of access to alcohol. PUBLIC HEALTH RELEVANCE: Alcohol remains the most abused psychoactive drug in adolescents with up to half of 12th graders reporting consumption in the past 30 days. The majority of alcohol using 12th graders report at least one heavy drinking episode (5 drinks or more) in the prior two weeks. Adolescence is a critical time for both brain development and the acquisition and refinement of many cognitive skills necessary for vocational success. These studies seek to identify the mechanisms by which alcohol drinking can interfere with learning, memory, attention and other critical cognitive functions.

6H-Dibenzo(b,d)pyran-1-ol, 6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-, (6aR-trans)-; 9-ene-Tetrahydrocannabinol; Acute; Address; Adolescent; Adolescent Youth; Affect; Animals; Behavior; Behavioral; Biologic Marker; Biological Markers; Brain; Cannabinoids; Cannabis; Cerebrospinal Fluid; Chronic; Cognitive; Cognitive Discrimination; Complement; Complement Proteins; Complex; Control Groups; Decision Making; Delta-9-Tetrahydrocannabinol; Development; Discrimination; Discrimination (Psychology); Dose; Dronabinol; Drugs; Encephalon; Encephalons; Evaluation; Exposure to; Functional Magnetic Resonance Imaging; Goals; Hemp Plant; Human; Human, General; Laboratories; MR Imaging; MR Tomography; MRI; MRI, Functional; Macaca mulatta; Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; Magnetic Resonance Imaging, Functional; Mammals, Rodents; Man (Taxonomy); Man, Modern; Marinol; Measures; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; Medication; Memory; Memory, Immediate; Memory, Short-Term; Memory, Shortterm; Methods and Techniques; Methods, Other; Modeling; Molecular Marker; Monitor; Monkeys; Motivation; Motor; NMR Imaging; NMR Tomography; Nature; Nervous System, Brain; Neurobiology; Neurochemistry; Neuropsychologic Tests; Neuropsychological Tests; Nuclear Magnetic Resonance Imaging; Pattern; Performance; Pharmaceutic Preparations; Pharmaceutical Preparations; Physiology; Recognition (Psychology); Reversal Learning; Rhesus; Rhesus Macaque; Rhesus Monkey; Rodent; Rodentia; Rodentias; SR 141716A; SR141716A; Sampling; Science of neurochemistry; Short-Term Memory; Signature Molecule; Specificity; Speed; Speed (motion); Staging; Task Performances; Techniques; Testing; Tetrahydrocannabinol; Withdrawal; Zeugmatography; adult youth; analog; behavior measurement; behavioral measure; behavioral measurement; biomarker; cognitive function; cohesion; day; delta(1)-THC; delta(1)-Tetrahydrocannabinol; delta(9)-THC; delta(9)-Tetrahydrocannabinol; drug withdrawal; drug/agent; executive control; executive function; experiment; experimental research; experimental study; fMRI; indexing; juvenile; juvenile human; male; memory recognition; neurobehavioral; neurobiological; neurochemistry; non-human primate; nonhuman primate; research study; spinal fluid; translational study; working memory; young adult

DESCRIPTION (provided by applicant): The abuse of, and addiction to, d-methamphetamine (METH) interferes with many aspects of personal health, vocational performance, interpersonal relationships and financial well-being. Behavioral consequences of METH abuse and the METH trade also strain legal and emergency medical resources throughout the US. METH is therefore a significant and continuing public health concern. Current therapeutic approaches for METH addiction are less than completely effective and no approved pharmacotherapies for METH addiction exist. Recent successes in early clinical trials using immunotherapeutic approaches for cocaine and nicotine addiction have motivated interest in creating similar approaches for methamphetamine addiction. Work under the initial funding interval of this project has created the MH6 vaccine which was shown to generate antibodies which sequester METH in the blood. The vaccine also attenuated METH effects on locomotor activity, thermoregulation and intravenous self-administration of METH. New studies seek to optimize the vaccine for higher antibody titer by determining effects of different carrier proteins and adjuvants. Studies in rats will use converging models of drug-related reward, including intracranial self-stimulation reward and the dopamine response in the nucleus accumbens shell, to determine how the vaccine alters the acquisition of self- administration. Additional work will determine if an optimized vaccine can prevent the escalation to unregulated METH intake using a long-access procedure and if the vaccine can reverse an established self-administration pattern. Together these studies will make significant progress on optimizing both the design and likely translational application of an anti-METH vaccine.

