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

Prinssen, Eric; Kleven, Mark S.; Koek, Wouter

doi:10.1007/s002130050972

Cited by 59 publications

(28 citation statements)

References 39 publications

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“…WAY-100635 has selective 5-HT 1A receptor antagonist activity at the doses used in this study (Prinssen et al, 1999). The doses of SB-269970A were selected based on pharmacokinetic analysis (Hagan et al, 2000), doses of SB-243213A (5-methyl-1- [[2-[92-methyl-3-pyridyl0oxy]-5-pyridyl]carbamoyl]-6-trifluoromethylindone hydrochloride) were selected based on effects observed in a study by Wood et al, (2001).…”

Section: Drugsmentioning

confidence: 99%

Role of 5-HT receptor mechanisms in sub-chronic PCP-induced reversal learning deficits in the rat

et al. 2009

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Section: Drugsmentioning

confidence: 99%

Role of 5-HT receptor mechanisms in sub-chronic PCP-induced reversal learning deficits in the rat

et al. 2009

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“…Besides, there is ample preclinical evidence that activation of 5-HT 1A receptors should also prove beneficial in schizophrenia (Millan, 2000;Bantick et al, 2001;Ichikawa et al, 2001). Hence, it has been repeatedly shown that 5-HT 1A receptor agonists prevent catalepsy (an animal model of EPS) produced by blockade of DA D 2 receptors (Wadenberg and Ahlenius, 1991;Wadenberg et al, 1994;Neal-Beliveau et al, 1993;Prinssen et al, 1998Prinssen et al, , 1999Depoortere et al, 2003;Kleven et al, 2005). Consistent with this idea, clinical studies have reported that buspirone and tandospirone, two partial agonists at 5-HT 1A receptors, reduce the incidence of EPS in schizophrenic patients treated with haloperidol (Sumiyoshi et al, 2001a, b).…”

Section: Introductionmentioning

confidence: 99%

Actions of Novel Antipsychotic Agents on Apomorphine-Induced PPI Disruption: Influence of Combined Serotonin 5-HT1A Receptor Activation and Dopamine D2 Receptor Blockade

Auclair

Kleven

Besnard

et al. 2006

Neuropsychopharmacol

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The dopamine D1/D2 agonist apomorphine (0.63 mg/kg) disrupted prepulse inhibition (PPI) of acoustic startle in rats, a model of sensorimotor gating deficits observed in schizophrenia. All current antipsychotics, which antagonize D 2 receptors, prevent this apomorphine-induced deficit. A novel class of antipsychotics possesses, in addition to D 2 antagonist property, various levels of 5-HT 1A agonist activity. Considering that the latter itself produces PPI deficits, it appeared necessary to assess the potential of this novel class of antipsychotics to reverse apomorphine-PPI deficits. Potent D 2 antagonists, like haloperidol (0.63-2.5 mg/kg), risperidone (0.63-10 mg/kg), and olanzapine (0.63-40 mg/kg) prevented apomorphine PPI disruption. The atypical antipsychotics, clozapine (40 mg/kg), nemonapride (0.01-2.5 mg/kg), ziprasidone (10 mg/kg), and aripiprazole (0.01 and 10 mg/kg), which all exhibit 5-HT 1A agonist properties, reversed PPI deficits at some doses only, whereas the anti-dyskinetic agent sarizotan (0.16-10 mg/kg), an efficacious 5-HT 1A agonist, did not. New generation antipsychotics with marked 5-HT 1A agonist properties, such as SLV313 and SSR181507 (0.0025-10 mg/kg and 0.16-10 mg/kg, respectively) did not reverse these deficits whereas bifeprunox (0.04-2.5 mg/kg) did. To reveal the contribution of 5-HT 1A agonist properties in the lack of effects of SLV313 and SSR181507, we pretreated rats with the 5-HT 1A antagonist WAY100635 (0.63 mg/kg). Under these conditions, significant reversal of PPI deficit was observed, indicating that D 2 antagonist properties of SLV313 and SSR181507 are now sufficient to overcome the disruptive effects of apomorphine. To summarize, antipsychotics possessing agonist efficacy at 5-HT 1A receptors exhibit diverse profiles against apomorphine-induced PPI deficits, depending on the balance between D 2 and 5-HT 1A activities, suggesting that they may display distinct activity on some aspects of gating deficits in schizophrenic patients.

