Destruction of the nucleus raphe obscurus and potentiation of serotonin-mediated behaviors following administration of the neurotoxin 3-acetylpyridine.
Systemic administration of the neurotoxin 3-acetylpyridine (3-AP) to rats produced spontaneous episodes of spasmodic movement involving the trunk and limbs including torticollis, contortions of the trunk and rigid extension of the limbs. Because the neurotransmitter serotonin (5-HT) has been implicated in various human involuntary movement disorders, the functional and anatomical integrity of the 5-HT system in rats treated with 3-AP were examined. 5-HT-containing neurons in the brain stem were studied using immunohistochemical labeling with antiserum to 5-HT. Cells in the nucleus raphe obscurus were found to be altered following 3-AP treatment as shown by a decrease in 5-HT immunoreactivity as compared to control rats. No changes in 5-HT immunoreactivity were observed in any other region containing 5-HT cell bodies. Behaviorally, rats treated with 3-AP were 2.5-fold more sensitive to the ability of the 5-HT1A agonist 8-OH-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.33-3.3 mg/kg) to produce the 5-HT syndrome. Similarly, 3-AP-treated rats were 2-fold more sensitive to the selective 5-HT2 agonist 1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB; 0-1.0 mg/kg) at producing the head shake response. Although these behaviors associated with brain stem 5-HT receptors were potentiated by 3-AP, the hypothermic effect of 8-OH-DPAT which involves ascending mesencephalic 5-HT neurons was unchanged following 3-AP treatment. Treatment with 3-AP did not produce significant alterations of 5-HT or 5-hydroxyindoleacetic acid (5-HIAA) content in any brain region studied. Quantitative autoradiographic analysis of the density of 5-HT1A receptors labeled with [3H]8-OH-DPAT revealed that these sites were unchanged in regions of the brain (frontal cortex, hippocampus and brain stem) and in the spinal cord. Similarly, few changes in the density of 5-HT2 receptors measured with [3H]ketanserin were observed in various brain regions. These results suggest that neurons from the nucleus raphe obscurus are involved in the elicitation of 5-HT-mediated behavioral responses by 5-HT1A and 5-HT2 receptor agonists that are though to be mediated through brain stem and spinal cord mechanisms. In addition, because of the close neuroanatomical relationship of the nucleus raphe obscurus with various brain regions known to be involved in motor control, the destruction of this region by 3-AP may contribute to the spasmodic motor behaviors observed following 3-AP treatment.
Department of Psychiatry, University of Pennsylvania, Philadelphia 19104.
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S
Wieland
M S
MS
Kreider
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P
McGonigle
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I
Lucki
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000818:Animals; D001833:Body Temperature Regulation / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009498:Neurotoxins / Q000633:toxicity*; D011725:Pyridines / Q000633:toxicity*; D011903:Raphe Nuclei / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013116:Spinal Cord / Q000378:metabolism; D013239:Stereotyped Behavior / Q000187:drug effects*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014202:Tremor / Q000503:physiopathology
D009498:Neurotoxins; D011725:Pyridines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013764:Tetrahydronaphthalenes; C010835:3-acetylpyridine; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin