Serotonin 5-HT1A receptor agonists reduce l-DOPA-induced dyskinesia (LID) in animal models of Parkinson's disease (PD). Here, we compared the effects of novel 5-HT1A receptor ‘biased agonists’ on LID ...in hemiparkinsonian rats. F13714 preferentially activates pre-synaptic 5-HT1A autoreceptors. F15599 preferentially activates cortical postsynaptic 5-HT1A heteroreceptors. The partial agonist, tandospirone, does not differentiate these receptor subpopulations. The drugs were also tested on rotational behavior, rotarod and cylinder test for evaluation of locomotor activity, motor coordination and forelimb akinesia. Finally, the effects of F13714 and F15599 on 5-HT, DA, glutamate, and GABA release were investigated by microdialysis.
F13714 abolished l-DOPA-induced AIMs even at very low doses (0.02–0.04 mg/kg). This effect was reversed by the selective 5-HT1A receptor antagonist, WAY100635. F13714 also elicited ipsilateral rotations (which were blocked by WAY100635) and potentiated the rotational activity of a sub-threshold dose of l-DOPA (2 mg/kg). F13714 profoundly inhibited striatal 5-HT release on both sides of the brain, and slightly increased DA release on the intact side. F15599 inhibited the l-DOPA-induced AIMs only at a dose (0.16 mg/kg) that reduced 5-HT release. Tandospirone produced a modest attenuation of peak AIMs severity and did not elicit rotations. F13714, F15599 and tandospirone did not modify the action of l-DOPA in the cylinder test but impaired rotarod performance at the highest doses tested.
Targeting 5-HT1A receptors with selective biased agonists exerts distinct effects in the rat model of PD and LID. Preferential activation of 5-HT1A autoreceptors could potentially translate to superior antidyskinetic and l-DOPA dose-sparing effects in PD patients.
•5-HT1A receptor agonists were tested on rat l-DOPA-induced dyskinesia (LID).•F13714 is a ‘biased agonist’ that preferentially activates 5-HT1A autoreceptors.•F13714 abolished LID, stimulated rotations and inhibited serotonin release.•F15599, a preferential postsynaptic 5-HT1A receptor agonist, was less active.•Preferential targeting 5-HT1A autoreceptors is a novel strategy for LID treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, SAZU, SBCE, UL, UM, UPCLJ, UPUK
l-DOPA is the gold-standard treatment for Parkinson's disease (PD), but induces troublesome dyskinesia after prolonged treatment. This is associated with the ‘false neurotransmitter’ conversion of ...l-DOPA to dopamine by serotonin neurons projecting from the raphe to the dorsal striatum. Reducing their activity by targeting pre-synaptic 5-HT1A receptors should thus be an attractive therapeutic strategy, but previous 5-HT1A agonists have yielded disappointing results. Here, we describe the activity of a novel, highly selective and potent 5-HT1A agonist, NLX-112 (also known as befiradol or F13640) in rat models relevant to PD and its associated affective disorders.
NLX-112 (0.16mg/kg, i.p.) potently and completely reversed haloperidol-induced catalepsy in intact rats and abolished l-DOPA-induced Abnormal Involuntary Movements (AIMs) in hemiparkinsonian rats, an effect that was reversed by the selective 5-HT1A antagonist, WAY100635. In microdialysis experiments, NLX-112 profoundly decreased striatal 5-HT extracellular levels, indicative of inhibition of serotonergic function. NLX-112 also blunted the l-DOPA-induced surge in dopamine levels on the lesioned side of the brain, an action that likely underlies its anti-dyskinetic effects.
NLX-112 (0.16mg/kg, i.p.) robustly induced rotations in hemiparkinsonian rats, suggesting that it has a motor facilitatory effect. Rotations were abolished by WAY100635 and were ipsilateral to the lesioned side, suggesting a predominant stimulation of the dopamine system on the non-lesioned side of the brain. NLX-112 also efficaciously reduced immobility time in the forced swim test (75% reduction at 0.16mg/kg, i.p.) and eliminated stress-induced ultrasonic vocalization at 0.08mg/kg, i.p., effects consistent with potential antidepressant- and anxiolytic-like properties.
