Evidence for specific interactions between 5-HT1A and dopamine D2 receptor mechanisms in the mediation of extrapyramidal motor functions in the rat

Wadenberg, Marie-Louise; Cortizo, Lourdes; Ahlénius, Sven

doi:10.1016/0091-3057(94)90152-x

Cited by 35 publications

(9 citation statements)

References 26 publications

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“…If it were the case that this, or some other metabolite, had a different profile of 5-HT 2 /D 2 affinity than the parent compound, it could explain the results. Aripiprazole also has moderately high affinity for the 5-HT 1A receptor (Jordan et al, 2002) and this could have influenced the induction of CAT or inhibition of CAR in rodents (Wadenberg et al, 1994;Andersen and Kilpatrick, 1996). However, in a recent study, pretreatment with the 5-HT 1A selective antagonist WAY 100635 did not precipitate CAT in aripiprazole-treated rats (at comparable doses with the present study), unlike other D 2 antagonists (ziprasidone) or partial agonists (SLV313, bifeprunox, and sarizotan) that also have 5-HT 1A receptor affinity (Kleven et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Dissociation between In Vivo Occupancy and Functional Antagonism of Dopamine D2 Receptors: Comparing Aripiprazole to Other Antipsychotics in Animal Models

Natesan

Reckless

Nóbrega

et al. 2005

Neuropsychopharmacol

180

116

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The novel antipsychotic aripiprazole requires high (490%) striatal D 2 receptor occupancy (D 2 RO) to be clinically active, but despite its high D 2 RO it does not show extrapyramidal symptoms. While most antipsychotics are active at nearly 65% D 2 RO, they show motor side effects when D 2 RO exceeds 80%. We investigated this discrepancy between D 2 RO, 5HT 2 receptor occupancy (5-HT 2 RO) and in vivo functional activity of aripiprazole in comparison to haloperidol (typical) and risperidone (atypical) in animal models. All three drugs showed dose-dependent D 2 RO. While risperidone clearly showed higher 5-HT 2 RO than D 2 RO, aripiprazole and haloperidol showed higher D 2 RO than 5-HT 2 RO at all doses. Haloperidol and risperidone induced catalepsy at doses producing 480% D 2 RO, while aripiprazole despite higher D 2 RO (490%) induced no catalepsy. Haloperidol and risperidone's ED 50 values for inhibition of conditioned avoidance response (CAR) and amphetamine-induced locomotor activity (AIL) corresponded to B60% D 2 RO. In contrast, aripiprazole showed a significant dissociation; while it blocked AIL at similar D 2 RO, a 23-fold higher dose (86% D 2 RO) was required to inhibit CAR. FOS expression in shell region of the nucleus accumbens was significant for all drugs at D 2 ROs that were effective in CAR. However, in the core region of the nucleus accumbens and dorsolateral striatum, aripiprazole differed from the others in that despite high D 2 RO it induced low FOS. Haloperidol and risperidone showed dose/occupancy-dependent prolactin elevations, while aripiprazole did not. Across models, haloperidol and risperidone show similar occupancy-functional antagonism of the D 2 system, while aripiprazole shows a clear dissociation. Partial agonism of aripiprazole offers a good explanation for this dissociation and provides a framework for understanding occupancy-functional relationships of partial D 2 agonist antipsychotics.

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Section: Discussionmentioning

confidence: 99%

Dissociation between In Vivo Occupancy and Functional Antagonism of Dopamine D2 Receptors: Comparing Aripiprazole to Other Antipsychotics in Animal Models

Natesan

Reckless

Nóbrega

et al. 2005

Neuropsychopharmacol

180

116

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“…The CAR model has very high predictive validity for antipsychotic efficacy, and this relationship is driven not only by drug effects on D 2 receptors, but, is also influenced by dopamine D 1 (McQuade et al, 1992), adrenergic (Hertel et al, 1999;Wadenberg et al, 2000a;Linner et al, 2002), glutaminergic (Takamori et al, 2003), muscarinic , and serotonergic (Wadenberg et al, 1994(Wadenberg et al, , 2001a receptor systems. NDMC was ineffective at the 20-90-min time point where all the other effective antipsychotics demonstrate efficacy.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of N-Desmethylclozapine as a Potential Antipsychotic—Preclinical Studies

Natesan

Reckless

Barlow

et al. 2006

Neuropsychopharmacol

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There is growing interest in N-desmethylclozapine (NDMC), the major metabolite of clozapine, as a unique antipsychotic because it acts in vitro as a 5-HT 2 antagonist and as a partial agonist to dopamine D 2 and muscarinic receptors. To explore this, we compared NDMC to a typical (haloperidol), atypical (clozapine), and partial-agonist atypical (aripiprazole) antipsychotic in preclinical models. The comparison was carried out using: brain D 2 and 5-HT 2 receptor occupancy; animal models predictive of antipsychotic efficacy (amphetamine-induced hyperlocomotion (AIL) and conditioned avoidance response (CAR) models); measures predictive of side effects (catalepsy and prolactin elevation); and molecular markers predictive of antipsychotic action (striatal Fos induction). NDMC (10-60 mg/kg/s.c.) showed high 5-HT 2 (64-79%), but minimal D 2 occupancy (o15% at 60 mg/kg) 1 h after administration. In contrast to other antipsychotics, NDMC was not very effective in reducing AIL or CAR and showed minimal induction of Fos in the nucleus accumbens. However, like atypical antipsychotics, it showed no catalepsy, prolactin elevation, and minimal Fos in the dorsolateral striatum. It seems unlikely that NDMC would show efficacy as a stand-alone antipsychotic, however, its freedom from catalepsy and prolactin elevation, and its unique pharmacological profile (muscarinic agonism) may make it feasible to use this drug as an adjunctive treatment to existing antipsychotic regimens.

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“…Broekkamp et al 1988;Invernizzi et al 1988;McMillen et al 1988;Wadenberg and Ahlenius 1991;Neal-Beliveau et al 1993) and on FRT in the paw test (Ellenbroek et al 1994). The effects of 8-OH-DPAT on neuroleptic-induced catalepsy likely involve 5-HT 1A receptor activation (Wadenberg et al 1994), are unrelated to increases in dopamine (Lucas et al 1997;cf. Neal-Beliveau et al 1993), and are selectively induced by its local administration in the raphe nuclei (Invernizzi et al 1988;Wadenberg and Hillegaart 1995).…”

Section: -Ht 1a Agonists and The Effects Of Neuroleptics On Catalepsmentioning

confidence: 96%

Interactions between neuroleptics and 5-HT 1A ligands in preclinical behavioral models for antipsychotic and extrapyramidal effects

1999

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Evidence for specific interactions between 5-HT1A and dopamine D2 receptor mechanisms in the mediation of extrapyramidal motor functions in the rat

Cited by 35 publications

References 26 publications

Dissociation between In Vivo Occupancy and Functional Antagonism of Dopamine D2 Receptors: Comparing Aripiprazole to Other Antipsychotics in Animal Models

Dissociation between In Vivo Occupancy and Functional Antagonism of Dopamine D2 Receptors: Comparing Aripiprazole to Other Antipsychotics in Animal Models

Evaluation of N-Desmethylclozapine as a Potential Antipsychotic—Preclinical Studies

Interactions between neuroleptics and 5-HT 1A ligands in preclinical behavioral models for antipsychotic and extrapyramidal effects

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