Serotonin 1A receptor (5-HT 1A R) agonists reduce both L-DOPA-and D1 receptor (D1R) agonistmediated dyskinesia, but their anti-dyskinetic mechanism of action is not fully understood. Given that 5-HT 1A R stimulation reduces glutamatergic neurotransmission in the dopamine-depleted striatum, 5-HT 1A R agonists may diminish dyskinesia in part through modulation of pro-dyskinetic striatal glutamate levels. To test this, rats with unilateral medial forebrain bundle dopamine or sham lesions were primed with L-DOPA (12 mg/kg + benserazide, 15 mg/kg, sc) or the D1R agonist SKF81297 (0.8 mg/kg, sc) until abnormal involuntary movements (AIMs) stabilized. On subsequent test days, rats were treated with vehicle or the 5-HT 1A R agonist ±8-OH-DPAT (1.0 mg/kg, sc), followed by L-DOPA or SKF81297, or intrastriatal ±8-OH-DPAT (7.5 or 15 mM), followed by L-DOPA. In some cases, the 5-HT 1A R antagonist WAY100635 was employed to determine receptor-specific effects. In vivo microdialysis was used to collect striatal samples for analysis of extracellular glutamate levels during AIMs assessment. Systemic and striatal ±8-OH-DPAT attenuated L-DOPA-induced dyskinesia and striatal glutamate efflux while WAY100635 reversed ±8-OH-DPAT's effects. Interestingly, systemic ±8-OH-DPAT diminished D1R-mediated AIMs without affecting glutamate. These findings indicate a novel anti-dyskinetic mechanism of action for 5-HT 1A R agonists with implications for the improved treatment of Parkinson's disease.

Depression and anxiety are prevalent non-motor symptoms that worsen quality of life for Parkinson's disease (PD) patients. While dopamine (DA) cell loss is a commonly proposed mechanism, the reported efficacy of DA replacement therapy with L-DOPA on affective symptoms is inconsistent. In order to delineate the effects of DA denervation and chronic L-DOPA treatment on affective behaviors, male Sprague-Dawley rats received unilateral 6-OHDA or sham lesions and were treated daily with L-DOPA (12 mg/kg + benserazide, 15 mg/kg, sc) or vehicle (0.9% NaCl, 0.1% ascorbic acid) for 28 days before commencing investigations into anxiety (locomotor chambers, social interaction) and depression-like behaviors (forced swim test) during the OFF phase of L-DOPA. One h after final treatments, rats were killed and striatum, prefrontal cortex, hippocampus, and amygdala were analyzed via high performance liquid chromatography for monoamine levels. In locomotor chambers and social interaction, DA lesions exerted mild anxiogenic effects. Surprisingly, chronic L-DOPA treatment did not improve these effects. While DA lesion reduced climbing behaviors on day 2 of exposure to the forced swim test, chronic L-DOPA treatment did not reverse these effects. Neurochemically, L-DOPA treatment in hemiparkinsonian rats reduced NE levels in the prefrontal cortex, striatum, and hippocampus. Collectively, the present data suggest that chronic L-DOPA therapy in severely DA-lesioned rats does not improve non-motor symptoms and may impair nondopaminergic processes, indicating that long-term L-DOPA therapy does not exert necessary cause neuroplastic changes for improving affect.

Chronic dopamine replacement therapy in Parkinson's disease (PD) leads to deleterious motor sequelae known as L-DOPAinduced dyskinesia (LID). No known therapeutic can eliminate LID, but preliminary evidence suggests that dl-1-isopropylamino-3-(1-naphthyloxy)-2-propanol [(Ϯ)propranolol], a nonselective ␤-adrenergic receptor (␤AR) antagonist, may reduce LID. The present study used the rat unilateral 6-hydroxydopamine model of PD to characterize and localize the efficacy of (Ϯ)propranolol as an adjunct to therapy with L-DOPA. We first determined whether (Ϯ)propranolol was capable of reducing the development and expression of LID without impairing motor performance ON and OFF L-DOPA. Coincident to this investigation, we used reverse-transcription polymerase chain reaction techniques to analyze the effects of chronic (Ϯ)propranolol on markers of striatal activity known to be involved in LID. To determine whether (Ϯ)propranolol reduces LID through ␤AR blockade, we subsequently examined each enantiomer separately because only the (Ϫ)enantiomer has significant ␤AR affinity. We next investigated the effects of a localized striatal ␤AR blockade on LID by cannulating the region and microinfusing (Ϯ)propranolol before systemic L-DOPA injections. Results showed that a dose range of (Ϯ)propranolol reduced LID without deleteriously affecting motor activity. Pharmacologically, only (Ϫ)propranolol had anti-LID properties indicating ␤AR-specific effects. Aberrant striatal signaling associated with LID was normalized with (Ϯ)propranolol cotreatment, and intrastriatal (Ϯ)propranolol was acutely able to reduce LID. This research confirms previous work suggesting that (Ϯ)propranolol reduces LID through ␤AR antagonism and presents novel evidence indicating a potential striatal locus of pharmacological action.

Dopamine (DA) replacement therapy with L-DOPA is the standard treatment for Parkinson’s disease (PD). Unfortunately chronic treatment often leads to the development of abnormal involuntary movements (AIMs) referred to as L-DOPA-induced dyskinesia (LID). Accumulating evidence has shown that compensatory plasticity in serotonin (5-HT) neurons contributes to LID and recent work has indicated that acute 5-HT transporter (SERT) blockade provides anti-dyskinetic protection. However neither the persistence nor the mechanism(s) of these effects have been investigated. Therefore the current endeavor sought to mimic a prolonged regimen of SERT inhibition in L-DOPA-primed and –naïve hemi-parkinsonian rats. Rats received 3 weeks of daily co-treatment of the selective 5-HT reuptake inhibitors (SSRIs) citalopram (0, 3, or 5 mg/kg) or paroxetine (0, 0.5, or 1.25 mg/kg) with L-DOPA (6 mg/kg) during which AIMs and motor performance were monitored. In order to investigate potential mechanisms of action, tissue levels of striatal monoamines were monitored and the 5-HT1A receptor antagonist WAY100635 (0.5 mg/kg) was used. Results revealed that prolonged SSRIs attenuated AIMs expression and development in L-DOPA-primed and –naïve subjects, respectively, without interfering with motor performance. Neurochemical analysis of striatal tissue indicated that a 3 week SERT blockade increased DA levels in L-DOPA-treated rats. Pharmacologically, anti-dyskinetic effects were partially reversed with WAY100635 signifying involvement of the 5-HT1A receptor. Collectively, these findings demonstrate that prolonged SERT inhibition provides enduring anti-dyskinetic effects in part via 5-HT1A receptors while maintaining L-DOPA’s anti-parkinsonian efficacy by enhancing striatal DA levels.

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

While serotonin 5-HT1A receptor (5-HT1AR) agonists reduce L-DOPA-induced dyskinesias (LID) by normalizing activity in the basal ganglia neurocircuitry, recent evidence suggests putative 5-HT1AR within the primary motor cortex (M1) may also contribute. To better characterize this possible mechanism, c-fos immunohistochemistry was first used to determine the effects of systemic administration of the full 5-HT1AR agonist ±8-OH-DPAT on L-DOPA-induced immediate early gene expression within M1 and the prefrontal cortex (PFC) of rats with unilateral medial forebrain bundle (MFB) dopamine (DA) lesions. Next, in order to determine if direct stimulation of 5-HT1AR within M1 attenuates the onset of LID, rats with MFB lesions were tested for L-DOPA-induced abnormal involuntary movements (AIMs) and rotations following M1 microinfusions of ±8-OH-DPAT with or without co-administration of the 5-HT1AR antagonist WAY100635. Finally, ±8-OH-DPAT was infused into M1 at peak dyskinesia to determine if 5-HT1AR stimulation attenuates established L-DOPA-induced AIMs and rotations. While no treatment effects were seen within the PFC, systemic ±8-OH-DPAT suppressed L-DOPA-induced c-fos within M1. Intra-M1 5-HT1AR stimulation diminished the onset of AIMs and this effect was reversed by WAY100635 indicating receptor specific effects. Finally, continuous infusion of ±8-OH-DPAT into M1 at peak dyskinesia alleviated L-DOPA-induced AIMs. Collectively, these findings support an integral role for M1 in LID and its modulation by local 5-HT1AR.

Long-term treatment of Parkinson's disease with L-DOPA almost always leads to the development of involuntary movements termed L-DOPA-induced dyskinesia. Whereas hyperdopaminergic signaling in the basal ganglia is thought to cause dyskinesia, alterations in primary motor cortex (M1) activity are also prominent during dyskinesia, suggesting that the cortex may represent a therapeutic target. The present study used the rat unilateral 6-hydroxydopamine lesion model of Parkinson's disease to characterize in vivo changes in GABA and glutamate neurotransmission within M1 and determine their contribution to behavioral output. 6-Hydroxydopamine lesion led to parkinsonian motor impairment that was partially reversed by L-DOPA. Among sham-lesioned rats, L-DOPA did not change glutamate or GABA efflux. Likewise, 6-hydroxydopamine lesion did not impact GABA or glutamate among rats chronically treated with saline. However, we observed an interaction of lesion and treatment whereby, among lesioned rats, L-DOPA given acutely (1 d) or chronically (14 -16 d) reduced glutamate efflux and enhanced GABA efflux. Site-specific microinjections into M1 demonstrated that L-DOPAinduced dyskinesia was reduced by M1 infusion of a D 1 antagonist, an AMPA antagonist, or a GABA A agonist. Overall, the present study demonstrates that L-DOPA-induced dyskinesia is associated with increased M1 inhibition and that exogenously enhancing M1 inhibition may attenuate dyskinesia, findings that are in agreement with functional imaging and transcranial magnetic stimulation studies in human Parkinson's disease patients. Together, our study suggests that increasing M1 inhibitory tone is an endogenous compensatory response designed to limit dyskinesia severity and that potentiating this response is a viable therapeutic strategy.

Dopamine (DA) replacement with L-DOPA remains the most effective pharmacotherapy for motor symptoms of Parkinson’s disease (PD) including tremor, postural instability, akinesia, and bradykinesia. Prolonged L-DOPA use frequently leads to deleterious side effects including involuntary choreic and dystonic movements known as L-DOPA induced dyskinesias (LID). DA loss in PD is frequently accompanied by concomitant noradrenergic (NE) denervation of the locus coeruleus (LC); however, the effects of NE loss on L-DOPA efficacy and LID remain controversial and are often overlooked in traditional animal models of PD. The current investigation examined the role of NE loss in L-DOPA therapy by employing the NE specific neurotoxin anti-DA-beta hydroxylase saporin (αDBH) in a rat model of PD. Rats received unilateral 6-hydroxydopamine lesions of the medial forebrain bundle to deplete nigral DA and intraventricular injection of vehicle (DA lesioned rats) or αDBH (DANE lesioned rats) to destroy NE neurons bilaterally. Results indicated that αDBH infusion drastically reduced NE neuron markers within the LC compared to rats that received vehicle treatment. Behaviorally, this loss did not alter the development or expression of L-DOPA- or DA agonist- induced dyskinesia. However, rats with additional NE lesions were less responsive to L-DOPA’s pro-motor effects. Indeed, DANE lesioned animals rotated less and showed less attenuation of parkinsonian stepping deficits following high doses of L-DOPA than DA lesioned animals. These findings suggest that severe NE loss may reduce L-DOPA treatment efficacy and demonstrate that degradation of the NE system is an important consideration when evaluating L-DOPA effects in later stage PD.