NLX-112, a novel 5-HT 1A receptor agonist for the treatment of l -DOPA-induced dyskinesia: Behavioral and neurochemical profile in rat

Iderberg, Hanna; McCreary, Andrew C.; Varney, Mark A.; Kleven, Mark S.; Koek, Wouter; Bardin, Laurent; Depoortère, R.; Cenci, M. Angela; Newman‐Tancredi, Adrian

doi:10.1016/j.expneurol.2015.05.021

Cited by 69 publications

(51 citation statements)

References 71 publications

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“…Secondly, NLX‐112 potently and efficaciously elicited adenylyl cyclase inhibition, ERK1/2 phosphorylation and h5‐HT 1A receptor internalization. The latter observation would be interesting to follow‐up in vivo as it may underlie the rapid desensitization to the rat ‘behavioural syndrome’ (flat body posture, forepaw treading) and hypothermia elicited by NLX‐112 . Interestingly, desensitization did not occur for the antidyskinetic or analgesic activity of NLX‐112, suggesting that other signalling pathways may mediate these responses.…”

Section: Discussionmentioning

confidence: 99%

“…It shows potent activity in a range of chronic rodent pain models, and completely reverses L‐DOPA‐induced abnormal involuntary movements (AIMS) in parkinsonian rats (i.e. unilaterally lesioned with 6‐OH‐DA, 6‐hydroxydopamine) . NLX‐112 exhibits nanomolar in vitro affinity for rat and human 5‐HT 1A receptors in competition binding experiments with the prototypical radioligand, [ 3 H]‐8‐OH‐DPAT (8‐hydroxy‐dipropylaminotetralin; pKi values of 9.1 and 9.5, respectively) and [ 3 H]NLX‐112 also binds to h5‐HT 1A receptors expressed in CHO cells with high affinity (pKd 8.7) …”

Section: Introductionmentioning

confidence: 99%

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Distinctive in vitro signal transduction profile of NLX-112, a potent and efficacious serotonin 5-HT1A receptor agonist

Newman‐Tancredi

Martel

Cosi

et al. 2017

Journal of Pharmacy and Pharmacology

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Distinctive in vitro signal transduction profile of NLX-112, a potent and efficacious serotonin 5-HT1A receptor agonist

Newman‐Tancredi

Martel

Cosi

et al. 2017

Journal of Pharmacy and Pharmacology

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“…The inhibition of serotonergic neurons by the stimulation of 5‐HT 1A autoreceptors, would reduce L‐DOPA‐stimulated dopamine release from serotonergic terminals (Tanaka et al , ; Navailles et al , ), thereby limiting the occurrence of dyskinesia. Our finding that the 5‐HT 1A receptor‐dependent control of serotonergic neurons is still fully operational in dyskinetic animals agrees with the efficacy of 5‐HT 1A agonists in reducing both dopamine release and dyskinesia (Kannari et al , ; Carta et al , ; Iderberg et al , ), particularly when targeting 5‐HT 1A autoreceptors (Iderberg et al , ). The SSRIs would be less efficacious than 5‐HT 1A receptor agonists against dyskinesia due to their loss of efficacy to modulate serotonergic neurons.…”

Section: Discussionmentioning

confidence: 99%

The acute and long‐term L‐DOPA effects are independent from changes in the activity of dorsal raphe serotonergic neurons in 6‐OHDA lesioned rats

