Antidepressant Drugs and Central 5-Ht Mechanisms

Fuxe, Kjell G.

Abstract

Effects of chronic oral administration of the antidepressant drugs imipranine, zimelidine and mianserine will be studied on 5-HT neuron systems and their transmitter-identified afferent input using newly developed morphometrical procedures as well as quantitative receptor autoradiography. Also the substance P immunoreactive cell groups and TRH immunoreactive cell groups within the medulla oblongata will be morphometrically characterized in a similar way. After morphometrical characterization of these types of transmitter-identified nerve cell groups the influence of chronic antidepressants on their cell body and cell group parameters will be studied. Also transmitter-identified afferent inputs to the raphe nuclei innervating the 5-HT nerve cell groups, such as the catecholamine afferents, enkephalin afferents and substance P afferents will be analyzed by performing density maps of the monoamine and neuropeptide afferents and relate them to the morphometrical features of the 5-HT cell body groups and by studying their modulation by chronic antidepressant treatment. By means of the radioactive 2-deoxy-d-glucose method a metabolic map of the 5-HT raphe nuclei will be made and this map will be related to the morphometrical maps of the 5-HT nerve cell groups. Also it will be studied if chronic antidepressant treatment can modulate the localization of metabolic (functional) activity in the various raphe nuclei. Effects of chronic antidepressant treatment on the 5-HT and the substance P immunoreactive nerve cell groups and terminal networks will also be tested by means of quantitative immunocytochemistry using monoclonal substance P antiserum and a 5-HT antiserum. By means of newly developed quantitative methodologies to determine the entity of coexistence it will be studied how chronic antidepressant treatment may modulate the entiry of coexistence of 5-HT, substance P- and TRH-like immunoreactivity in the bulbospinal 5-HT neurons. Finally, by means of quantitative autoradiography the distribution and characteristics of 3H-neuropeptide and 3H-monoamine binding sites of various types will be evaluated in relation to the 5-HT neurons as well as their modulation by chronic antidepressants. These new methodologies and the experiments described above will open up new aspects on the possible mechanisms of action of -antidepressant compounds.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Mental Health (NIMH)
• Type: Research Project (R01)
• Project #: 5R01MH025504-11
• Application #: 3374927
• Study Section: (BPNA)
• Project Start: 1977-06-01
• Project End: 1986-11-30
• Budget Start: 1984-12-01
• Budget End: 1985-11-30
• Support Year: 11
• Fiscal Year: 1985

Institution

• Name: Karolinska Institute
• DUNS #: 350582235
• City: Stockholm
• Country: Sweden
• Zip Code: 171 77

Publications

Agnati, L F; Fuxe, K; Zoli, M et al. (1988) Morphometrical and microdensitometrical studies on phenylethanolamine-N-methyltransferase- and neuropeptide Y-immunoreactive neurons in the rostral medulla oblongata of the adult and old male rat. Neuroscience 26:461-78

Agnati, L F; Fuxe, K; Zoli, M et al. (1988) Morphometrical evidence for a complex organization of tyrosine hydroxylase-, enkephalin- and DARPP-32-like immunoreactive patches and their codistribution at three rostrocaudal levels in the rat neostriatum. Neuroscience 27:785-97

Benfenati, F; Agnati, L F; Fuxe, K (1988) Development of computer-assisted simulation procedure to analyze receptor modulatory processes. J Neural Transm 71:143-58

Kitayama, I; Janson, A M; Cintra, A et al. (1988) Effects of chronic imipramine treatment on glucocorticoid receptor immunoreactivity in various regions of the rat brain. Evidence for selective increases of glucocorticoid receptor immunoreactivity in the locus coeruleus and in 5-hydroxytryptamine nerve c J Neural Transm 73:191-203

Fuxe, K; Agnati, L F; Kitayama, I et al. (1987) Evidence for discrete alterations in central cardiovascular catecholamine and neuropeptide Y immunoreactive neurons in aged male rats and in genetically hypertensive male rats of the Lyon strain. Eur Heart J 8 Suppl B:139-45

Harfstrand, A; Fuxe, K; Terenius, L et al. (1987) Neuropeptide Y-immunoreactive perikarya and nerve terminals in the rat medulla oblongata: relationship to cytoarchitecture and catecholaminergic cell groups. J Comp Neurol 260:20-35

Fuxe, K; Cintra, A; Agnati, L F et al. (1987) Studies on the cellular localization and distribution of glucocorticoid receptor and estrogen receptor immunoreactivity in the central nervous system of the rat and their relationship to the monoaminergic and peptidergic neurons of the brain. J Steroid Biochem 27:159-70

Cintra, A; Fuxe, K; Harfstrand, A et al. (1987) Presence of glucocorticoid receptor immunoreactivity in corticotrophin releasing factor and in growth hormone releasing factor immunoreactive neurons of the rat di- and telencephalon. Neurosci Lett 77:25-30

Cummins, J T; von Euler, G; Fuxe, K et al. (1987) Chronic imipramine treatment reduces (+)2-[125I]iodolysergic acid, diethylamide but not 125I-neuropeptide Y binding in layer IV of rat cerebral cortex. Neurosci Lett 75:152-6

Kitayama, I; Janson, A M; Fuxe, K et al. (1987) Effects of acute and chronic treatment with imipramine on 5-hydroxytryptamine nerve cell groups and on bulbospinal 5-hydroxytryptamine/substance P/thyrotropin releasing hormone immunoreactive neurons in the rat. A morphometric and microdensitometric analy J Neural Transm 70:251-85