Potent antagonism of 5-HT3 and 5-HT6 receptors by olanzapine

Bymaster, Frank P.; Falcone, Julie F.; Bauzon, Delbert; Kennedy, J. S.; Schenck, Kathryn W.; DeLapp, Neil W.; Cohen, Marlene L.

doi:10.1016/s0014-2999(01)01399-1

Cited by 111 publications

(63 citation statements)

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“…There were no serious adverse events related to olanzapine, and no patient discontinued olanzapine because of toxic effects. In view of the temporary drowsiness reported in this trial and previous reports of temporary drowsiness, [13][14][15] more detailed information on drowsiness ratings, as well as the use of a lower dose of olanzapine (5 mg), could be explored in future trials.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 Olanzapine is approved by the Food and Drug Administration (FDA) as an antipsychotic agent that blocks multiple neurotransmitters: dopamine at D 1 , D 2 , D 3 , and D 4 receptors; serotonin at 5-HT type 2a, 5-HT type 2c (5-HT 2c ), 5-HT 3 , and 5-HT type 6 receptors; catecholamines at alpha 1 -adrenergic receptors; acetylcholine at muscarinic receptors; and histamine at H 1 receptors in the central nervous system. 8,9,13 Side effects may include mild short-term sedation, [13][14][15] as well as weight gain and an increased risk of diabetes mellitus with prolonged use (>6 months). [15][16][17] The activity of olanzapine at multiple receptors, particularly the D 2 , 5-HT 2c , and 5-HT 3 receptors, which may be involved in nausea and vomiting, suggests that it might have clinically significant antiemetic properties.…”

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confidence: 99%

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Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting

Navari

Qin

Ruddy

et al. 2016

Management of Chemotherapy-Induced Nausea and Vomiting

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting

Navari

Qin

Ruddy

et al. 2016

Management of Chemotherapy-Induced Nausea and Vomiting

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“…Despite different chemical structures and pharmacodynamic signalling pathways, a number of antipsychotics inhibit ion fluxes through 5-HT 3 receptors in a noncompetitive manner, with the exception of the known competitive antagonists mirtazapine, olanzapine and clozapine (Bymaster et al, 2001;Rammes et al, 2004;Eisensamer et al, 2005). In accord with these findings, it has been shown that 5-HT 3 receptor antagonists ondansetron and tropisetron dose dependently reversed the haloperidol-induced VCMs and reduced haloperidol-induced wet dog shakes, further supporting the possibility of an alteration in the serotonergic system after chronic haloperidol treatment (Naidu and Kulkarni, 2001b).…”

Section: Role Of 5-ht In Apd-induced Extrapyramidal Side Effectsmentioning

confidence: 99%

Serotonin modulation of the basal ganglia circuitry: therapeutic implication for Parkinson's disease and other motor disorders

Matteo

Pierucci

Esposito

et al. 2008

Progress in Brain Research

138

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Several recent studies have emphasized a crucial role for the interactions between serotonergic and dopaminergic systems in movement control and the pathophysiology of basal ganglia. These observations are supported by anatomical evidence demonstrating large serotonergic innervation of all the basal ganglia nuclei. In fact, serotonergic terminals have been reported to make synaptic contacts with both substantia nigra dopamine-containing neurons and their terminal areas such as the striatum, the globus pallidus and the subthalamus. These brain areas contain a high concentration of serotonin (5-HT), with the substantia nigra pars reticulata receiving the greatest input. In this chapter, the distribution of different 5-HT receptor subtypes in the basal ganglia nuclei will be described. Furthermore, evidence demonstrating the serotonergic control of basal ganglia activity will be reviewed and the contribution of the different 5-HT receptor subtypes examined. The new avenues that the increasing knowledge of 5-HT in motor control has opened for exploring the pathophysiology and pharmacology of Parkinson's disease and other movement disorders will be discussed. It is clear that these avenues will be fruitful, despite the disappointing results so far obtained by clinical studies with selective 5-HT ligands. Nevertheless, these studies have led to a great increase in the attention given to the neurotransmitters of the basal ganglia and their connections.

