1988 — 1989 |
Gold, Lisa H. |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
Psychoparmacology of Cocaine &Herion Conditioned Act- @ Scripps Research Institute |
0.93 |
1994 — 1998 |
Gold, Lisa H. |
R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Neuropsychopharmacological Effects of Mdma @ Scripps Research Institute
Methylenedioxymethamphetamine (MDMA) is a drug of abuse that was proposed for use as an adjunct to psychotherapy. Such potential therapeutic benefic was abandoned when the drug was found to have neurotoxic, serotonin-depleting actions. Nevertheless, MDMA is still widely used and abused. Although MDMA-induced toxicity has been an area of considerable research, the long-term effects of MDMA on neuropsychological function remain unknown. Results in animals suggest alterations of function in brain areas thought to subserve cognition, but little alteration in neurobehavioral function has been demonstrated. Sophisticated cognitive testing is critical to examine neuropsychological function in animals that have received repeated administration MDMA under conditions known to cause serotonergic depletion. Testing in non-human primates will allow evaluation of the complex cognitive functions, not testable in rodents, which may be most sensitive to the MDMA-induced neurotoxicity, and allows for data collection both pre- and post-treatment, not possible in drug abusing humans. In addition, monkeys are more sensitive than rodents to the neurotoxic effects of MDMA and metabolize the amphetamines, like MDMA, via the same pathways as humans, whereas rodents metabolize these drugs via an alternate pathway. The purpose of this proposal is to study the neuropsychopharmacological effects of MDMA in rhesus monkeys using a computerized test battery. The hypothesis to be tested is that repeated MDMA administration produces neurochemical changes that have cognitive behavioral correlates. Rhesus monkeys can be trained on the identical neuropsychological tasks as humans using a touch-sensitive computerized apparatus. The test battery includes probes of memory (delayed non-matching to sample, spatial working memory), attention (intradimensional/extra-dimensional shift task) and motor performance, as well as an estimate of relative reinforcement efficacy (progressive-ratio) and reaction-time. These tasks were chosen because they represent psychological processes which are associated with distinct neurological substrates. Drug challenges will be combined with behavioral testing to reveal changes in brain neurochemistry not observable under basal conditions. Further, the ability of MDMA to function as a reinforcer will be examined after repeated administration. Alterations in serotonergic function following repeated MDMA administration may contribute to changes in the potency and efficacy of MDMA, as well as other drugs of abuse, such as cocaine and methamphetamine, to act as reinforcers. These studies will not only provide critical information about the neurotoxic potential of MDMA on a functional level, but the ability of MDMA to selectively destroy certain serotonergic pathways makes it a useful tool to study the role of serotonin in cognitive function and stimulant drug abuse.
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0.93 |
1996 — 1999 |
Gold, Lisa H. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Drug Self Administration in Mouse Models of Neuroaids @ Scripps Research Institute
There are presently over 18 million people abusing cocaine in the US and more than 2 million heroin abusers. Combination drug use includes the "speedball" mixture of cocaine and heroin and widespread cocaine use in methadone-maintained intravenous drug users (IVDU's). Intravenous injection of cocaine and speedball mixtures, as well as lifestyles that promote high risk behaviors, renders the drug abusing population particularly vulnerable to the spread of HIV infection. A critical hypothesis for this vulnerability is the influence of drugs of abuse on disease progression. Neurobehavioral dysfunction is a significant aspect of HIV infection, neuropathology is observed in about 80-90% of AIDS patients at autopsy and virus can be measured in the cerebrospinal fluid of 50-70% of HIV infected individuals (NeuroAIDS). Direct neurotoxic effects of drugs, in addition to their effects on immunocompetence, may contribute to an enhancement of NeuroAIDS disease or accelerate its onset. Candidate mediators of neuropathogenesis include virus-derived (gp120) and host-derived (IL6, IFNalpha) factors. One experimental model involves the transgenic expression of gp120, the HIV coat protein, which has been shown to be toxic in vitro and to produce retardation of developmental milestones and spatial learning impairments in vivo. Two additional models involve the transgenic expression of the cytokines, IL6 and IFNalpha. IL6 has been shown to have a direct pathogenic role in various inflammatory, infectious, and neurodegenerative CNS diseases. The