Down-regulation of dopamine D-2, 5-HT2 receptors and beta-adrenoceptors in rat brain after prolonged treatment with a new potential antidepressant, Lu 19-005.
Lu 19-005 is a new phenylindan derivative with strong and equipotent inhibitory effect on dopamine (DA), noradrenaline (NA) and serotonin (5-HT) uptake. The adaptive effects of 2 weeks treatment with Lu 19-005, on receptor binding in vitro and on d-amphetamine responsiveness in vivo have been investigated in rats. One or 3 days after the final dose the number of beta-adrenoceptors and of 5-HT2 and DA D-2 receptors was decreased by 20-30%, whereas alpha 1-adrenoceptor number was slightly decreased only 1 day after withdrawal. The DA D-2 receptor number remained decreased at 7 days withdrawal, but returned to normal after another 3 days. The brain levels of DA, NA and 5-HT were not changed by 2 weeks' Lu 19-005 treatment. The down-regulation of DA D-2 receptors was accompanied by tolerance to d-amphetamine-induced hypermotility (after low doses) and stereotyped licking or biting (after a high dose). The tolerance to d-amphetamine-induced hypermotility was maximal at 3-5 days withdrawal time, and remained significant also 15 days after the last dose. An acute dose of Lu 19-005 did not modify the effects of d-amphetamine. The results are discussed in relation to the effect of prolonged treatment with other antidepressant drugs.
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Nowak
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Arnt
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Hyttel
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Svendsen
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001923:Brain Chemistry / Q000187:drug effects; D002395:Catecholamines / Q000032:analysis; D003913:Dextroamphetamine / Q000494:pharmacology; D004347:Drug Interactions; D007189:Indans / Q000494:pharmacology*; D007192:Indenes / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011941:Receptors, Adrenergic / Q000187:drug effects*; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D011954:Receptors, Dopamine / Q000187:drug effects*; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin / Q000187:drug effects*
D000928:Antidepressive Agents; D002395:Catecholamines; D007189:Indans; D007192:Indenes; D011941:Receptors, Adrenergic; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; C045117:Lu 19005; D003913:Dextroamphetamine