Identification and characterization of alpha(2C)-adrenoceptors in rat striatum.

摘要

Three subtypes of {dollar}alphasb2{dollar}-adrenoceptors {dollar}(alphasb{lcub}rm 2A{rcub}, alphasb{lcub}rm 2B{rcub}, alphasb{lcub}rm 2C{rcub}){dollar} have been identified by pharmacological characterization and molecular cloning. In the brain, {dollar}alphasb{lcub}rm 2A{rcub}{dollar}- and {dollar}alphasb{lcub}rm 2C{rcub}{dollar}-adrenoceptors are the predominate subtypes and coexist in many regions. As a group, {dollar}alphasb2{dollar}-adrenoceptors play a role in a variety of brain functions including arousal, mood, motor function, pain, and cardiovascular regulation. In most brain areas, {dollar}alphasb2{dollar}-adrenoceptors either occur on noradrenergic neurons or are innervated by noradrenergic or adrenergic neurons, since presynaptic markers of noradrenergic innervation, e.g. dopamine beta-hydroxylase and/or norepinephrine transporters, occur in the same regions as {dollar}alphasb2{dollar}-adrenoceptors. In contrast, the caudate-putamen, or striatum, contains a moderate to high density of {dollar}alphasb2{dollar}-adrenoceptors but little or no dopamine beta-hydroxylase immunostaining and norepinephrine transporters. Thus, whether {dollar}alphasb2{dollar}-adrenoceptors in the striatum are functionally relevant remains unknown.; The overall goal of this dissertation was to explore the potential physiological functions of {dollar}alphasb{lcub}rm 2C{rcub}{dollar}-adrenoceptors in the rat striatum. Since there is a lack of selective ligands for subtypes of {dollar}alphasb2{dollar}-adrenoceptors, a secondary goal of this research was to develop a strategy to study {dollar}alphasb{lcub}rm 2C{rcub}{dollar}-adrenoceptors selectively.; The major findings of this dissertation are that (1) agonist activation of {dollar}alphasb2{dollar}-adrenoceptors do not affect the release of acetylcholine, GABA, or dopamine in rat striatum, (2) activation of {dollar}alphasb2{dollar}-adrenoceptors inhibits adenylyl cyclase in the rat striatum, (3) {dollar}alphasb{lcub}rm 2C{rcub}{dollar}-adrenoceptors occur in rat striatum, (4) {dollar}alphasb{lcub}rm 2C{rcub}{dollar}-antisense oligodeoxynucleotides can selectively reduce the expression of {dollar}alphasb{lcub}rm 2C{rcub}{dollar}-adrenoceptors in the rat striatum, and (5) {dollar}alphasb{lcub}rm 2C{rcub}{dollar}-adrenoceptors mediate inhibition of adenylyl cyclase in rat striatum.; These findings support the hypothesis that {dollar}alphasb{lcub}rm 2C{rcub}{dollar}-adrenoceptors have a functional role in the striatum. Furthermore, data reveal that {dollar}alphasb{lcub}rm 2C{rcub}{dollar}-adrenoceptors in rat striatum appear to be tonically activated. Since there is little or no noradrenergic innervation of the striatum, it is likely that the endogenous neurotransmitter tonically activating these receptors is not norepinephrine. Given the rich supply of dopamine to the striatum, a likely candidate for the endogenous activator of striatal {dollar}alphasb{lcub}rm 2C{rcub}{dollar}-adrenoceptors is dopamine. If this is the case, it will represent a novel mechanism of catecholamine signaling in the brain. This research also provided a novel tool, an antisense oligodeoxynucleotide, to study the pharmacology of {dollar}alphasb{lcub}rm 2C{rcub}{dollar}-adrenoceptors. For example, using the antisense oligodeoxynucleotide developed in my research, Aley and Levine (1997) recently demonstrated that the {dollar}alphasb{lcub}rm 2C{rcub}{dollar}-adrenoceptor mediates antinociception in rat spinal cord and that this receptor interacts with {dollar}mu{dollar}-opioid receptor and A{dollar}sb1{dollar}-adenosine receptor. Therefore, the results of my research will be useful for the identification of agents interacting selectively with a particular {dollar}alphasb2{dollar}-adrenoceptor subtype.