In other tests, NLX-112 (0.01–0.16mg/kg, i.p.) did not impair the ability of l-DOPA to rescue forepaw akinesia in the cylinder test but decreased rotarod performance, probably due to induction of flat body posture and forepaw treading which are typical of 5-HT1A agonists upon acute administration. However, upon repeated administration of NLX-112 (0.63mg/kg, i.p., twice a day), flat body posture and forepaw treading subsided within 4days of treatment.
Taken together, these observations suggest that NLX-112 could exhibit a novel therapeutic profile, combining robust anti-dyskinetic properties without impairing the therapeutic properties of l-DOPA, and with additional beneficial effects on non-motor (affective) symptoms.
•NLX-112 is a highly-selective and efficacious serotonin 5-HT1A receptor agonist.•NLX-112 potently and completely abolishes l-DOPA-induced dyskinesia (LID) in rat.•NLX-112 also stimulates rotations and exhibits antidepressant-like properties.•NLX-112 inhibits 5-HT neurons mediating ‘false neurotransmitter’ dopamine release.•NLX-112 is a promising clinical candidate to treat LID in Parkinson's disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Striatal function adapts to the loss of nigrostriatal dopaminergic input in Parkinson's disease (PD) to initially maintain voluntary movement, but subsequently changes in response to drug ...treatment leading to the onset of motor complications, notably dyskinesia. Alterations in presynaptic dopaminergic function coupled to changes in the response of post-synaptic dopaminergic receptors causing alterations in striatal output underlie attempts at compensation and the control of movement in early PD. However, eventually compensation fails and persistent changes in striatal function ensue that involve morphological, biochemical and electrophysiological change. Key alterations occur in cholinergic and glutamatergic transmission in the striatum and there are changes in motor programming controlled by events involving LTP/LTD. Dopamine replacement therapy with L-DOPA modifies altered striatal function and restores motor function but non-physiological dopamine receptor stimulation leads to altered signalling through D1 and D2 receptor systems and changes in striatal function causing abnormalities of LTP/LTD mediated through glutamatergic/nitric oxide (NO) mechanisms. These lead to the onset of dyskinesia and underlie the priming process that characterise dyskinesia and its persistence.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Nicotine is a highly addictive drug and exerts this effect partially through the modulation of dopamine release and increasing extracellular dopamine in regions such as the brain reward systems. ...Nicotine acts in these regions on nicotinic acetylcholine receptors. The effect of nicotine on the frequency dependent modulation of dopamine release is well established and the purpose of this study was to investigate whether dopamine D
1
receptor (D
1
R) ligands have an influence on this. Using fast cyclic voltammetry and rat corticostriatal slices, we show that D
1
R ligands are able to modulate the effect of nicotine on dopamine release. Nicotine (500 nM) induced a decrease in dopamine efflux at low frequency (single pulse or five pulses at 10 Hz) and an increase at high frequency (100 Hz) electrical field stimulation. The D
1
R agonist SKF-38393, whilst having no effect on dopamine release on its own or on the effect of nicotine upon multiple pulse evoked dopamine release, did significantly prevent and reverse the effect of nicotine on single pulse dopamine release. Interestingly similar results were obtained with the D
1
R antagonist SCH-23390. In this study we have demonstrated that the modulation of dopamine release by nicotine can be altered by D
1
R ligands, but only when evoked by single pulse stimulation, and are likely working via cholinergic interneuron driven dopamine release.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Polarization-resolved Raman spectroscopy was performed and analyzed from large, high-quality, monodomain single crystal of α−RuCl3, a proximate Kitaev quantum spin liquid. Spectra were collected with ...laser polarizations parallel and perpendicular to the honeycomb plane. Pairs of nearly degenerate phonons were discovered and show either a fourfold or twofold polarization angle dependence in their Raman intensity, thereby providing evidence to definitively assign the bulk crystal point group as C2h. The low-frequency continuum that is often attributed to scattering from pairs of Majorana fermions was also examined and found to disappear when the laser excitation and scattered photon polarizations were perpendicular to the honeycomb plane. This disappearance, along with the behavior of the phonon spectrum in the same polarization configuration, strongly suggests that the scattering continuum is two-dimensional. We argue that this scattering continuum originates from the Kitaev magnetic interactions that survives up to room temperature, a scale larger than the bare Kitaev exchange energy of approximately 50 K.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
▸ CMP 42 is a CNS available, selective 5-HT6 antagonist. ▸ CMP 42 was effective in reducing nicotine self-administration in Wistar rats. ▸ CMP 42 reduced reinstatement of both nicotine and ethanol ...seeking. ▸ The 5-HT6 receptor is a viable pharmacological target for the control of drug abuse. ▸ CMP 42 did not affect anticipatory responding, showing no effects on impulse control.
