Sigma ligands, but not N-methyl-D-aspartate antagonists, reduce levodopa-induced dyskinesias

Paquette, Melanie; Brudney, Elizabeth G.; Putterman, Daniel; Meshul, Charles K.; Johnson, Steven W.; Berger, Stanley A.

doi:10.1097/wnr.0b013e3282f3b0d1

Cited by 19 publications

(32 citation statements)

References 21 publications

(23 reference statements)

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“…The glutamate modulating agents amantadine, MTEP and IEM1460 were not able to sufficiently reduce amphetamine driven AIMs in transplanted rats, in contrast to their function in LID (Dekundy et al, 2007;Kobylecki et al, 2010;Lundblad et al, 2002Lundblad et al, , 2005Paquette et al, 2010;Paquette et al, 2008;Rylander et al, 2009). Amantadine has an additional role as a dopamine releasing agent, therefore the lack of effect of could be due to a similar competing mechanism to amphetamine.…”

Section: Discussioncontrasting

confidence: 49%

Pharmacological modulation of amphetamine-induced dyskinesia in transplanted hemi-parkinsonian rats

Smith¹,

Breger²,

Lane³

et al. 2012

Neuropharmacology

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Section: Discussioncontrasting

confidence: 49%

Pharmacological modulation of amphetamine-induced dyskinesia in transplanted hemi-parkinsonian rats

Smith¹,

Breger²,

Lane³

et al. 2012

Neuropharmacology

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“…The DHEA (15 mg/kg) dose is within the range that increases or reactivates cocaine CPP (Romieu et al 2003, 2004). Carbetapentane and dextromethorphan are anticonvulsant at similar doses (Leander 1989); the dose of carbetapentane selected (45 mg/kg) is within the anticonvulsant range and is identical to the dose of dextromethorphan previously shown to suppress abnormal involuntary movements in the 6-OHDA rat (Paquette et al 2008). The opipramol dose (10 mg/kg) has been shown to increase DA overflow and metabolism (Rao et al 1990).…”

Section: Methodsmentioning

confidence: 99%

“…In the 6-hydroxydopamine (6-OHDA) rat model of PD, L-DOPA induces a similar phenomenon, termed abnormal involuntary movement (AIM). We recently demonstrated that the expression of AIM is prevented by BMY-14802, a widely used sigma-1 antagonist (Paquette et al 2008). BMY-14802 has other notable mechanisms, including agonism at serotonin (5-HT) 1A and adrenergic α -1 receptors.…”

Section: Introductionmentioning

confidence: 99%

The sigma-1 antagonist BMY-14802 inhibits L-DOPA-induced abnormal involuntary movements by a WAY-100635-sensitive mechanism

Paquette

Foley²,

Brudney³

et al. 2009

Psychopharmacology

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Rationale Levodopa (L-DOPA), the gold standard treatment for Parkinson's disease (PD), eventually causes L-DOPA-induced dyskinesia (LID) in up to 80% of patients. In the 6-hydroxydopamine (6-OHDA) rat model of PD, L-DOPA induces a similar phenomenon, which has been termed abnormal involuntary movement (AIM). We previously demonstrated that BMY-14802 suppresses AIM expression in this model. Objectives Although BMY-14802 is widely used as a sigma-1 antagonist, it is also an agonist at serotonin (5-HT) 1A and adrenergic α-1 receptors. The current study was conducted to determine which of these mechanisms underlies BMY-14802's AIM-suppressing effect. This characterization included testing the 5-HT1A agonist buspirone and multiple sigma agents. When these studies implicated a 5-HT1A mechanism, we subsequently undertook a pharmacological reversal study, evaluating whether the 5-HT1A antagonist WAY-100635 counteracted BMY-14802's AIM-suppressing effects. Results Buspirone dose-dependently suppressed AIM, supporting past findings. However, no AIM-suppressing effects were produced by drugs with effects at sigma receptors, including BD-1047, finasteride, SM-21, DTG, trans-dehydroandrosterone (DHEA), carbetapentane, and opipramol. Finally, we show for the first time that the AIM-suppressing effect of BMY-14802 was dose-dependently prevented by WAY-100635 but not by the α-1 antagonist prazosin. Conclusions BMY-14802 exerts its AIM-suppressing effects via a 5-HT1A agonist mechanism, similar to buspirone. Other 5-HT1A agonists have failed clinical trials, possibly due to submicromolar affinity at other receptors, including D2, which may exacerbate PD symptoms. BMY-14802 is a promising candidate for clinical trials due to its extremely low affinity for the D2 receptor and lack of extrapyramidal effects during prior clinical trials for schizophrenia.

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“…The s-1 receptor is involved in the modulation of dopaminergic transmission by amantadine [82]. BMY-14802 is known to reduce levodopa-induced dyskinesia [83]. It has been hypothesized that dehydroepiandrosterone displays Review s-1 receptors in major depression & anxiety antidepressant effects by enhancing the release of glutamate in the rat prelimbic cortex through activation of the dopamine D 1 and s-1 receptors [84].…”

Section: Enhancement Of Dopaminergic Neurotransmissionmentioning

confidence: 99%

σ-1 receptors in major depression and anxiety

Kulkarni¹,

Dhir²

2009

Expert Review of Neurotherapeutics

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Major depression and anxiety are two of the major psychiatric disorders that have some overlapping pathophysiologies, the most significant being the dysfunction in the monoaminergic, GABAergic and glutamatergic systems. A large number of drugs that alter these neurotransmitter levels/systems are effective in the treatment of major depression and anxiety. However, full remission of the clinical symptoms has not been achieved, perhaps owing to the complex pathophysiology of the diseases. Thus, the search for newer targets and target-specific drugs continues. Recently, the role of sigma-receptors, particularly the sigma-1 receptor subtype, has been identified as a target for the pathophysiology of neuropsychiatric disorders, and sigma-1 receptor modulators are considered to be the drugs of the future for the treatment of major depression and anxiety. The present review attempts to discuss the role of sigma-1 receptors in the pathophysiology of major depression and anxiety and also tries to position the use of its receptor modulators in the treatment of these two major disorders. The role of sigma-1 receptors in the mechanism of antidepressant action of venlafaxine, bupropion, neurosteroids and one of the herbal antidepressants, berberine, is reviewed. Although, sigma-1 receptor modulators may be future therapeutic options, either as individual agents or adjuvants in the treatment of mental disorders, the topic needs further preclinical and clinical exploration.

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Sigma ligands, but not N-methyl-D-aspartate antagonists, reduce levodopa-induced dyskinesias

Cited by 19 publications

References 21 publications

Pharmacological modulation of amphetamine-induced dyskinesia in transplanted hemi-parkinsonian rats

Pharmacological modulation of amphetamine-induced dyskinesia in transplanted hemi-parkinsonian rats

The sigma-1 antagonist BMY-14802 inhibits L-DOPA-induced abnormal involuntary movements by a WAY-100635-sensitive mechanism

σ-1 receptors in major depression and anxiety

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