Marc J. Kaufman - US grants

DESCRIPTION (provided by applicant): Amyotrophic Lateral Sclerosis (ALS) is a fatal progressive motor neuron degeneration disease. Current treatment options are inadequate and only minimally improve quality of life and survival times. There is an acute need for novel treatments that prolong lifespans of ALS patients and improve their quality of life. Xenon (Xe) gas has been used clinically as an anesthetic, it is considered safe and induces few side effects, and data exist suggesting that it may be therapeutically useful via several mechanisms for counteracting neurodegenerative processes. Accordingly, we propose an initial pilot study to assess xenon efficacy for delaying onset of motor impairments and reducing apoptosis and glial activation in the C57Bl/6 SOD1G93A model of familial ALS. We hypothesize that continuous Xe inhalational exposure will delay development of motor impairments and reduce apoptosis and glial activation in C57Bl/6 SOD1G93A mice. Should we validate our hypotheses, this will set the stage for systematic investigations to optimize Xe exposure conditions in the C57Bl/6 SOD1G93A model, which could ultimately lead to the clinical use of Xe to treat ALS. PUBLIC HEALTH RELEVANCE: Amyotrophic lateral sclerosis (ALS) is a chronic progressive neurodegenerative disorder with major public health implications. Xenon gas has been used clinically as an anesthetic and it may be useful for slowing ALS- associated neurodegeneration. This project aims to initially test whether xenon can slow or prevent the development of motor system dysfunction and markers of apoptosis and glial activation in the C57Bl/6 SOD1G93A mouse model of familial ALS.

DESCRIPTION (provided by applicant): Nicotine dependence remains the leading cause of preventable mortality in the United States, accounting for nearly 450,000 deaths annually. Tobacco smoking cessation offers clear health benefits and partially effective cessation pharmacotherapies exist. However, 65-80 percent of initially abstinent smokers relapse within 12 months. Since smoking cue reactivity is strongly associated with craving and, in smokers trying to quit, with relapse, discovering treatments that reduce smoking cue reactivity may help promote sustained tobacco abstinence. !n preclinical studies, dopamine (DA) D3 receptor antagonists effectively reduced nicotine and other drug- conditioned responses including cue-induced reinstatement of nicotine seeking. Therefore, D3 receptors may moderate nicotine and other drug cue-reactivity and may play a role in cue-induced relapse. This Exploratory Developmental R21 project aims to determine whether D3 receptors are elevated in smokers and whether correlations exist between D3 receptor binding and functional MRI (fMRI) reactivity to smoking cues, which has been associated with smoking relapse vulnerability. Neuroimaging measures will be collected concurrently in otherwise healthy nicotine-dependent smokers and age-matched nonsmokers using a 3 Tesla MRI scanner configured to conduct fMRI and Positron Emission Tomography (PET). We propose to measure PET D3 receptor binding using radiolabeled [11C]-(+)-PHNO, which has a relatively higher affinity for D3 receptors over other radiotracers labeling D2/D3 receptors. Prior studies reported that D3 antagonist treatment decreased [11C]-(+)-PHNO binding in brain regions involved in reward learning including the substantia nigra (SN), globus pallidus (GP), and ventral pallidum (VP). Thus, SN, GP, and VP D3 receptors may play a role in relapse, possibly by moderating behavioral responses to drug cues. Because preclinical and clinical evidence suggest that stimulant exposures increase D3 receptor levels, we hypothesize that PET [11C]-(+)-PHNO binding in SN, in which binding is almost exclusively to D3 receptors, will be elevated in smokers when compared to nonsmokers. We also hypothesize that within smokers, SN [11C]-(+)-PHNO binding will be positively correlated with fMRI smoking cue reactivity in brain areas previously shown to exhibit high smoking cue fMRI reactivity, including anterior insula, amygdala, and dorsal striatum. Validation of these hypotheses may help clarify mechanisms underlying relapse vulnerability and may help identify smokers who would particularly benefit from D3 antagonist treatment, thereby enabling a personalized medicine approach. PUBLIC HEALTH RELEVANCE: Nicotine dependence remains the leading cause of preventable mortality in the United States. This Exploratory Developmental R21 program aims to determine whether smokers exhibit increased levels of dopamine D2/D3 receptors and whether there is an association between D2/D3 level, as measured with Positron Emission Tomography (PET), and smoking cue functional MRI reactivity, which when increased predicts heightened relapse vulnerability. PET and fMRI scans will be acquired simultaneously on an MRI scanner fit with a PET imaging insert. Program findings may lead to new smoking cessation and relapse prevention treatments.

