1998 — 2002 |
Steiner, Heinz |
R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Opioid Peptides and Cocaine Abuse @ University of Tennessee Health Sci Ctr
DESCRIPTION: Applicant's Abstract The long-term objective of this research proposal is to determine functional consequences of changed gene expression in neurons of the basal ganglia after chronic treatment with psychomotor stimulants such as cocaine. The reinforcing effects of such drugs of abuse are thought to be mediated by the dopamine neurotransmission in the forebrain. Evidence has been presented that excessive stimulation of dopamine receptors produced by such drugs results in neuroadaptive changes in dopamine-receptive neurons including changes in gene expression. Such neuronal alterations may play a role in the behavioral changes that occur during chronic cocaine use/treatment. Research in animal models and studies of brains of human cocaine addicts have shown that changes in gene regulation produced by cocaine include increased expression of the opioid peptide dynorphin in neurons of the striatum that project to the basal ganglia output nuclei (e.g., substantia nigra). Our previous results indicate that such increased dynorphin levels function to reduce or blunt dopamine input to striatonigral neurons. The proposed research will investigate functional consequences of increased dynorphin expression on different levels. (1) We will determine whether dynorphin/kappa opioid receptor agonists can act in the striatum to inhibit dopamine receptor responses (i.e., induction of immediate-early genes) in striatonigral neurons. (2) Our studies will also determine whether repeated cocaine treatment affects gene expression in target neurons of the striatonigral pathway, and whether such changes are related to the increased dynorphin expression. (3) In these studies, changes in gene regulation will be correlated with behavioral changes that occur during repeated cocaine treatment, to determine the contribution of changed dynorphin function to behavioral effects of chronic cocaine treatment. Changes in gene expression will be assessed with quantitative in situ hybridization histochemistry. This work will provide new insights into mechanisms of opioid and dopamine receptor regulation of basal ganglia function. Furthermore, by showing how altered dynorphin function during chronic cocaine treatment affects the striatonigral pathway and behavior, this work may help to establish a cellular basis for new approaches in the treatment of cocaine abuse.
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0.981 |
2002 — 2003 |
Steiner, Heinz |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Behavior/Drug Interactions in Striatal Gene Regulation @ Rosalind Franklin Univ of Medicine &Sci
DESCRIPTION: (provided by applicant) Exposure to psychostimulants such as cocaine and amphetamine causes behavioral changes including addiction and dependence. Addiction is defined by compulsive drug taking and may involve abnormal motor learning/habit formation, a function that has been ascribed to dorsal parts of the striatum. Motor learning likely involves modification of synaptic connections and altered gene regulation. Many studies have shown that psychostimulants produce changes in the expression of various genes, including genes that encode transcription factors, structural proteins and signaling molecules. Moreover, such gene regulation preferentially occurs in dorsal striatal sectors that are part of "motor" loops that interconnect the cortex and the basal ganglia. Neuronal changes related to motor learning/habit formation would be expected to be triggered during (or in close association with) motor performance and be related to such performance. The experiments of the present proposal will investigate whether the behavior performed during the influence of cocaine can modify neuronal changes produced by cocaine. Thus, we propose to test the hypothesis that different behaviors during cocaine action will be associated with different changes in gene expression in striatal neurons. Differential "behavioral treatment" will consist of repeated exposure to a running wheel vs. a small open field immediately after the cocaine injection. In situ hybridization histochemistry will be used to compare changes in gene expression in various striatal sectors between such differentially treated rats. Initially, a short-term molecular marker (c-fos induction by a cocaine challenge) and longer-term markers (neuropeptides such as dynorphin) will be assessed. As a first step to determine behavioral effects, open-field behavior induced by a cocaine or vehicle challenge will be examined subsequent to the repeated treatments. These studies should provide new insights into how the behavior executed during the drug action can influence drug-induced neuroplasticity in the striaturn.
