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

Abstract

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.

Axial levodopa-induced dyskinesias and neuronal activity in the dorsal striatum

“…and ipsilateral rotations were recorded 30 min post-injection (Healy-Stoffel et al, 2012; Chotibut et al, 2013). Animals that did not show >5 ipsilateral rotations per minute were not included in this study (Chang et al, 1999; Paquette et al, 2009); animals used in the study performed 11±2 ipsilateral rotations per minute. Only complete rotations (360°) were counted.…”

MK-801 inhibits l-DOPA-induced abnormal involuntary movements only at doses that worsen parkinsonism

“…6-OHDA lesions were conducted as previously described (Paquette et al, 2008, 2009a). Briefly, during stereotaxic surgery under isoflurane anesthesia, a 30 gauge infusion cannula, attached via PE20 tubing to a 25 μl Hamilton gastight syringe and driven by a microinfusion pump (Harvard Apparatus, Holliston, MA, USA) was used to infuse 6-OHDA hydrobromide (22.8 μg/2 μl of 0.9% saline with 0.2% ascorbic acid, 0.5 μl/min; Sigma-Aldrich, St. Louis, MO, USA) into each of 2 sites within the right medial forebrain bundle (AP −4.3 and −4.8, ML ±1.2, DV −8.6 in mm relative to Bregma; Paxions and Watson, 1998) at least 30 min after desipramine hydrochloride (25 mg/kg, i.p.…”

“…was used to select rats with significant hemi-parkinsonism (Paquette et al, 2008, 2009a). Lesion size was later confirmed by quantification of tyrosine hydroxylase protein levels via Western blotting.…”

“…Amantadine and dextromethorphan have long been thought to suppress AIMs and LID via their known noncompetitive N-methyl-D-aspartate (NMDA) antagonist effects (Chase et al, 2000; Del Dotto et al, 2001; Marin et al, 2000; Verhagen-Metman, 1998a,b,c,d). However, these drugs are also thought to cause serotonin (5-HT) overflow (Baptista et al, 1997; Gaikwad et al, 2005), which would stimulate 5-HT1A autoreceptors, a mechanism known to suppress AIMs and LID (Bishop et al, 2009; Paquette et al, 2009a). We therefore questioned whether selective NMDA antagonism could reduce L-DOPA-induced AIMs at doses below those that produce competing behaviors (e.g., locomotor stimulation or ataxia; Frantz and Van Hartesveldt, 1999; Haggerty and Brown, 1996).…”

Sigma-1 receptor chaperones in neurodegenerative and psychiatric disorders

“…The Sig-1R antagonist BMY-14802 suppressed L-dopa induction of dyskinesias; however, it is unclear if this is due to nonspecific actions of the ligand [61]. Dextromethorphan, a Sig-1R agonist and NMDA receptor ligand was also able to suppress L-dopa-associated involuntary movements; however, NMDA antagonists were unable to block these effects, thereby indicating Sig-1R mechanisms are likely involved [62].…”