Chronic effects of fluoxetine, a selective inhibitor of serotonin uptake, on neurotransmitter receptors

Abstract

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.

Buprenorphine and a CRF1 Antagonist Block the Acquisition of Opiate Withdrawal-Induced Conditioned Place Aversion in Rats

“…Fluoxetine, at a dose shown to block reuptake in rats (Wong et al, 1985) and decrease cocaine self-administration (Porrino et al, 1989), failed to block conditioned place aversion to opiate withdrawal. Similarly, the dopamine partial agonist terguride at a dose that blocks cocaine selfadministration (Pulvirenti et al, 1998), methamphetamine self-administration (O Kitamura, GF Koob, L Pulvirenti, unpublished results), and psychostimulant withdrawal (Orsini et al, 2001) failed to block conditioned place aversion to opiate withdrawal.…”

Fluoxetine: a case history of its discovery and preclinical development

“…Chronic fluoxetine administration did not produce adaptive changes or downregulation of other neurotransmitter receptors (opioids, adrenergic, muscarinic or histamine H1 receptors) [40,47,48]. This favours possible advantages in the long-term treatment with fluoxetine because this compound will be less cardiotoxic than TCAs, with fewer anticholinergic and antihistaminergic side effects [11,13,40].…”

“…This favours possible advantages in the long-term treatment with fluoxetine because this compound will be less cardiotoxic than TCAs, with fewer anticholinergic and antihistaminergic side effects [11,13,40]. As the adaptive changes described above must be produced, it is widely accepted that chronic fluoxetine treatment is necessary to obtain a therapeutic effect.…”

“…Microdialysis and electrophysiology studies support the desensitisation of raphe somatodendritic 5-HT 1A autoreceptors [19,33,36] that negatively regulate the release of 5-HT in terminal areas [37]. Through radioligand-binding assay and autoradiographic quantification, it was revealed that the ability of fluoxetine to downregulate the density of these autoreceptors might explain this altered sensitivity, although this hypothesis remains somewhat controversial [36,[38][39][40]. However, it has also been suggested that the desensitisation of 5-HT 1A autoreceptors may be due to alterations in their signal transduction, which involves G-protein [39,41].…”

Chronic Antidepressant Treatment Causes a Selective Reduction of μ-Opioid Receptor Binding and Functional Coupling to G Proteins in the Amygdala of Fawn-Hooded Rats

“…A major reason for choosing the present sampling time is based on consideration that -opioid receptors may undergo a second adaptation (withdrawal effect) after long-term treatment with ATD, because we knew this receptor system showed a dynamic response to alcohol withdrawal in FH rats (Chen and Lawrence, 2000;Djouma and Lawrence, 2002). However, the interpretation of any alteration of -opioid receptor binding must be taken cautiously due to potential interactions between -opioid receptors and TCAs or SSRIs (Wahlstrom et al, 1994), even though such an interaction has been questioned (Wong et al, 1985). Lines of evidence do, however, support that the de- (Fig.…”