? DESCRIPTION (provided by applicant): Cocaine abuse and dependence are long-standing, significant public health issues. Yet, no drug treatments have been approved for these disorders. People with chronic cocaine use histories exhibit cognitive deficits including impulsivity and impaired executive function. Among those attempting to quit, cognitive deficits increase relapse vulnerability and reduce effectiveness of behavioral interventions. Accordingly, developing a better understanding of the cognitive sequelae of chronic cocaine exposure and their relationships to neurochemical abnormalities may lead to new treatments and new ways to optimize existing behavioral interventions. Controlled prospective studies in nonhuman primates will play a key role in this endeavor because they enable baseline (pre-cocaine) cognitive assessment and because amounts and durations of cocaine exposure are defined. Further, such studies are absent the many confounds present in human studies, including polydrug abuse and pre-/co-morbid psychiatric and medical disorders. With this R21 Exploratory/Developmental project, we aim to establish a translational platform to assess, within individual subjects, effects of chronic cocaine self-administration on cognition and on neurochemistry, using touch screen technology and ultra high magnetic field (9.4 Tesla) in vivo proton magnetic resonance spectroscopy (MRS), respectively. Both methodologies have been implemented in our laboratories and used separately to assess cognition or MRS effects of chronic cocaine in squirrel monkeys. Our prior MRS studies have revealed striatal intracellular glutamate increases after chronic cocaine administration to squirrel monkeys, which may be relevant as glutamate abnormalities contribute to behavioral inflexibility (e.g., impulsivity). We will prospectively assess effects of chronic cocaine self-administration on acquisition and reversal learning, on reinstatement as a measure of relapse vulnerability, and on brain glutamate levels. Then, we will examine effects of short-term treatment with N-acetylcysteine (NAC), which has shown promise in human cocaine users for reducing cocaine use and for correcting brain glutamate abnormalities. We will assess NAC effects on cognition, glutamate levels, reinstatement, and on relationships between these variables. We hypothesize that chronic cocaine will impair acquisition and reversal learning, will enhance reinstatement, and will increase intracellular glutamate levels, and that NAC treatment will normalize cognition, reduce reinstatement, and reduce glutamate levels. These experiments will establish a platform for future studies evaluating effects of chronic cocaine or other chronic drug exposures on cognitive function across a number of cognitive domains, on neurochemistry, and for evaluating novel interventions designed to improve cognition, neurochemistry, and cocaine/other drug treatment outcomes.

