Evaluation of nefazodone as a serotonin uptake inhibitor and a serotonin antagonist in vivo

doi:10.1016/0024-3205(94)00739-X

Life Sciences

Volume 55, Issue 7, 1994, Pages 479-483

https://doi.org/10.1016/0024-3205(94)00739-X Get rights and content

Abstract

Nefazodone (2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one) has been reported to be effective in the treatment of depression. Antagonism of serotonin type 2A (5HT_2A) receptors, as well as inhibition of the serotonin (5HT) uptake carrier, has been suggested to contribute to the antidepressant action of nefazodone in vivo (Eison et al., 1990). Nefazodone weakly antagonized the quipazine-induced rise in rat serum corticosterone levels and the quipazine-induced increase in rat hypothalamic 3-methoxy-4-hydroxy-phenylglycol sulfate, suggesting blockade of 5HT_2A receptors in vivo. Nefazodone, however, failed to antagonize the p-chloroamphetamine-induced depletion of mouse or rat brain 5HT, displaying a lack of effect on the 5HT uptake carrier. These data extend previous in vitro and in vivo data (Eison, et al. 1990) reporting nefazodone to be an antagonist at 5HT_2A receptors, but fail to show inhibition of the 5HT uptake carrier in the same dose range.

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The 5-HT2A receptors may mediate some of the antidepressant effects seen in experimental animal models of depression (Skrebuhhova et al., 1999). An antidepressant drug such as nefazodone was found to (partially) exert its therapeutic effect via a 5-HT2A receptor antagonism (Hemrick-Luecke et al., 1994). The gene coding for 5-HT2A receptor was mapped to chromosome 13q14-q21 (Campbell et al., 1997).
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The definition of a genetic liability profile for specific antidepressant treatment will soon be available offering considerable help in early detection of effective therapy in affective disorders. The search for genetic factors predisposing to drug response or side-effects in affective disorders started only in the last few years. The efficacy of antidepressant action was associated with several polymorphisms, located on coding genes of proteins thought to be involved in the different mechanisms of action of antidepressant treatments. Among these, gene variants in sequences of serotonin pathway proteins were candidate, both for the well known evidence of its involvement in the development of depressive symptomathology and for the wide-world use of selective serotonin reuptake inhibitors as first choice treatment of depression. A polymorphism in the promoter region of the serotonin transporter (SERTPR) was independently associated with efficacy for a range of treatments, other polymorphism located on the tryptophan hydroxylase gene, 5-HT2a receptor and G-protein beta 3 showed some association, while other candidate genes were not associated with treatment efficacy. Possible liability genes controlling at least to some extent both acute and long-term treatment were identified, and the further objective is to identify other candidate genes in order to define individualized treatments according to genetic profile in a future. The present paper reviews the pharmacogenetic studies published to date, focusing the attention on the serotonergic pathway.
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Nefazodone is presently marketed as an antidepressant that inhibits both serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine reuptake while antagonizing pirenpirone (5-HT₂) receptors. This 5-HT receptor type is believed to play a prominent role in the underlying mechanism of action of serotonergic hallucinogens. Antidepressant medications now represent the most commonly prescribed psychoactive medications in the world and are likely to be ingested in the presence of hallucinogens with increased frequency; the consequences are largely unknown. The present investigation examined the interaction between the serotonergic phenethylamine hallucinogen [−]-2,5-dimethoxy-4-methylamphetamine ([−]-DOM), and nefazodone, in rats trained with [−]-DOM [0.6 mg/kg; 75 min pretreatment time] as a discriminative stimulus. The data indicate that maximal substitution of nefazodone for the [−]-DOM stimulus was present using a 45-min pretreatment time before testing. Using this pretreatment time, a dose of nefazodone of 12.0 mg/kg administered alone resulted in 76% DOM-appropriate responding. When a range of doses of nefazodone was combined with the training dose of [−]-DOM, a pattern of responding compatible with partial agonism was observed. The intermediate degree of [−]-DOM generalization to nefazodone was significantly antagonized by the 5-HT antagonists, 5-HT₂, SR 46349B (5HT_2A/2C), and M100907 (5-HT_2A). Taken together, the present data suggest that (a) nefazodone acts as a partial agonist and (b) these effects are mediated by the 5-HT_2A receptor.
Reboxetine: A pharmacologically potent, selective, and specific norepinephrine reuptake inhibitor
