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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29DA011261-02
Application #
2898174
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Pilotte, Nancy S
Project Start
1998-09-30
Project End
2000-04-30
Budget Start
1999-07-01
Budget End
2000-04-30
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Alter, David; Beverley, Joel A; Patel, Ronak et al. (2017) The 5-HT1B serotonin receptor regulates methylphenidate-induced gene expression in the striatum: Differential effects on immediate-early genes. J Psychopharmacol 31:1078-1087
Pedron, Solène; Beverley, Joel; Haffen, Emmanuel et al. (2017) Transcranial direct current stimulation produces long-lasting attenuation of cocaine-induced behavioral responses and gene regulation in corticostriatal circuits. Addict Biol 22:1267-1278
Van Waes, Vincent; Ehrlich, Sarah; Beverley, Joel A et al. (2015) Fluoxetine potentiation of methylphenidate-induced gene regulation in striatal output pathways: potential role for 5-HT1B receptor. Neuropharmacology 89:77-86
Van Waes, Vincent; Vandrevala, Malcolm; Beverley, Joel et al. (2014) Selective serotonin re-uptake inhibitors potentiate gene blunting induced by repeated methylphenidate treatment: Zif268 versus Homer1a. Addict Biol 19:986-95
Steiner, Heinz; Warren, Brandon L; Van Waes, Vincent et al. (2014) Life-long consequences of juvenile exposure to psychotropic drugs on brain and behavior. Prog Brain Res 211:13-30
Unterwald, Ellen M; Page, Michelle E; Brown, Timothy B et al. (2013) Behavioral and transcriptome alterations in male and female mice with postnatal deletion of TrkB in dorsal striatal medium spiny neurons. Mol Neurodegener 8:47
Steiner, Heinz; Van Waes, Vincent (2013) Addiction-related gene regulation: risks of exposure to cognitive enhancers vs. other psychostimulants. Prog Neurobiol 100:60-80
Van Waes, Vincent; Carr, Betsy; Beverley, Joel A et al. (2012) Fluoxetine potentiation of methylphenidate-induced neuropeptide expression in the striatum occurs selectively in direct pathway (striatonigral) neurons. J Neurochem 122:1054-64
Heng, Lijun; Beverley, Joel A; Steiner, Heinz et al. (2011) Differential developmental trajectories for CB1 cannabinoid receptor expression in limbic/associative and sensorimotor cortical areas. Synapse 65:278-86
Van Waes, Vincent; Tseng, Kuei Y; Steiner, Heinz (2011) GPR88 - a putative signaling molecule predominantly expressed in the striatum: Cellular localization and developmental regulation. Basal Ganglia 1:83-89

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