DESCRIPTION (provided by applicant): Epidemiological reports show that (1)3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) continues to be used by large fractions of young adults. Studies have further suggested that up to 40 percent of users become at least temporarily dependent on MDMA, experienced users abuse an array of other substances and may abuse MDMA several times per week or even daily. It is also known that some Ecstasy users exhibit lasting cognitive and mood alterations, even years after discontinuing Ecstasy use. Nevertheless, in comparison with structurally related drugs such as amphetamine and methamphetamine minimal animal research has been devoted to understanding the determinants of repeated MDMA self-administration. Initial work has shown that MDMA appears to be a weak reinforcer compared with other psychomotor stimulants, thus additional study of factors which create a transition to frequent or compulsive MDMA use is needed. The hypothesis that differences in the self administration of MDMA are related to the increased serotonergic agonist properties of MDMA is supported by prior observations that drugs which increase serotonergic tone may decrease self- administration of psychomotor stimulants. Such work will not only contribute to understanding the development of MDMA/Ecstasy abuse but may generalize to understanding factors which influence which of a minority of individuals exposed to other psychomotor stimulants will eventually transition to dependence. The proposed studies will use rat intravenous self-administration models to test factors which may underlie a transition from casual to compulsive Ecstasy use. The experiments will first examine methodological variables such as training dose, route of administration and duration of access session that have not been systematically addressed for MDMA self-administration. Additional studies will examine situational factors intended to model the human user milieu (such as high ambient temperature and hyperthermia, running wheel activity and exposure to a serotonin-depleting high dose regimen of MDMA) which may facilitate a transition to dependence. PUBLIC HEALTH RELEVANCE: Approximately 15-20 percent of young adults have used the recreational drug 3,4-methylenedioxy- methamphetamine (MDMA, known as Ecstasy) and many of these users become dependent on Ecstasy while using; clinically significant symptoms of depression and anxiety, and poor cognitive performance can persist years after discontinuing Ecstasy use. Furthermore, in the US about 8,500 individuals per year have critical hyperthermia, seizure and other medical symptoms requiring emergency medical intervention after Ecstasy use. The proposed studies seek to determine situational and neurochemical factors which may increase use of this recreational drug and/or facilitate a transition from casual use to dependence.

DESCRIPTION (provided by applicant): Cannabis remains the most popular illicit psychoactive drug used in the US. Some 70-80 percent of 40- 50 year olds have tried it at least once in their lifetime and 18-19 percent of 18-21 years olds have used cannabis in the past month. There are more people in the US who meet criteria for cannabis dependence than have used cocaine in the past month or ever tried heroin; it is of further concern that the use of cannabis under medical marijuana laws continues to expand in the US as dispensaries proliferate. Trends for increased medical use may continue following, e.g., findings that smoked marijuana or a combined-cannabinoid spray can improve symptoms in multiple sclerosis. Studies have shown that acute intoxication with cannabis impairs cognitive function, however cannabidiol (CBD), a constituent of some cannabis strains, may provide some protection from the acute and lasting detrimental effects of cannabis. The studies in this project seek to determine if CBD can attenuate specific cognitive disruptions caused by D9-tetrahydrocannabinol (THC), using a nonhuman primate model. A battery of tests shown sensitive to THC will be used to determine if CBD can block the effects of both acute and chronic administration of THC. The goal is to determine the extent to which CBD might be used to moderate effects of THC in the therapeutic setting, although there are also implications for the recreational user.