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These include dual serotonergic antidepressants, such as nefazodone, which block both 5-HT reuptake and postsynaptic 5-HT2 receptors (Taylor et al 1995), noradrenergic and serotonergic reuptake inhibitors (SNRI), such as venlafaxine (Muth et al 1991), noradrenergic and specific serotonergic antidepressants (NaSSA), such as mirtazapine (de Boer et al 1996), and dopaminergic reuptake inhibitors, such as bupropion (Archer et al 1995). A substantial body of data exists to support the hypothesis that serotonergic receptors and reuptake mechanisms play an important role in antidepressant activity (Hemrick-Luecke et al 1994). The role that noradrenergic mechanisms play in psychiatric function is also well recognized (e.g., Aston-Jones et al 1991), but has not been actively exploited for the development of novel antidepressants.
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Methods: Pharmacological selectivity for uptake systems was defined by uptake and binding assays for the three monoamine uptake sites. Specificity was determined in 39 different receptor and 6 enzyme assays. In vivo selectivity was defined by measurement of neuronal firing rates in the locus coeruleus, dorsal raphe, and substantia nigra. Reserpine-induced blepharospasm and hypothermia, clonidine-induced hypothermia, defined reboxetine’s in vivo pharmacology. Reboxetine’s antidepressant potential was evaluated behaviorally by the tail-suspension test, forced swimming, and the DRL₇₂ operant responding test.
Results: Reboxetine is a potent, selective, and specific norepinephrine reuptake inhibitor (selective NRI) as determined by both in vitro and in vivo measurements. Unlike desipramine or imipramine, reboxetine has weak affinity (Ki > 1000 nmol/L) for muscarinic, histaminergic H1, adrenergic α₁, and dopaminergic D₂ receptors. In vivo action of reboxetine is entirely consistent with the pharmacological action of an antidepressant with preferential action at the norepinephrine reuptake site. Reboxetine showed an antidepressant profile in all tests of antidepressant activity used. Significant decreases in immobility were observed in the tail suspension test and behavioral despair test. Increased efficiency in responding was observed in the DRL₇₂ test.
Conclusions: Reboxetine is a potent, selective, and specific noradrenergic reuptake inhibitor. It has a superior pharmacological selectivity to existing tricyclic antidepressants and selective serotonin reuptake inhibitors when tested in a large number of in vitro and in vivo systems. Given the pharmacological profile, reboxetine is expected to be a selective and potent tool for psychopharmacological research. The use of reboxetine in the clinic will also help clarify the role norepinephrine plays in depression.
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The atypical antipsychotic olanzapine has relatively high affinity for a number of neuronal receptors in radioreceptor binding assays. The ability of olanzapine to activate or antagonize a number of neuronal receptors was investigated in vitro, in cell lines transfected selectively with receptor subtypes and in receptor-selective isolated tissue studies. Olanzapine had no agonist activity at any of the receptors examined. However, olanzapine was a potent antagonist of 5-HT-stimulated increases in IP₃ in cell lines transfected with 5-HT_2A or 5-HT_2B receptors with IC₅₀ values of 30–40 nM. Olanzapine weakly blocked 5-HT-induced formation of IP₃ in cell lines transfected with 5-HT_2C receptors, but in this cell line potently inhibited 5-HT-stimulated [ $^{35} S$ ]GTPγS binding with a K_i value of 15 nM. Olanzapine blocked dopamine-stimulated adenylyl cyclase in rat retina with modest potency (K_i=69 nM), consistent with its relatively low affinity for dopamine D1 receptors. Olanzapine blocked agonist-induced activities at the muscarinic receptor subtypes M₁, M₂, M₃, and M₅ with K_i values of 70, 622, 126, and 82 nM, respectively. In studies using cell lines transfected with muscarinic M₄ receptors, olanzapine and the atypical antipsychotic clozapine did not have agonist activities as determined with cAMP inhibition and stimulation assays, arachidonic acid release and [ $^{35} S$ ]GTPγS binding assays. However, olanzapine antagonized agonist-induced effects in muscarinic M₄ cells with a K_i value of 350 nM. In isolated tissue studies, olanzapine potently blocked agonist-induced effects at α₁-adrenergic and histamine H₁ receptors (K_B=9 and 19 nM, respectively). Thus, olanzapine was an antagonist at all receptors investigated and was a particularly potent antagonist at 5-HT_2A, 5-HT_2B, 5-HT_2C, α₁-adrenergic and histamine H₁ receptors. Olanzapine was a weaker antagonist at muscarinic and dopamine D1 receptors.

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Evaluation of nefazodone as a serotonin uptake inhibitor and a serotonin antagonist in vivo

Abstract

Trends in Pharmacol. Sci.

Eur. J. Pharmacol.

Biochem. Pharmacol.

Neuropharmacology

Psychopharmacol. Bull.

Psychopharmacol. Bull.

Psychopharmacol. Bull.