Localization and differential regulation of dopamine D2 and D3 receptors in the rat brain / Gregg D. Stanwood.

Format:

Book

Manuscript

Microformat

Thesis/Dissertation

Author/Creator:

Stanwood, Gregg D.

Contributor:

Palmer, Larry, advisor.

McGonigle, Paul, advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Neuroscience.

Neuroscience--Penn dissertations.

Neurosciences.

Academic Dissertations as Topic.

Medical Subjects:

Neurosciences.

Academic Dissertations as Topic.

Local Subjects:

Penn dissertations--Neuroscience.

Neuroscience--Penn dissertations.

Physical Description:

xviii, 176 pages : illustrations (some color) ; 29 cm

Production:

1998.

Summary:

Alterations in the expression and functional activity of dopamine D2 and D3 receptors are thought to contribute to several motor and cognitive disturbances including Parkinson's disease, schizophrenia and drug addiction. The localization and regulatory properties of D2 and D3 receptors were therefore examined in the rat brain. The binding of a novel dopamine receptor radioligand, ($\sp{125}$I) -7-OH-PIPAT, was characterized using quantitative receptor autoradiography. Kinetic, saturation, and competition analyses demonstrated that under the appropriate conditions ($\sp{125}$I) -7-OH-PIPAT selectively labels D3 receptors in rat brain sections. D3 receptors were found in the islands of Calleja, nucleus accumbens shell, ventral pallidum, substantia nigra and cerebellum. The presence of low densities of D3 receptor expression were also detected in several regions not previously reported including the serotonergic raphe nuclei. Comparison of the distribution of D3 receptors with that of D2 receptors labeled with ($\sp{125}$I) -NCQ 298 revealed a lower level of expression and more restricted distribution for D3 receptors. Examination of the early postnatal ontogeny of D3 and D2 receptors indicated that D2 receptors are expressed significantly earlier than D3 receptors which may account for changes in the sensitivity to dopaminergic agonists observed during development. The cellular localization of D3 and D2 receptors in adult animals was studied using neurochemical lesion techniques. Destruction of dopaminergic neurons originating in the substantia nigra and ventral tegmental area with 6-OHDA resulted in decreases in D3 receptor levels in these regions consistent with D3 receptor expression by dopaminergic cells. Destruction of GABAergic projection neurons in the NA with quinolinic acid resulted in decreases in the nucleus accumbens, ventral pallidum, and substantia nigra consistent with expression of D3 receptors on the cell bodies and axon terminals of these neurons. Based on lesions using 5,7-DHT, neither D2 nor D3 receptors appear to be expressed on serotonergic neurons in the rat brain. The regulatory properties of D2 and D3 receptors were assessed using several chronic drug treatments designed to increase or decrease dopammergic neurotransmission. Depletion of dopamine with chronic reserpine treatment significantly increased D2 receptor levels in all regions examined while concomitantly decreasing D3 receptor levels in these regions. Conversely, chronic administration of the D2-1ike receptor agonists quinpirole or 7-OH-DPAT produced decreases in D2 receptors, but significant increases in D3 receptors. Treatment with the irreversible antagonist EEDQ revealed markedly greater occupancy of D3 receptors than D2 receptors by dopamine in vivo and regional heterogeneity in the extent of inactivation that correlated with the changes induced by agonist administration. Chronic administration of the psychomotor stimulant cocaine to increase dopaminergic activity, or the GABA$\sb{\rm b}$ agonist baclofen to inhibit dopamine neuronal firing produced no changes in either D2 or D3 receptor expression. These data on the regional and cellular location of the D3 receptor and differential regulatory properties of D2 and D3 receptors provide insights into the possible functions of these receptors.

Notes:

Advisers: Larry Palmer; Paul McGonigle.

Thesis (Ph.D. in Neuroscience) -- University of Pennsylvania, 1998.

Includes bibliographical references.

Local Notes:

University Microfilms order no.: 98-29996.

OCLC:

187470997