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“…For example, in the conditioned avoidance response (CAR) model of schizophrenia the nonselective 5-HT 1A agonist (7)-8-hydroxy (di-n-aminopropylamino) tetralin (8-OH-DPAT) not only induced CAR disruption but enhanced the effects of the dopamine D 2 receptor antagonists haloperidol and raclopride (Wadenberg and Ahlenius, 1991;Prinssen et al, 1996). Rather than increasing EPS the 5-HT 1A agonists 8-OHDPAT and ipsapirone reduced EPS-like symptoms in rodents and non-human primates (Prinssen et al, 1999(Prinssen et al, , 2000Wadenberg and Ahlenius, 1991;Wadenberg, 1996;Wadenberg et al, 1999;Christoffersen and Meltzer, 1998). These preclinical studies are supported by the finding that buspirone and tandospirone attenuated Parkinsonian-like signs and tardive dyskinesia seen in schizophrenics (Goff et al, 1991;Yoshida et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

SLV313 (1-(2,3-Dihydro-Benzo[1,4]Dioxin-5-yl)-4- [5-(4-Fluoro-Phenyl)-Pyridin-3-ylmethyl]-Piperazine Monohydrochloride): A Novel Dopamine D2 Receptor Antagonist and 5-HT1A Receptor Agonist Potential Antipsychotic Drug

McCreary

Glennon

Ashby

et al. 2006

Neuropsychopharmacol

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Combined dopamine D 2 receptor antagonism and serotonin (5-HT) 1A receptor agonism may improve efficacy and alleviate some side effects associated with classical antipsychotics. The present study describes the in vitro and in vivo characterization of 1-(2,3-dihydrobenzo[1,4]dioxin-5-yl)-4-[5-(4-fluoro-phenyl)-pyridin-3-ylmethyl]-piperazine monohydrochloride (SLV313), a D 2/3 antagonist and 5-HT 1A agonist. SLV313 possessed high affinity at human recombinant D 2 , D 3 , D 4 , 5-HT 2B , and 5-HT 1A receptors, moderate affinity at 5-HT 7 and weak affinity at 5-HT 2A receptors, with little-no affinity at 5-HT 4 , 5-HT 6 , a 1 , and a 2 (rat), H 1 (guinea pig), M 1 , M 4 , 5-HT 3 receptors, and the 5-HT transporter. SLV313 had full agonist activity at cloned h5-HT 1A receptors (pEC 50 ¼ 9.0) and full antagonist activity at hD 2 (pA 2 ¼ 9.3) and hD 3 (pA 2 ¼ 8.9) receptors. In vivo, SLV313 antagonized apomorphine-induced climbing and induced 5-HT 1A syndrome behaviors and hypothermia, the latter behaviors being antagonized by the 5-HT 1A antagonist WAY100635. In a drug discrimination procedure SLV313 induced full generalization to the training drug flesinoxan and was also antagonized by WAY100635. In the nucleus accumbens SLV313 reduced extracellular 5-HT and increased dopamine levels in the same dose range. Acetylcholine and dopamine were elevated in the hippocampus and mPFCx, the latter antagonized by WAY100635, suggesting possible 5-HT 1A -dependent efficacy for the treatment of cognitive and attentional processes. SLV313 did not possess cataleptogenic potential (up to 60 mg/kg p.o.). The number of spontaneously active dopamine cells in the ventral tegmental area was reduced by SLV313 and clozapine, while no such changes were seen in the substantia nigra zona compacta following chronic administration. These results suggest that SLV313 is a full 5-HT 1A receptor agonist and full D 2/3 receptor antagonist possessing characteristics of an atypical antipsychotic, representing a potential novel treatment for schizophrenia. Neuropsychopharmacology (2007) 32, 78-94.

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

Cited by 59 publications

References 39 publications

Role of 5-HT receptor mechanisms in sub-chronic PCP-induced reversal learning deficits in the rat

Role of 5-HT receptor mechanisms in sub-chronic PCP-induced reversal learning deficits in the rat

Actions of Novel Antipsychotic Agents on Apomorphine-Induced PPI Disruption: Influence of Combined Serotonin 5-HT1A Receptor Activation and Dopamine D2 Receptor Blockade

SLV313 (1-(2,3-Dihydro-Benzo[1,4]Dioxin-5-yl)-4- [5-(4-Fluoro-Phenyl)-Pyridin-3-ylmethyl]-Piperazine Monohydrochloride): A Novel Dopamine D2 Receptor Antagonist and 5-HT1A Receptor Agonist Potential Antipsychotic Drug

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