DESCRIPTION (provided by applicant): A major and growing problem in the field of drug abuse is prescription opioid abuse and dependence, which has reached epidemic proportions. A major question is whether there are any unique pharmacodynamics or neuroadaptations to explain this epidemic. One largely unexplored hypothesis to explain the high abuse potential of the prescription opioid medicines such as oxycodone is that there are neurobiological vulnerabilities in response to chronic administration of these drugs that predispose individuals to addiction on such opioids and that these neurobiological vulnerabilities are exaggerated by the pharmacodynamics of certain synthetic opioids. To test this hypothesis, in the present proposal, individual differences in compulsive drug seeking and dependence will be correlated with individual neuroadaptational changes in brain stress systems known to drive dependence. In Specific Aim 1, animal models of compulsive drug seeking and dependence will be developed for oxycodone and compared to drug seeking for heroin and buprenorphine. Using such animal models, individual differences in compulsive drug seeking, withdrawal and re-escalation of compulsive drug seeking will be characterized. In parallel, in Specific Aim 2 dysregulation of neural systems known to drive the development of compulsive opioid seeking will be characterized. These include alteration of the brain corticotropin releasing factor (CRF) systems and brain dynorphin kappa systems in brain reward and stress circuits. Finally, in Specific Aim 3 microinjection of antagonists of the CRF system and the kappa system in specific brain regions and gene silencing of specific CRF and dynorphin neurocircuits will be employed to reverse neuroadaptive changes and consequent re-escalation of drug seeking in subgroups of rats with high levels of compulsive drug seeking. The present proposal will go far towards elucidating the neurobiological systems within specific neurobiological circuits of the ventral striatum and extended amygdala, which are critical for the motivational aspects of prescription opioid abuse and dependence. The present proposal also will provide important information for identifying novel non- mu opioid treatments for opioid addiction.

The use of synthetic psychoactive cathinone drugs (?bathsalts?) continues to expand worldwide and in the United States of America despite legal control efforts internationally, at the US federal level, within multiple US states and even the local US jurisdictions. The established stimulants such as cocaine and methamphetamine are highly addictive, can be acutely lethal and can result in long- term brain alterations with many implications for health and well-being. Recent studies show that 3,4- methylenedioxypyrovalerone (MDPV) is a highly potent and efficacious reinforcer, predicting abuse liability equal to or greater than that of cocaine and methamphetamine. Compounds such as Mephedrone and Methylone produce subjective properties that are similar to 3,4- methylenedioxymethamphetamine (MDMA) but have exhibit much greater propensity for compulsive use in human report and rodent self-administration studies. This project responds to the goals of PAR-14-106 Synthetic Psychoactive Drugs and Strategic Approaches to Counteract Their Deleterious Effects by determining structural determinants of the addiction liability of synthetic cathinones. Tremendous diversity of cathinone structure exists in the recreational market, driven in part by legal control of earlier-appearing drugs. This reality demands approaches which can both advance understanding of the actions of currently popular drugs and generate better predictions regarding which design motifs may convey increased abuse liability in emerging compounds. To that end, studies under Aim I and Aim II will elucidate the contributions of the 3,4-methylenedioxy and 4- methyl aromatic ring substitutions, respectively, to the reinforcement potency and efficacy of cathinones. One distinct feature of MDPV is an extended carbon chain which confers enhanced lipophilicity. The goal of Aim III is to determine if stimulant drug efficacy in intravenous self- administration is affected by lipophilicity, which affects speed of brain entry. In total, these proposed studies on the reinforcing effects of various synthetic cathinones will advance our understanding of the health risks associated with designer stimulant drugs.