Summary/Abstract Anabolic-androgenic steroids (AAS) use is a significant public health problem, with nearly 4 million Americans having used AAS. Roughly 30% of AAS users develop AAS dependence, among the highest dependence rates of all abused drugs. Polydrug abuse is highly prevalent among AAS users. AAS use causes acute psychiatric effects such as aggression and violence, and as we reported in past, long-term AAS use is associated with visuospatial memory dysfunction on tests predictive of early dementia. To date, human brain correlates of long-term AAS use are largely unexplored. Our pilot imaging studies in long-term AAS users produced 3 compelling findings. First, the amygdala is enlarged by AAS, consistent with controlled preclinical studies. Second, AAS reduced functional connectivity between the amygdala and dorsal anterior cingulate cortex (dACC), a cognitive control region. Third, in magnetic resonance spectroscopy studies, AAS users had elevated glutamine/glutamate ratios and lower scyllo-inositol levels in dACC, suggestive of ongoing dysfunction and possible neurotoxicity. As the amygdala participates in emotion regulation, visuospatial processing, sensory integration/processing of appetitive/aversive stimuli, cost/benefit decision-making, and drug reward, seeking, and cue reactivity, and together with the dACC modulates approach/avoidance learning and monitors emotional conflicts, amygdala and dACC abnormalities could impair all of these processes. Because commonly used AAS increase ?-amyloid levels and scyllo-inositol prevents ?-amyloid clumping, our scyllo- inositol finding may be particularly important. In this R01 application, we aim to build upon initial findings by directly probing amygdala and hippocampal function with task-based BOLD fMRI paradigms, including a source memory paradigm and the Hariri emotional face paradigm. We also will acquire MRS spectra from dACC and parieto-occipital cortex, the latter of which is a target for early ?-amyloid accumulation, to determine whether glutamine/glutamate and scyllo-inositol/creatine metabolite ratio abnormalities also occur in posterior cingulate cortex, a region normally exhibiting early ?-amyloid accumulation. Proposed studies involve large sample sizes that are adequately powered to test a priori hypotheses. Resulting data will help to identify the neural bases for psychiatric and cognitive abnormalities in AAS users, to gauge the severity of brain effects from long-term AAS use, and to inform the design of future studies to examine the progression of such effects with continued AAS use and/or aging, including interventional studies with agents such as scyllo-inositol or NMDA receptor antagonists. We have access to well-characterized AAS users and controls, recruited for our nearly-completed NIDA-funded cardiovascular studies, and the ability to recruit new subjects meeting inclusion/exclusion criteria. Our team is highly experienced with these populations and with proposed assessment methods, and thus is uniquely poised to conduct this research. Accordingly, this program is feasible and, if successful, likely will exert a sustained and powerful influence on the field.

Summary/Abstract Between 3-4 million Americans, mostly men, have used anabolic-androgenic steroids (AAS) illicitly to increase muscularity. There are nearly 100,000 new AAS users each year and more than 30% of AAS users, or about 1 million men, have developed AAS dependence, among the highest dependence rates of all abused drugs. Emerging data from our group and others indicate that long-term AAS use impairs memory, alters brain structure and chemistry, induces abnormal androgen levels and increases excess oxidative stress, effects similar to those found in people diagnosed with or who develop Alzheimer?s Disease and its related dementias (AD/ADRD). The abnormally high and low androgen levels experienced by AAS users when taking and abstaining from AAS, respectively, induce excess oxidative stress. Chronic high or low androgen levels or excess oxidative stress increase the production of and reduce the elimination of beta-amyloid and hyperphosphorylated Tau (Tau-P) proteins, thereby increasing beta-amyloid and Tau-P burdens. Thus, a strong scientific premise supports our hypothesis that nearly 1 million AAS-dependent men are at increased risk for developing AD/ADRD as they age. In spontaneous AD/ADRD, beta-amyloid burdens begin to increase at about age 40. We hypothesize that AAS use, which begins at a median age of 22, initiates beta-amyloid and Tau-P protein increases nearly 2 decades earlier than would occur naturally, resulting in higher beta-amyloid and Tau-P burdens in middle-aged AAS users. This Administrative Supplement to R01DA041866-01A1 seeks support to assess, for the first time, whether long-term AAS users have elevated brain beta-amyloid and Tau-P burdens, using Positron Emission Tomography of [11C]-Pittsburgh compound B and [18F]-Flortaucipir, respectively. Brain beta-amyloid and Tau-P burdens in AAS users will be compared to burdens in healthy controls on file matched for age and other demographic factors. Additionally, using cognitive testing and magnetic resonance spectroscopy procedures that are part of our parent R01, we will assess whether beta- amyloid and Tau-P burdens in AAS users are associated with visuospatial memory performance and anterior cingulate scyllo-inositol levels, the former of which predicts development of AD/ADRD and the latter of which reduces beta-amyloid burdens, to determine whether memory performance and scyllo-inositol levels predict beta-amyloid or Tau-P burdens. The resulting data will either refute our hypothesis or form a foundation that supports future studies of beta-amyloid and Tau-P burdens in AAS users. Since hypogonadism and excess oxidative stress occur as a consequence of normal aging in men and in women, and because both conditions can be mitigated by existing therapies and by newer more potent antioxidants, the data we obtain could lead to new ways to diagnose or treat AD/ADRD in the general population as well as in AAS users.