Miguélez

Navailles

Deurwaerdère

et al. 2016

British J Pharmacology

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Background and PurposeL‐DOPA is still the most efficacious pharmacological treatment for Parkinson's disease. However, in the majority of patients receiving long‐term therapy with L‐DOPA, its efficacy is compromised by motor complications, notably L‐DOPA‐induced dyskinesia. Evidence suggests that the serotonergic system is involved in the therapeutic and the side effects of L‐DOPA. Here, we investigate if long‐term L‐DOPA treatment alters the activity of the dorsal raphe nucleus (DRN) and its responses to serotonergic drugs.Experimental ApproachWe measured the responses of serotonergic neurons to acute and chronic L‐DOPA treatment using in vivo electrophysiological single unit‐extracellular recordings in the 6‐OHDA‐lesion rat model of Parkinson's disease.Key ResultsThe results showed that neither acute nor chronic L‐DOPA administration (6 mg·kg−1 s.c.) altered the properties of serotonergic‐like neurons. Furthermore, no correlation was found between the activity of these neurons and the magnitude of L‐DOPA‐induced dyskinesia. In dyskinetic rats, the inhibitory response induced by the 5‐HT1A receptor agonist 8‐OH‐DPAT (0.0625–16 μg·kg−1, i.v.) was preserved. Nonetheless, L‐DOPA impaired the ability of the serotonin reuptake inhibitor fluoxetine (0.125–8 mg·kg−1, i.v) to inhibit DRN neuron firing rate in dyskinetic animals.Conclusions and ImplicationsAlthough serotonergic neurons are involved in the dopaminergic effects of L‐DOPA, we provide evidence that the effect of L‐DOPA is not related to changes of the activity of DRN neurons. Rather, L‐DOPA might reduce the efficacy of drugs that normally enhance the extracellular levels of serotonin.Linked ArticlesThis article is part of a themed section on Updating Neuropathology and Neuropharmacology of Monoaminergic Systems. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.13/issuetoc

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“…The efficacy of eltoprazine is not superior to existing treatment such as amantadine (Bezard and Carta, 2015). In terms of new strategies, particular attention has been given to 5-HT 1A receptor biased agonists, such as NLX-112, which acts preferentially at somatodendritic, rather than post-synaptic, 5-HT 1A receptors (Iderberg et al, 2015; McCreary et al, 2016). It has also been proposed that SSRIs lower L-DOPA-induced dyskinesia, as a result of their ability to indirectly reduce the firing rate of 5-HT neurons in the DRN (see above for the mechanism of action).…”

Section: From Pathophysiology To Treatmentsmentioning

confidence: 99%

Monoaminergic and Histaminergic Strategies and Treatments in Brain Diseases

et al. 2016

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The monoaminergic systems are the target of several drugs for the treatment of mood, motor and cognitive disorders as well as neurological conditions. In most cases, advances have occurred through serendipity, except for Parkinson's disease where the pathophysiology led almost immediately to the introduction of dopamine restoring agents. Extensive neuropharmacological studies first showed that the primary target of antipsychotics, antidepressants, and anxiolytic drugs were specific components of the monoaminergic systems. Later, some dramatic side effects associated with older medicines were shown to disappear with new chemical compounds targeting the origin of the therapeutic benefit more specifically. The increased knowledge regarding the function and interaction of the monoaminergic systems in the brain resulting from in vivo neurochemical and neurophysiological studies indicated new monoaminergic targets that could achieve the efficacy of the older medicines with fewer side-effects. Yet, this accumulated knowledge regarding monoamines did not produce valuable strategies for diseases where no monoaminergic drug has been shown to be effective. Here, we emphasize the new therapeutic and monoaminergic-based strategies for the treatment of psychiatric diseases. We will consider three main groups of diseases, based on the evidence of monoamines involvement (schizophrenia, depression, obesity), the identification of monoamines in the diseases processes (Parkinson's disease, addiction) and the prospect of the involvement of monoaminergic mechanisms (epilepsy, Alzheimer's disease, stroke). In most cases, the clinically available monoaminergic drugs induce widespread modifications of amine tone or excitability through neurobiological networks and exemplify the overlap between therapeutic approaches to psychiatric and neurological conditions. More recent developments that have resulted in improved drug specificity and responses will be discussed in this review.

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NLX-112, a novel 5-HT 1A receptor agonist for the treatment of l -DOPA-induced dyskinesia: Behavioral and neurochemical profile in rat

Cited by 69 publications

References 71 publications

Distinctive in vitro signal transduction profile of NLX-112, a potent and efficacious serotonin 5-HT1A receptor agonist

Distinctive in vitro signal transduction profile of NLX-112, a potent and efficacious serotonin 5-HT1A receptor agonist

The acute and long‐term L‐DOPA effects are independent from changes in the activity of dorsal raphe serotonergic neurons in 6‐OHDA lesioned rats

Monoaminergic and Histaminergic Strategies and Treatments in Brain Diseases

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