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“…It displays affinity for many neuronal receptors including histamine H 1 , serotonin 5-HT 2A , 5-HT 2B , 5-HT 2C , 5-HT 3 , and 5-HT 6 , dopamine D 1 -D 5 , muscarinic, a and glutamate receptors (Richelson and Souder, 2000). The multiple binding property of olanzapine contributes to its varied pharmacological and therapeutic effects (Roth et al, 1994;Bymaster and Falcon, 2000;Bymaster et al, 1996Bymaster et al, , 1999Bymaster et al, , 2001). However, the precise mechanism underlying its antipsychotic action remains unclear.…”

Section: Introductionmentioning

confidence: 99%

“…The potent 5-HT 2 receptor antagonism and weak D 1 and D 2 receptor antagonism have been suggested to play a key role in its atypical antipsychotic activity (Beasley et al, 1996). Furthermore, the potent antagonistic activity of olanzapine on 5-HT 3 and 5-HT 6 receptors may also contribute towards its antipsychotic effect (Bymaster et al, 2001). Emerging evidence suggests that in addition to dopaminergic and serotonergic antagonism, GABAergic neurotransmission may serve as a primary locus for some antipsychotic drugs, including olanzapine (Farnbach-Pralong et al, 1998;Carpenter et al, 1999;O'Connor, 2001).…”

Section: Introductionmentioning

confidence: 99%

Role of Neuroactive Steroid Allopregnanolone in Antipsychotic-like Action of Olanzapine in Rodents

Ugale

Hirani

Morelli

et al. 2004

Neuropsychopharmacol

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Olanzapine increases brain allopregnanolone (ALLO) levels sufficiently to modulate neuronal activity by allosterically regulating GABA A receptors. Recently, we reported the antipsychotic-like profile of ALLO in rodents. The present study examined the hypothesis that olanzapine-induced elevation of endogenous neurosteroid ALLO is vital for its neuroleptic-like action. The conditioned avoidance response (CAR) and apomorphine-induced climbing behavioral paradigms were used in rodents. Administration of ALLO (1 mg, intracerebroventricular (i.c.v.)) or neurosteroidogenic agents such as the mitochondrial diazepam binding inhibitor receptor agonist, FGIN 1-27 (0.5 mg, i.c.v.) or the ALLO precursor, progesterone (10 mg/kg, i.p.) significantly potentiated olanzapine-induced blockade of CAR and apomorphine-induced climbing. In contrast, these agents failed to alter the antipsychotic-like effect of risperidone and haloperidol. On the other hand, inhibition of the endogenous biosynthesis of neurosteroids by the 3b-hydroxysteroid dehydrogenase inhibitor, trilostane (30 mg/kg, i.p.), the 3a-hydroxysteroid oxidoreductase inhibitor, indomethacin (5 mg/kg, i.p.), or the GABA A receptor antagonist bicuculline (1 mg/kg, i.p.) and dehydroepiandrosterone sulfate (DHEAS) (1 mg/kg, i.p.) blocked the effect of olanzapine, but not of risperidone and haloperidol. Socially isolated animals, known to exhibit decreased brain ALLO and GABA A receptor functions, displayed a shortening in the muscimol-induced loss of righting reflex and an increased susceptibility to apomorphine-induced climbing. Administration of olanzapine, but not of haloperidol and risperidone, normalized the duration of muscimol-elicited loss of righting reflex. Although all three antipsychotics proved capable of antagonizing the apomorphine-induced climbing, a dose almost five times higher of olanzapine was required in socially isolated animals. The data obtained suggest that enhancement of the GABAergic tone plays a key role in the antipsychotic-like effect exerted by olanzapine in rodents, likely as a consequence of augmented levels of neuroactive steroids, in particular ALLO, in the brain. The present findings provide the first specific behavioral evidence in support of the hypothesis that neuroactive steroid ALLO-mediated GABAergic modulation is essential for the antipsychotic-like action of olanzapine.

show abstract

Potent antagonism of 5-HT3 and 5-HT6 receptors by olanzapine

Cited by 111 publications

References 50 publications

Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting

Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting

Serotonin modulation of the basal ganglia circuitry: therapeutic implication for Parkinson's disease and other motor disorders

Role of Neuroactive Steroid Allopregnanolone in Antipsychotic-like Action of Olanzapine in Rodents

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