Recent studies suggest a potential role for 5-hydroxytryptamine6 (5-HT6) receptors in the regulation of addictive behavior. In the present study, our aim was to investigate whether the novel highly selective 5-HT6 receptor antagonist compound (CMP) 42 affected nicotine and ethanol seeking behavior in Wistar rats. We have also studied whether CMP 42 had beneficial effects in a model of impulse control, as measured in the 5-choice serial reaction time task (5-CSRTT).
Rats were trained to nose poke to receive intravenous infusions of nicotine or an ethanol drop. CMP 42 (3–30mg/kg intraperitoneally, i.p.) was administered to investigate the effects on nicotine self-administration. Rats were also tested for cue-induced reinstatement of nicotine and ethanol seeking. In addition, the effects of CMP 42 were studied on the number of anticipatory responses in the 5-CSRTT.
CMP 42 was effective in reducing nicotine self-administration and reinstatement of nicotine seeking at a dose of 30mg/kg (i.p.). CMP 42 was also effective in reducing reinstatement of ethanol seeking (30mg/kg i.p.). In contrast, CMP 42 did not affect anticipatory responding at doses tested, indicating no effects on impulse control.
These results add to a body of evidence implicating the 5-HT6 receptor as a viable target for the control of drug abuse. Specifically, we demonstrated for the first time effects on nicotine self-administration and on nicotine and ethanol reinstatement. Further, these effects are probably not mediated by effects on impulse control.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Dopamine agonist treatment in early Parkinson's disease (PD) induces less dyskinesia than
l-dopa. However, once dyskinesia has developed, dopamine agonists administered with
l-dopa exacerbate ...involuntary movements. The dopamine partial D2/D3 agonist pardoprunox reverses motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-treated primates without hyperactivity, indicating that pardoprunox may alleviate dyskinesia without compromising
l-dopa's beneficial actions. This study examines a clinical scenario in which pardoprunox was introduced, in an
l-dopa sparing strategy, to existing
l-dopa treatment in MPTP-treated marmosets previously primed to express dyskinesia.
l-Dopa (5–10
mg/kg) produced effects, which were stable over the 13 treatment days, of increased locomotor activity, reversed motor disability and marked dyskinesia. Pardoprunox (SLV308; 0.0125–0.025
mg/kg) plus
l-dopa (3–10
mg/kg) administration increased locomotor activity over the same treatment period and initially produced an equivalent reversal of motor disability compared to
l-dopa, however this effect was enhanced as treatment progressed. This reflected the prolonged duration of effect of pardoprunox compared to that of
l-dopa. While pardoprunox plus
l-dopa treatment initially produced dyskinesia to the same extent as
l-dopa alone, the intensity diminished as treatment progressed and it was significantly different at the end of the study. On subsequent
l-dopa challenge there was no difference in motor disability reversal between those animals previously treated with pardoprunox plus
l-dopa compared to
l-dopa alone but the combination treatment produced significantly less dyskinesia. These data suggest that pardoprunox may provide therapeutic benefit in mid to late stage PD by reducing dyskinesia while maintaining efficacy when used with concomitant
l-dopa treatment.
