Serotonin 5-HT1A agonist improves motor complications in rodent and primate parkinsonian models

Bibbiani, Francesco; Oh, Justin D.; Chase, Thomas N.

doi:10.1212/wnl.57.10.1829

Cited by 230 publications

(150 citation statements)

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“…Furthermore, sarizotan behaved as a partial DA D2 receptor agonist Kuzhikandathil et al, 2004). These observations indicate that the 5HT 1A receptor agonist properties of sarizotan are predominant: this most likely explains the lack of activity of this compound against apomorphine-induced PPI disruption, and might also be the reason why it was originally developed as an antipsychotic, but has been more recently re-oriented towards an anti-dyskinetic indication (Bibbiani et al, 2001). SSR181507 exhibited a moderate efficacy at 5-HT 1A receptors (39% that of ( + )8-OH-DPAT) with a rKi of 0.8, and also behaved as a partial DA D 2 receptor agonist (18% that of apomorphine, Cosi et al, in press).…”

Section: Discussionmentioning

confidence: 99%

“…These considerations have led to the development of compounds with preferential DA D 2 receptor antagonist or partial agonist, and 5-HT 1A agonist activities, such as bifeprunox (Feenstra et al, 2001;Wolf, 2003), SSR181507 (Claustre et al, 2003;Depoortere et al, 2003;Boulay et al, 2004), SLV313 McCreary et al, 2002), and sarizotan (that has been re-oriented towards an antidyskinetic indication: Bibbiani et al, 2001;Rabiner et al, 2002;Bartoszyk et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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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“…497,498 Sarizotan is a D2 receptor antagonist and a 5HT1A agonist that has been shown to have antidyskinesia effects in MPTP monkeys. 499 An openlabel clinical trial reported significant benefits with doses up to 10 mg/d, but these doses were associated with worsening of parkinsonism.…”

Section: Pharmacologic Management Of Advanced Pd Patientsmentioning

confidence: 99%

The scientific and clinical basis for the treatment of Parkinson disease (2009)

Olanow¹,

Stern²,

Sethi³

2009

Neurology

737

649

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Parkinson disease (PD) is an age-related neurodegenerative disorder that affects as many as 1-2% of persons aged 60 years and older. With the aging of the population, the frequency of PD is expected to increase dramatically in the coming decades. Current therapy is largely based on a dopamine replacement strategy, primarily using the dopamine precursor levodopa. However, chronic treatment is associated with the development of motor complications, and the disease is inexorably progressive. Further, advancing disease is associated with the emergence of features such as freezing, falling, and dementia which are not adequately controlled with dopaminergic therapies. Indeed, it is now appreciated that these nondopaminergic features are common and the major source of disability for patients with advanced disease. Many different therapeutic agents and treatment strategies have been evaluated over the past several years to try and address these unmet medical needs, and many promising approaches are currently being tested in the laboratory and in the clinic. As a result, there are now many new therapies and strategic approaches available for the treatment of the different stages of PD, with which the treating physician must be familiar in order to provide patients with optimal care. This monograph provides an overview of the management of PD patients, with an emphasis on pathophysiology, and the results of recent clinical trials. It is intended to provide physicians with an understanding of the different treatment options that are available for managing the different stages of the disease and the scientific rationale of the different approaches. 1 PD is the second most common neurodegenerative disorder, with an average age at onset of about 60 years. An estimated 5 million people throughout the world have PD, with 1 million individuals each in the United States and in Europe with the disorder. PD affects approximately 0.3% of the population and 1% to 2% of those older than 60 years.2 With the aging of the population and the substantial increase in the number of at-risk individuals older than 60 years, it is anticipated that the prevalence of PD will increase dramatically in the coming decades.

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“…5-HT 1A receptor plays an important role for the control of sleep, feeding and anxiety. 5-HT 1A receptor agonists have also neuroprotective effects in animal models including central nervous system ischemia (Saruhashi et al, 2002, Mauler & Horvath, 2005, Ramos et al, 2004, Kukley et al, 2001, Torup et al, 2000, Piera et al, 1995, acute subdermal hematoma (Fournier et al, 1993), traumatic brain injury (Alessandri et al, 1999, Kline et al, 2002, excitotoxicity (Oosterink et al, 2003, Cosi et al, 2005, a Parkinson's disease model animal induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (Bibbiani et al, 2001, Bezard et al, 2006, and sciatic nerve crush (Fournier et al, 1993). Additionally, it was reported that the 5-HT 1A agonists delayed the progression of motor neuron degeneration in pmn mice (Duong et al, 1998) and reduced lipid peroxidation in a rat epilepsy model (de Freitas et al, 2010).…”

Section: Tandospironementioning

confidence: 99%

Clinical Application of Drug Delivery Systems for Treating AMD

Kuno¹,

Fujii²

2012

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Serotonin 5-HT1A agonist improves motor complications in rodent and primate parkinsonian models

Abstract: Pharmaceuticals acting to stimulate 5-HT1A receptors could prove useful in the treatment of the motor response complications in parkinsonian patients.

Cited by 230 publications

References 34 publications

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

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

The scientific and clinical basis for the treatment of Parkinson disease (2009)

Clinical Application of Drug Delivery Systems for Treating AMD

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