[Effects of lithium and antidepressants on monoaminergic receptors and receptor-coupled adenylate cyclase system in rat brain].
The mechanisms of action of lithium and antidepressants were investigated with reference to effects of these drugs on monoaminergic receptors and receptor-coupled adenylate cyclase systems in rat brain. Oral administration of lithium carbonate for 21 days decreased significantly the density of beta-adrenergic receptors in rat cerebral cortex, which is the same change as reported as the result of long-term treatment with many antidepressants. With regard to 5-hydroxytryptamine (5-HT) receptor subtypes, lithium treatment reduced the maximum number of 5-HT1A receptors in rat hippocampus but not in cerebral cortex, whereas repetitive injections with imipramine or desipramine did not. beta-Adrenoceptor-coupled adenylate cyclase activity was subsensitized by long-term lithium treatment in consistency with above-mentioned down-regulation of beta-adrenergic receptors. Stimulation of adenylate cyclase activity by non-hydrolyzable GTP analogue, guanyl-5'-ylimidodiphosphate (Gpp(NH)p), was, however, unaltered in lithium-treated rats as compared with controls. On the other hand, 5-HT1A-mediated inhibition of forskolin-stimulated adenylate cyclase in rat hippocampal membranes was not altered by chronic treatment with lithium or antidepressants. Gpp(NH)p-induced inhibition of forskolin-stimulated adenylate cyclase activity was not influenced by lithium treatment, either. [3H]Forskolin binding to rat cerebral cortex, which is assumed to be associated with the activated complex of catalytic subunit of adenylate cyclase and stimulatory guanine nucleotide-binding regulatory proteins (Gs), was not changed by administration of lithium or antidepressants under any condition studied. Pertussis toxin (islet-activating protein, IAP) sensitive G proteins (Gi/Go) as determined by using IAP-catalyzed [32P]ADP-ribosylation was not altered by lithium- or antidepressant-treatment, either. The implication of these results is discussed with a view of clarifying the mechanisms of action of these thymoleptic drugs.
Odagaki
Y
Y
Department of Psychiatry and Neurology, Hokkaido University School of Medicine, Sapporo, Japan.
D000262:Adenylyl Cyclases / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D015306:Biogenic Monoamines / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D016651:Lithium Carbonate / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects
D000928:Antidepressive Agents; D015306:Biogenic Monoamines; D011943:Receptors, Adrenergic, beta; D011985:Receptors, Serotonin; D016651:Lithium Carbonate; D000262:Adenylyl Cyclases