interferons are antiviral host defense molecules, and exogenous administration of IFN mimics many of the CNS symptoms of HIV infection. These transgenic mouse models exhibit unique neuropathological changes that replicate specific aspects of clinicopathology seen in NeuroAIDS. A standard procedure to study drug abuse in laboratory animals is the intravenous drug self-administration procedure. In this proposal, transgenic mice will be trained to self-administer cocaine, heroin or cocaine+heroin ("speedball") and then tested for neurobehavioral function and responsiveness to acute drug probes in tasks assessing learning (nonconditional spatial discrimination), motor activity (locomotion, catalepsy), and analgesia. Behavioral studies will be complemented by studies of molecular and cellular neuropathology and peripheral immune parameters. This research plan integrates analysis of drug effects on CNS and immune function, as relates to components of HIV disease progression, across several levels of investigation. Converging results should go far in identifying critical viral- and host-derived factors associated with increased susceptibility to the pathobiological effects of drugs of abuse and consequent synergistic neurotoxicity. Equally important, these studies will help to determine the nature of viral neuropathogenesis to specific brain systems relevant to drug reward, which may have significant clinical outcomes in terms of altered neurobehavioral and pharmacological sensitivity to drugs of abuse in HIV infected individuals.
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0.93 |
1996 — 2000 |
Gold, Lisa H |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Neurobehavioral Sequelae of Neuroaids--Siv Model @ Scripps Research Institute
The neurobehavioral sequelae of HIV infection arise from poorly understood pathological effects on brain structure and function; we use the term NeuroAIDS to represent this complex of brain changes. Neuropathology is observed in about 80-90% of AIDS patients at autopsy and virus can be measured in the cerebrospinal fluid of 50-70 % of HIV infected individuals. Cognitive and motor impairments may affect up to 30% of patients in the early stages of immune suppression and up to 50% of symptomatic patients, while about 10-20 % of those with AIDS develop frank dementia. These neurobehavioral disturbances severely impact social and occupational functioning in HIV+ adults and children, thereby greatly reducing their quality of life. A neuropsychological testing battery employing a touch- sensitive computer screen has been developed to detect changes in cognitive performance in rhesus monkeys. The test battery includes probes of memory (delayed non-matching to sample, spatial working memory), attention (intra- dimensional/extra-dimensional shift task) and motor performance (bimanual motor task), as well as an estimate of relative reinforcement efficacy (progressive-ratio) and reaction-time. HIV+ patients tested in the human version of this battery exhibited a specific profile of cognitive deficits suggestive of fronto-striatal dysfunction. A model is proposed in which a neurovirulent form of simian immunodeficiency virus (SIV) is hypothesized to produce CNS changes in rhesus monkeys reminiscent of those seen in NeuroAIDS and to result in analogous behavioral deficits. The time course of disease progression will be characterized using functional measures of cognition and motor skill, as well as telemetric monitoring of gross activity, temperature and EEG. Concomitant measurement of immunological and virological parameters, may reveal correspondence between behavioral performance and the physiologic state of the monkeys across measures will ultimately be correlated with neuropathology permitting a convergence of information from all levels of analysis. The utility of an animal model rests in its ability to permit the study of a disease process under controlled conditions and the evaluation of potential therapeutic agents. An animal model that recapitulates the pathogenic and functional outcomes seen with HIV infection in humans has both face and predictive validity for use in drug treatment studies. The accelerated time course of disease compared to HIV infection,a nd the sophistication with which monkeys can be tested, makes the SIV model ideal for testing new therapies aimed at preventing or arresting cognitive decline. The study of treatment drugs with known mechanisms of action in the SIV model will not only be important as a screen for therapeutic efficacy and side effects, but will also yield important clues as to the mechanisms of the behavioral impairments associated with immunodeficiency virus infections. In this component of the Center, the SIV model will be used to explore the neurobehavioral sequelae of NeuroAIDS, the viral and host factors leading to neuronal dysfunction, and to begin testing potential therapeutic agents.
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0.93 |