Chronic effects of fluoxetine, a selective inhibitor of serotonin uptake, on neurotransmitter receptors.
Fluoxetine administration to rats at a dose of 10 mg/kg i.p. daily up to 12 or 24 days failed to change the concentration-dependent binding of [3H]WB4101, [3H]clonidine and [3H]dihydroalprenolol to alpha 1-, alpha 2- and beta-adrenergic receptors, respectively; [3H]quinuclidinyl benzilate to muscarinic receptors; [3H]pyrilamine to histamine H1 receptors and [3H]naloxone to opiate receptors. Persistent and significant decreases in receptor number (Bmax value) without changes in the dissociation constant (KD value) of [3H]5-HT binding in cortical membranes were observed upon chronic treatment with fluoxetine administered either by intraperitoneal injection or incorporation in the diet. A detectable reduction of 5-HT1 receptor number occurred after once-daily injections of fluoxetine at 10 mg/kg i.p. within 49 hours. After pretreatment for 3 days with p-chlorophenylalanine, an inhibitor of 5-HT synthesis, followed by repeated administration of fluoxetine, 5-HT1 receptor numbers were higher than those of normal rats, suggesting a dependence on synaptic concentration of 5-HT for fluoxetine to affect a receptor down-regulation. These studies provide further evidence for the selectivity of fluoxetine as an inhibitor of 5-HT reuptake, resulting in a selective down-regulation of 5-HT1 receptors in the cerebral cortex of rat brain.
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects*; D005473:Fluoxetine / Q000494:pharmacology*; D008297:Male; D011437:Propylamines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D011969:Receptors, Histamine H1 / Q000187:drug effects; D011976:Receptors, Muscarinic / Q000187:drug effects; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D011957:Receptors, Opioid / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects
D011437:Propylamines; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D011969:Receptors, Histamine H1; D011976:Receptors, Muscarinic; D017981:Receptors, Neurotransmitter; D011957:Receptors, Opioid; D005473:Fluoxetine