1998 — 2000 |
Rademacher, David J |
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.). |
Cns Mediation of Cocaine Induced Substrate Interactions @ University of Wisconsin Milwaukee
DESCRIPTION: (Applicant's Abstract) The appetitive properties of cocaine are widely believed to be mediated through dopamine transmission in the mesocorticolimbic system. There is extensive evidence documenting opioid-catacholamine interactions, and it has been suggested that drugs used to treat opiate addiction may be effective in treating cocaine addiction. While naltrexone is an opioid pharmacological treatment for addiction, methylnaloxonium is a structurally similar opioid compound that may be more useful for examining dopamine turnover because it does not diffuse as readily into surrounding structures therefore making discrete central injections possible. The goal of the present study is to determine in vivo the relative efficacy of these compounds in the rat by testing the hypothesis that these compounds will differ in terms of their effects on both acute and chronic cocaine-induced extracellular dopamine and dopamine metabolite elevations in the ventral segmental area, the nucleus accumbens, and the prefrontal cortex. This will be accomplished by intracranial administration of these opioid antagonists to one mesocorticolimbic structure and the systemic administration of cocaine while simultaneously sampling from another mesocorticolimbic structure via microdialysis. The results of the study will provide scientists with a better understanding of: (l) the substrate through which opioid antagonists interfere with cocaine's rewarding effects, and (2) the relative usefulness of methylnaloxonium over naltrexone in vivo central nervous system studies of dopamine interactions.
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1 |
2003 — 2005 |
Rademacher, David J |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Characterization of the Anandamide Uptake Transporter @ Medical College of Wisconsin
[unreadable] DESCRIPTION (provided by applicant): [unreadable] Some very exciting and important pathophysiological roles for the anandamide/cannabinoid receptor signaling system have been identified. Cannabinoid receptor activation by anandamide has been implicated in hemorrhagic hypotension, endotoxin-induced septic shock, pain perception, neuroprotection, and the alleviation of spasticity in a variety of conditions. The anandamide/cannabinoid receptor signaling pathway is important for normal embryonic fertilization, implantation, and development. The purpose of the present research is to provide for a better understanding of the biochemistry of anandamide inactivation through an uptake carrier. [unreadable] [unreadable] This will be accomplished by: (a) Measuring the accumulation of anandamide in a model devoid of intracellular binding sites and fatty acid amide hydrolase (FAAH); (b) Determining under what conditions, cell types, and to what extent a coupling between anandamide uptake and FAAH activity occurs; and (c) Isolating, purifying, and sequencing an intracellular anandamide binding protein. [unreadable] [unreadable] [unreadable] [unreadable]
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0.943 |
2006 |
Rademacher, David J. |
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. |
Cart Peptide Modulation of Stimulant Reward @ Rosalind Franklin Univ of Medicine &Sci
DESCRIPTION (provided by applicant): Drug abuse is a chronic relapse mental disorder that affects millions of people. However, there are few effective treatments and the outlook for new ones is not promising because of the poor understanding of the causes of addiction. In recent years, several novel genes and proteins have been described that may have a role in drug addiction and merit consideration for study. CART (Cocaine and Amphetamine-Regulated Transcript) peptides are a family of neuropeptides whose function in the brain is poorly understood but are thought to be important to the motivation and in the addictive properties of stimulants such as cocaine and amphetamine. This proposal will test the hypothesis that CART peptides modulate the rewarding properties of stimulants such as cocaine and amphetamine. CART peptides are thought to enhance the neural coding for reward associated with stimulants. Although CART peptides are best known for their ability to suppress food intake -- a classic feature of stimulants, they were initially identified by us because cocaine and amphetamine increase its expression of its gene in the rat nucleus accumbens, a brain area associated with motivation. The distribution of CART and CART peptides in neural circuitry of motivation is unique among chemical transmitters and receptors. Our recent studies show that CART knockout (KO) mice exhibit decreased locomotor responses to amphetamine compared to wild-type mice. A recent report shows that CART peptides produce conditioned place preference in rats. These and other data suggest that the rewarding property of stimulants is regulated by CART peptides. The role of CART peptides in the rewarding properties of stimulants will be tested three ways. First, a series of CART peptides, some of which are novel, will be produced by expression in heterologous cells. Second, the stimulatory and conditioning properties of these CART peptides as well as endogenous ones will be tested by measuring their effects on locomotor activity and conditioned place preference in rats. Third, the effects of cocaine and amphetamine as well as CART peptides on CART KO mice will be investigated at a behavioral, cellular and molecular level. These studies will determine whether CART peptides modulate the rewarding properties of stimulants. CART peptides may be possible substrates of stimulant addiction, and as such, they represent a novel therapeutic target. Selective CART peptide pharmacotherapies for stimulant addiction may be successful because these peptides show a restricted distribution in brain, and as neuropeptides, they have modulatory functions in chemical signaling. These medications may also find use in the treatment of obesity and eating related disorders. Hence, this work has implications for the biology and treatment of drug addiction, but also for food related disorders.
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0.918 |
2009 — 2010 |
Rademacher, David J. |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
The Role of Activity-Regulated Cytoskeletal-Associated Protein in Amphetamine Pla @ Rosalind Franklin Univ of Medicine &Sci
DESCRIPTION (provided by applicant): According to incentive-sensitization theory of addiction, the critical change in addiction leading to compulsive drug pursuit is in the ability of drug-associated cues to engage a sensitized motivational response that, in turn, leads to enhanced drug pursuit. In this view, the problem is not the formation of aberrant and/or excessively strong associations between environmental cues and drug, but rather enhanced ability of drug-associated stimuli to engage brain motivational systems. Associations between a contextual conditioned stimulus and the drug unconditioned stimulus are formed in the basolateral amygdala. The conditioned place preference (CPP) paradigm models the formation of the associations between contextual cues and the rewarding effects of drugs of abuse and there is evidence to suggest that formation of associations between context and drug is accompanied by increased synapses in the basolateral amygdala (Rademacher et al. 2006). Activity-regulated cytoskeletal associated protein (Arc) is induced by acute psychostimulant administration (Tan et al., 2000) and behavioral experience that leads to long-lasting synaptic modifications (Kelly &Deadwyler, 2003). Importantly, there is a correlation between Arc protein expression in dendritic spines and the onset of synaptogenesis (Wang &Pickel, 2004). In this application, the hypothesis that amphetamine- (AMPH) induced CPP targets Arc to dendritic structures such as the spines of pyramidal neurons and/or dendrites of interneurons of the basolateral amygdala will be tested. If the data support this hypothesis, then memories for contextual cues paired with drug could be disrupted by blocking Arc, which would diminish drug-craving and drug-seeking behavior and decrease the probability of relapse. In Specific Aim 1, dual-label immunohistochemistry and laser-scanning confocal microscopy will be used to determine whether AMPH place conditioning alters Arc expression in basolateral amygdala pyramidal neurons and/or interneurons. In Specific Aim 2, light microscopy, a dual label immunoperoxidase/immunogold technique, electron microscopy, and unbiased stereology will be used to determine whether AMPH place conditioning alters Arc expression in dendritic structures of pyramidal neurons and/or interneurons in the basolateral amygdala. In human addicts, exposure to environmental cues previously associated with drug use strongly increases the risk of relapse. Developing effective treatments for addiction requires a better understanding of the neural substrates responsible for drug-seeking behavior. This proposal is intended to study how the neural circuitry in the basolateral amygdala is altered after repeated pairings between environmental context and drug.
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0.918 |