On the mechanism underlying drug -evoked gene expression in striatopallidal neurons: Implications for psychomotor sensitization.
Ferguson, Susan Marie
2004
Abstract
Psychostimulants and morphine produce many shared behavioral and neurobiological adaptations, such as psychomotor sensitization and the induction of immediate early genes (IEGs) in the striatum. Previous studies have found that the environmental context surrounding drug administration can profoundly influence the development of psychomotor sensitization to these drugs. In addition, this factor can have a large impact on which neural circuits are engaged by psychostimulants. When given in the home cage, psychostimulants induce IEGs predominately in striatal neurons that co-express mRNA for preprodynorphin and preprotachykinin and are part of the striatonigral pathway. When given in a novel test environment, however, psychostimulants also induce IEGs in striatal neurons that contain preproenkephalin mRNA and are part of the striatopallidal pathway. The purpose of the experiments presented in this dissertation was to explore the mechanism by which environmental context modulates the ability of psychostimulants and morphine to induce IEGs in these striatofugal circuits, and produce psychomotor sensitization. Specifically, the following questions were addressed: (1) How do dopamine D1 and D2 receptors modulate amphetamine-evoked c-<italic>fos</italic>+ striatonigral and striatopallidal neurons? (2) How do glutamate NMDA receptors and corticostriatal glutamatergic afferents modulate amphetamine-evoked c-<italic>fos</italic>+ striatonigral and striatopallidal neurons? (3) What is the role of the ERK/MAPK signaling cascade in psychostimulant-evoked c-<italic>fos</italic>+ striatonigral and striatopallidal neurons, and psychomotor sensitization? (4) Do factors such as dose, the environmental context surrounding drug administration and drug history have similar influences over morphine-induced c-<italic>fos</italic>+ striatonigral and striatopallidal neurons, as has been found with psychostimulants? We report that psychostimulant-evoked c-<italic>fos</italic>+ striatopallidal neurons are highly susceptible to regulation by dopamine D1 and D2 receptors, NMDA glutmate receptors and the ERK/MAPK signaling cascade, and that corticostriatal afferents are the likely source of glutamatergic regulation of these neurons. In addition, we report that the ERK/MAPK signaling cascade modulates the development of psychomotor sensitization to psychostimulant drugs. Finally, we report that dose, the environmental context surrounding drug administration and drug history have a large influence over which neural circuits are engaged by morphine. This work has important implications for the role that environmental context may play in facilitating psychomotor sensitization as well as in initiating the neuroadaptations associated with this form of drug experience-dependent behavioral plasticity.Subjects
Drug-evoked Expression Gene Implications Mechanism Neurons Psychomotor Sensitization Striatopallidal Underlying
Types
Thesis
Metadata
Show full item recordCollections
Remediation of Harmful Language
The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.
Accessibility
If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.