The caudate-putamen (CPu) is the major input and processing component of the basal ganglia. Dysfunctions involving the basal ganglia, and the CPu in particular, have been linked to a number of neuropsychiatric disorders, including Tourette's syndrome, ADHD, autism, and pediatric obsessive-compulsive disorder. The goal of this project is to employ an ontogenetic research strategy to examine the maturation of dopamine (DA) mediated behaviors in preweanling, adolescent, and adult rats. In the first set of experiments (Specific Aim 1), locomotor activity and stereotypy will be assessed after DA drugs are infused into discrete subregions of the CPu. It is anticipated that DA agonists and antagonists will induce a different pattern of behavioral effects in the three age groups, thus indicating that the neural mechanisms mediating behavior undergo substantial ontogenetic modification.
In Specific Aims 2 and 3, EEDQ will be utilized because it is a drug known to cause pronounced age-dependent behavioral effects in preweanling and adult rats. Specifically, infusing EEDQ into the dorsal CPu attenuates the DA agonist-induced locomotion of adult rats, while potentiating the locomotor activity of preweanling rats. In the behavioral experiments (Specific Aim 2), D1 and/or D2 receptors will be selectively protected from EEDQ-induced inactivation in order to determine which receptor type is responsible for causing locomotor potentiation in preweanling and adolescent rats. NonDA drugs will also be used to determine whether DA receptor inactivation causes a generalized increase in behavioral responsiveness or whether the locomotor potentiation exhibited by preweanling rats is unique to DA agonists. The neural basis of EEDQ's paradoxical behavioral effects will be determined in Specific Aim 3. One explanation is that preweanling rats have a substantial D2 receptor reserve that allows them to exhibit DA agonist-induced behaviors even after a large number of receptors are inactivated by EEDQ. Alternatively, it is possible that surviving or newly synthesized DA receptors are supersensitive and, thus, are capable of mediating a potentiated locomotor response. To test these ideas, D1 agonist-stimulated adenylyl cyclase activity and D2 agonist-modulated acetylcholine release will be used to estimate the size of D1 and D2 receptor reserves in the CPu of preweanling, adolescent, and adult rats. Various techniques will be used to assess receptor super sensitivity, including agonist competition and GTP?S binding assays, as well as G?olf and RGS9 immunoblotting (these proteins are associated with super sensitized D1 and D2 receptors). We predict that age- dependent changes in EEDQ-induced receptor super sensitivity, perhaps caused by a rapid repopulation of D2 receptors, is responsible for the paradoxical behavioral effects produced by DA receptor inactivation. In summary, the goal of this grant proposal is to employ an innovative combination of established techniques to examine ontogenetic changes in the way the CPu mediates behavior. This type of ontogenetic research is necessary to determine the neural bases of developmental neuropsychiatric disorders.

Public Health Relevance

Dysfunctions within the dopamine-rich caudate-putamen (CPu) have been linked to a number of developmental psychiatric and neurological disorders, including Tourette's syndrome, ADHD, autism, tic disorder, conduct disorder, and pediatric obsessive-compulsive disorder. In order to determine the ontogeny of dopamine- mediated behaviors, various dopaminergic compounds will be directly infused into discrete sub regions of the caudate-putamen during adulthood, adolescence, and the preweanling period (analogous to childhood). Understanding how dopamine system functioning changes across ontogeny will provide important insights into the neural mechanisms underlying syndromes associated with CPu dysfunction.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Enhancement Award (SC1)
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Special Emphasis Panel (ZGM1-TWD-7 (SC))
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Winsky, Lois M
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California State University San Bernardino
Schools of Arts and Sciences
San Bernardino
United States
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