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0.981 |
2005 — 2009 |
Steiner, Heinz |
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. |
Basal Ganglia Output and Psychostimulant Abuse @ Rosalind Franklin Univ of Medicine &Sci
DESCRIPTION (provided by applicant): Interactions between the basal ganglia and the cerebral cortex are critical for the organization of motivated behavior and are implicated in psychostimulant addiction. Dopamine in the striatum regulates these interactions. Exposure to psychostimulants such as cocaine produces changes in gene expression in striatal neurons that are part of the anatomical circuits that interconnect the basal ganglia and the cortex. Such molecular changes likely alter activity in these circuits and seem to play a role in drug-induced behavioral changes such as addiction and dependence. The long-term objective of this research project is to determine functional consequences of psychostimulant-induced molecular changes in striatal output neurons, with focus on their effects on cortical function. The proposed research will investigate how changes in striatal output produced by cocaine affect cortical function, by using immediate-early genes (lEGs) as functional markers. For one, "basal" expression of lEGs in defined cortical regions will be assessed. In addition, sensory-evoked responses in the sensorimotor cortex (i.e., lEG expression evoked by whisker stimulation) will be examined as a model of cortical function. The proposed studies will (1) determine and compare the effects of acute and repeated cocaine treatment on "basal" and sensory-evoked cortical lEG expression. (2) The relative contributions of D1- and D2 dopamine receptor-regulated striatal outputs to these cortical effects will be assessed by intrastriatal administration of selective dopamine receptor antagonists. (3) Other studies will investigate the anatomical pathways that mediate this basal ganglia-cortical regulation. These studies will further our understanding of the mechanisms that govern basal ganglia-cortical interactions and will show how these interactions are changed by the psychostimulant cocaine. This work will help establish an improved cellular framework necessary to understand and successfully treat cocaine addiction.
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0.981 |
2019 — 2021 |
Bolanos, Carlos A. Steiner, Heinz |
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. |
Serotonin Receptors That Potentiate Addiction-Related Behavioral and Molecular Effects Induced by Methylphenidate Plus Ssri Exposure @ Rosalind Franklin Univ of Medicine & Sci
Project Summary/Abstract: Scores of people are being exposed to drug combinations that include methylphenidate (Ritalin) plus a selective serotonin reuptake inhibitor (SSRI). Such drug combinations are indicated for attention-deficit hyperactivity disorder (ADHD)/depression or anxiety comorbidity (in up to 40% of pediatric ADHD) and other psychiatric disorders. High-dose co-exposure also occurs, for example, in patients on SSRIs who abuse methylphenidate as a ?cognitive enhancer? or party drug. Many of these subjects are children or adolescents. This is a public health concern because of potential long-term behavioral and neuronal changes induced by these psychotropic drugs. Methylphenidate (a dopamine/norepinephrine reuptake inhibitor), given alone, mimics some, but not other, molecular effects of cocaine. These effects are less robust presumably because methylphenidate does not affect serotonin systems. Indeed, research in the applicants' laboratories shows that treatment with an SSRI in conjunction with methylphenidate potentiates abuse/addiction-related behavior and gene regulation, thus producing ?cocaine-like? behavioral and molecular profiles. It is unknown which serotonin receptor subtype(s) mediate these SSRI (serotonin) effects. The long-term goal of this project is to better understand how serotonin and dopamine interact to induce their effects on drug addiction-related behavior and neuronal processes. The objective of this application is to determine serotonin receptor subtypes and cell types that mediate the effects of methylphenidate plus SSRI combinations on behavioral responses to cocaine and gene regulation in striatum and nucleus accumbens in adolescent male and female rats. The central hypothesis is that SSRIs potentiate methylphenidate effects on both cocaine-induced behavior and gene regulation via activation of specific serotonin receptor subtypes. This hypothesis is based on preliminary data from the applicants' laboratories. The rationale for the proposed work is the necessity to determine the involved serotonin receptor subtypes and neuron populations, in order to lay the groundwork for identifying novel pharmacological interventions that avoid these effects. The central hypothesis will be tested by pursuing three specific aims: 1) Determine behavioral and neuronal consequences of combined methylphenidate+SSRI (fluoxetine) treatment, comparing clinically relevant doses and ?abuse doses?; 2) Determine serotonin receptor subtypes that contribute to the methylphenidate+SSRI effects on behavior and gene regulation; 3) Determine brain sites and cell populations that mediate these behavioral and molecular changes. Effects on behavior will be determined using the cocaine-induced place preference conditioning (CPP) and sensitization models. Effects on gene regulation will be assessed by in situ hybridization, RT-qPCR, and Western blot analyses. These techniques are well-established in our labs. The proposed research is significant, because elucidating the mechanisms by which serotonin potentiates psychostimulant-induced behavioral and neuronal changes will inform the future development of novel antidepressants that avoid these potential health risks.
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0.981 |