Side effect profile of 5‐HT treatments for Parkinson's disease and L‐DOPA‐induced dyskinesia in rats

Abstract

BACKGROUND AND PURPOSETreatment of Parkinson's disease (PD) with L-DOPA eventually causes abnormal involuntary movements known as dyskinesias in most patients. Dyskinesia can be reduced using compounds that act as direct or indirect agonists of the 5-HT1A receptor, but these drugs have been reported to worsen PD features and are known to produce '5-HT syndrome', symptoms of which include tremor, myoclonus, rigidity and hyper-reflexia. EXPERIMENTAL APPROACHSprague-Dawley rats were given unilateral nigrostriatal dopamine lesions with 6-hydroxydopamine. Each of the following three purportedly anti-dyskinetic 5-HT compounds were administered 15 min before L-DOPA: the full 5-HT1A agonist ±-8-hydroxy-2-dipropylaminotetralin (±8-OH-DPAT), the partial 5-HT1A agonist buspirone or the 5-HT transporter inhibitor citalopram. After these injections, animals were monitored for dyskinesia, 5-HT syndrome, motor activity and PD akinesia. KEY RESULTSEach 5-HT drug dose-dependently reduced dyskinesia by relatively equal amounts (±8-OH-DPAT ≥ citalopram ≥ buspirone), but 5-HT syndrome was higher with ±8-OH-DPAT, lower with buspirone and not present with citalopram. Importantly, with or without L-DOPA, all three compounds provided an additional improvement of PD akinesia. All drugs tempered the locomotor response to L-DOPA suggesting dyskinesia reduction, but vertical rearing was reduced with 5-HT drugs, potentially reflecting features of 5-HT syndrome. CONCLUSIONS AND IMPLICATIONSThe results suggest that compounds that indirectly facilitate 5-HT1A receptor activation, such as citalopram, may be more effective therapeutics than direct 5-HT1A receptor agonists because they exhibit similar anti-dyskinesia efficacy, while possessing a reduced side effect profile.Abbreviations 5-HIAA, 5-hydroxyindolacetic acid; 6-OHDA, 6-hydroxydopamine; AIMs, abnormal involuntary movements; DOPAC, 3,4-dihydroxyphenylacetic acid; FAS, forepaw adjusting steps; LID, L-DOPA-induced dyskinesia; MAD, median absolute deviation; PD, Parkinson's disease; SSRI, selective 5-HT re-uptake inhibitor

Diverse serotonin actions of vilazodone reduce l‐3,4‐dihidroxyphenylalanine–induced dyskinesia in hemi‐parkinsonian rats

“…Within a week of treatment, an effective preclinical antidepressant dose of Vilazodone (10 mg/kg) facilitated stepping improvements and appeared to be more effective at reducing LID than 5‐HT 1A agonists previously tested by our group . We did note that similar to SSRIs, Vilazodone treatment acutely suppressed l ‐dopa‐induced motor improvements, particularly at the higher dose, but this was transient and side effects, such as 5‐HT syndrome, were not observed . Indeed, effective adjuvant strategies will require chronic administration, which will change 5‐HT neurotransmission.…”

Effect of selective and non-selective serotonin receptor activation on l-DOPA-induced therapeutic efficacy and dyskinesia in parkinsonian rats

“…Moreover, unlike 5-HT1A receptor agonists, SSRIs administration did not induce serotonin syndrome, and did not interfere with l-DOPAinduced motor activation [15]. Thus, non-selective activation of serotonin receptors by either SSRIs or 5-HTP appears to exert similar anti-dyskinetic efficacy observed with selective 5-HT1 receptor activation, most likely due to the ability of these drugs to activate serotonin auto-receptors; in addition, 5-HTP and SSRIs appear to preserve the therapeutic efficacy of l-DOPA (opposite to what seen with selective 5-HT1 receptor agonists), at least in the rat model of PD, possibly due to the activation of post-synaptic 5-HT1 receptors.…”

“…http However, administration of 5-HT1 receptor agonists to dyskinetic animals and patients is associated with worsening of PD symptoms [7,[12][13][14]. Interestingly, administration of drugs that indirectly facilitate 5-HT1 receptor activation may be effective in reducing LID in animal models without compromising the therapeutic properties of l-DOPA [15,16]. Indeed, treatments with the serotonin precursor 5-hydroxy-tryptophan (5-HTP), or with selective serotonin transporter inhibitors (SSRIs), have been found to dampen dyskinesia without reducing the ability of l-DOPA to ameliorate motor impairment caused by 6-hydroxydopamine (6-OHDA) lesion in rats [16][17][18].…”

Alterations in primary motor cortex neurotransmission and gene expression in hemi-parkinsonian rats with drug-induced dyskinesia

“…This finding is commensurate with the idea that 6-OHDA is a general catecholamine toxin since it principally enters cells through the DA and NE transporters (Schober, 2004). Injecting 6-OHDA into the MFB in rats has been shown to reduce striatal NE concentrations; however, TH cell counts in the locus coeruleus were not reduced, suggesting NE terminal loss in the absence of apoptosis (Barnum et al, 2012; Fulceri et al, 2007; Lindenbach et al, 2015). Given that we found significant loss of cortical NE after 6-OHDA in the current study, our data suggest that more rigorous investigations of locus coeruleus pathology may be important for understanding aspects of cortical dysfunction in PD and LID.…”