Plasticity in the dopamine 1 receptor system : behavior and cell biological studies
Author: Scott, Lena
Date: 2004-10-01
Location: Skandiasalen, Astrid Lindgrens Barnsjukhus, Q3:01
Time: 9.00
Department: Institutionen för kvinnors och barns hälsa / Department of Women's and Children's Health
Abstract
Dopamine is a key neurotransmitter in the brain, and has an important
modulatory role in the control of motor activity and cognitive processes.
Dysfunctions of the dopamine system have been implicated in several
neuropsychiatric disorders such as schizophrenia and
attention-deficit/hyperactivity disorder.
In this thesis we address questions concerning plasticity of the dopamine DI receptor system by performing both behavioral studies, looking at potential postnatal maturational changes in D1 receptor mediated motor activity, and in vitro studies, looking at potential effects of NMDA receptor activation on dopamine signaling. We show that DI receptor activation can induce both inhibition and stimulation of motor activity, and that the development of these two response patterns are different, and associated with distinct patterns of c-fos expression within the prefrontal cortex and striatum. We also show that functional DARPP-32 signaling is necessary for the development of the motor stimulatory effects of D1 receptors. There is increasing evidence indicating that interactions between different types of neurotransmitter receptors represent a major mechanism of neuronal plasticity.
To explore the molecular mechanisms behind dopamine plasticity, we have performed a series of experimental studies on primary cell cultures and organotypic cultures. We have shown that NMDA receptor activation induces DI receptor recruitment to dendritic spines and that this recruitment is dependent on interaction between the D1 receptor and the NMDA receptor. We demonstrate that there is a reservoir pool of DI receptors diffusing in dendrites and that these receptors can, following NMDA receptor activation, be trapped by interaction with NMDA receptors. We have shown with behavior studies a series of manifestations of plasticity in dopamine signaling, and provided evidence for a regulated recruitment of a G-protein coupled receptor to functional sites in neurons, and provided a basis for the regulatory effect of the glutamate system on dopamine signaling.
In this thesis we address questions concerning plasticity of the dopamine DI receptor system by performing both behavioral studies, looking at potential postnatal maturational changes in D1 receptor mediated motor activity, and in vitro studies, looking at potential effects of NMDA receptor activation on dopamine signaling. We show that DI receptor activation can induce both inhibition and stimulation of motor activity, and that the development of these two response patterns are different, and associated with distinct patterns of c-fos expression within the prefrontal cortex and striatum. We also show that functional DARPP-32 signaling is necessary for the development of the motor stimulatory effects of D1 receptors. There is increasing evidence indicating that interactions between different types of neurotransmitter receptors represent a major mechanism of neuronal plasticity.
To explore the molecular mechanisms behind dopamine plasticity, we have performed a series of experimental studies on primary cell cultures and organotypic cultures. We have shown that NMDA receptor activation induces DI receptor recruitment to dendritic spines and that this recruitment is dependent on interaction between the D1 receptor and the NMDA receptor. We demonstrate that there is a reservoir pool of DI receptors diffusing in dendrites and that these receptors can, following NMDA receptor activation, be trapped by interaction with NMDA receptors. We have shown with behavior studies a series of manifestations of plasticity in dopamine signaling, and provided evidence for a regulated recruitment of a G-protein coupled receptor to functional sites in neurons, and provided a basis for the regulatory effect of the glutamate system on dopamine signaling.
List of papers:
I. Heijtz RD, Beraki S, Scott L, Aperia A, Forssberg H (2002). "Sex differences in the motor inhibitory and stimulatory role of dopamine D1 receptors in rats. " Eur J Pharmacol 445(1-2): 97-104
Pubmed
II. Diaz Heijtz R, Scott L, Forssberg H (2004). "Alteration of dopamine D1 receptor-mediated motor inhibition and stimulation during development in rats is associated with distinct patterns of c-fos mRNA expression in the frontal-striatal circuitry. " Eur J Neurosci 19(4): 945-56
Pubmed
III. Scott L, Forssberg H, Aperia A, Diaz-Heijtz R (2004). "Post-weanling development of dopamine 1 receptor/DARPP-32 regulated motor activity." (Manuscript)
IV. Scott L, Kruse MS, Forssberg H, Brismar H, Greengard P, Aperia A (2002). "Selective up-regulation of dopamine D1 receptors in dendritic spines by NMDA receptor activation." Proc Natl Acad Sci U S A 99(3): 1661-4. Epub 2002 Jan 29
Pubmed
V. Scott L, Zelenin S, Malmersjo S, Zettergren-Markus E, Greengard P, Brismar H, Aperia A (2004). "NMDA receptor activation traps diffusible dopamine 1 receptors in spines." (Manuscript)
I. Heijtz RD, Beraki S, Scott L, Aperia A, Forssberg H (2002). "Sex differences in the motor inhibitory and stimulatory role of dopamine D1 receptors in rats. " Eur J Pharmacol 445(1-2): 97-104
Pubmed
II. Diaz Heijtz R, Scott L, Forssberg H (2004). "Alteration of dopamine D1 receptor-mediated motor inhibition and stimulation during development in rats is associated with distinct patterns of c-fos mRNA expression in the frontal-striatal circuitry. " Eur J Neurosci 19(4): 945-56
Pubmed
III. Scott L, Forssberg H, Aperia A, Diaz-Heijtz R (2004). "Post-weanling development of dopamine 1 receptor/DARPP-32 regulated motor activity." (Manuscript)
IV. Scott L, Kruse MS, Forssberg H, Brismar H, Greengard P, Aperia A (2002). "Selective up-regulation of dopamine D1 receptors in dendritic spines by NMDA receptor activation." Proc Natl Acad Sci U S A 99(3): 1661-4. Epub 2002 Jan 29
Pubmed
V. Scott L, Zelenin S, Malmersjo S, Zettergren-Markus E, Greengard P, Brismar H, Aperia A (2004). "NMDA receptor activation traps diffusible dopamine 1 receptors in spines." (Manuscript)
Issue date: 2004-09-10
Publication year: 2004
ISBN: 91-7140-060-5
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