DESCRIPTION (provided by applicant): The purpose of this program is to train promising young scientists at the postdoctoral level in the multi- disciplinary strategies of molecular, cellular, behavioral, and clinical neuropsychopharmacology of ethanol. The Scripps Research Institute Alcohol Research Center (TSRI-ARC), combined with a very active independent but interactive San Diego Alcohol Research Community, has developed a conceptual framework for the study of the neurobiology of alcoholism and the neurobiological basis for individual differences in vulnerability to alcoholism. Methods have been developed by combining biochemical, morphological, physiological and behavioral research to arrive at broad based studies of the neuropsychopharmacology of alcoholism through such fields as molecular biology, immunocytochemistry, electrophysiologic analysis (in vitro and in vivo), neuroendocrinology, behavioral pharmacology, and cognitive and motivational testing applied to animal and human subjects, and clinical studies. In addition, we also attempt to develop other important skills for pathways to independence: creative research expression, critical selection of problems, experimental design, data recording, validation and security, data interpretation, manuscript and grant preparation, promotion of transition awards, and ethical conduct of research. Trainees participate in scientific project development, research seminars from visiting scientists and journal clubs is well as actively participating in research programs. Each trainee will also receive a course on ethanol neuropsychopharmacology and a course in ethical conduct of research. Both informal and formal recruitment mechanisms are well established and have provided a sufficient number of high quality applicants. Extensive programs are in place for recruitment of minority and for facilitating minority interest in alcohol research. Significant success in the past funding period has resulted in retaining and promoting two minority faculty to the training program, training of two minorities and recruitment of two young faculty members. An evaluation of the success of the program is in place charting the career development of pathways to independence in alcohol research of former fellows with use of a formal evaluation survey. Postdoctoral fellows and other advanced trainees are selected with preferential weighting towards those seeking interdisciplinary methodologies. They are then assigned to one of the Principal Investigators of the training grant who coordinates their initial research project selections. Depending upon a trainee's prior research skills, collaborations with more than one senior scientist are encouraged. All combined, the training program provides a dynamic environment for fellows to develop and pursue a foundation for career in the neuropsychopharmacology of alcoholism.

The purpose of this program is to provide promising young scientists with mentor-based training in a dynamic, highly collaborative and interactive environment to promote their development as independent investigators engaged in alcohol research. Highly qualified candidates are competitively selected from a large applicant pool recruited through advertisements in addiction- and neuroscience-related societies and publications, referrals from established colleagues in the field of alcohol research, and from letters of inquiry resulting from the Training Faculty?s publications and public presentations. Mechanisms are in place to encourage applications from underrepresented groups, to foster diversity in the training program and the field of addiction research. A rigorous training program has been established to develop trainees? skills in (i) identifying important, relevant and testable hypotheses, (ii) experimental design and conduct, (iii) data analysis and interpretation, and (iv) scientific communication through written and oral presentation. Emphasis is placed on career development, and trainees complete an Individual Development Plan (IDP) upon admission to the program to generate trainee-mentor discussions of career plans and goals, strategies and timelines for achieving these goals, and ways in which these goals may have changed during the training period. Trainees are encouraged to engage in numerous workshops and resources available at The Scripps Research Institute (TSRI) on effective CV development, networking, job applications and interviewing techniques. In addition, mentors and Program Faculty actively engage trainees in discussions of each of these skills on an ongoing basis. Throughout their tenure in the program, trainees are educated in the responsible conduct of research, and this occurs via courses offered through the TSRI Career and Postdoctoral Services Office, the annual Neuropsychopharmacology of Addiction course taught by the Program Faculty, and through day-to-day input from mentors and Program Faculty regarding ethical practices in laboratory research. The highly collaborative group of 16 Program Faculty members is characterized by strong, well-funded programs in alcohol and addiction research incorporating multidisciplinary experimental approaches combining biochemical, morphological, physiological, and behavioral techniques. This is a translational training program associated with the longstanding TSRI P60 Alcohol Research Center, and trainees can engage in studies spanning the molecular and cellular domains, through investigations of neurobiological mechanism in whole animals, and clinical studies in humans on the vulnerability to alcoholism, and the development of therapeutics for this prevalent disorder. The training program has functioned continuously since 1979 under three successive Program Directors, and has a consistent record of preparing outstanding young investigators for a rapid transition to independent and impactful careers in alcohol research and addiction neuroscience.