►Pardoprunox
+
l-dopa can enhance motor disability reversal compared to
l-dopa alone ►Chronic Pardoprunox treatment leads to a reduction of
l-dopa induced dyskinesia ►Dyskinesia reducing action persists temporarily after withdrawal of Pardoprunox ►This persistent action may indicate adaptive changes in basal ganglia response
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Behavioral sensitization is a phenomenon which can develop following repeated intermittent administration of a range of psychostimulants, and other compounds, and may model neuroplastic ...changes seen in addictive processes and neuropsychiatric disease. The aim of the present study was to investigate the effect of dopamine D1 receptor (D1 R) ligands on nicotine-induced behavioral sensitization and their molecular consequences in the striatum. Wistar rats were chronically treated (5 days) with vehicle or nicotine (0.4 mg/kg; s.c.) and locomotor activity was measured. Following a 5 day withdrawal period, rats were pretreated with vehicle or the D1 R antagonist SCH-23390 (0.03 mg/kg; i.p.) and challenged with nicotine. Either 45 min or 24 h post-challenge, the striatum was isolated and ex vivo receptor binding and cAMP accumulation (using LC–MS/MS) were assessed. It was shown that chronic nicotine administration induced the development and expression of locomotor sensitization, of which the latter was blocked by SCH-23390. Nicotine-induced sensitization had no effect on forskolin stimulated cAMP accumulation but increased the efficacy of dopamine for the D1 R and decreased the potency of D1 R agonists. These effects were antagonized by in vivo pre-challenge with SCH-23390. No effect on D1 receptor binding was observed. Moreover, time dependent effects were observed between tissue taken 45 min and 24 h post-challenge. The present findings provide a connection between behavioral sensitization and intracellular cAMP accumulation through the D1 R. Together these data suggest that changes in D1 R signaling in the dorsal striatum may play an important role in the underlying mechanisms of nicotine-induced behavioral sensitization.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The treatment of the motor symptoms of Parkinson’s disease (PD) is dependent on the use of dopamine replacement therapy in the form of
l
-dopa and dopamine agonist drugs. However, the development of ...dyskinesia (chorea, dystonia, athetosis) can become treatment limiting. The initiation of dyskinesia involves a priming process dependent on the presence of nigral dopaminergic cell loss leading to alterations in basal ganglia function that underlie the expression of involuntary movements following the administration of each drug dose. Once established, dyskinesia is difficult to control and it is even more difficult to reverse the priming process. Dyskinesia is more commonly induced by
l
-dopa than by dopamine agonist drugs. This has been associated with the short duration of
l
-dopa causing pulsatile stimulation of postsynaptic dopamine receptors compared to the longer acting dopamine agonists that cause more continuous stimulation. As a result, the concept of continuous dopaminergic stimulation (CDS) has arisen and has come to dominate the strategy for treatment of early PD. However, CDS has flaws that have led to the general acceptance that continuous drug delivery (CDD) is key to the successful treatment of PD. Studies in both experimental models of PD and in clinical trials have shown CDD to improve efficacy, but reduce dyskinesia induction, and to reverse established involuntary movements. Two key clinical strategies currently address the concept of CDD: (1) in early-, mid- and late-stage PD, transdermal administration of rotigotine provides 24 h of drug delivery; (2) in late-stage PD, the constant intraduodenal administration of
l
-dopa is utilized to improve control of motor symptoms and to diminish established dyskinesia. This review examines the rationale for CDD and explores the clinical benefit of using such a strategy for the treatment of patients with PD.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Recent reports indicate that endocannabinoid (eCB) system may be involved in depression and in the antidepressant-like activity demonstrated in experimental models. The present study examined the ...effects of the eCB uptake inhibitor 4-hydroxyphenyl-5Z,8Z,11Z,14Z-eicosatetraenamide (AM404; 0.1-3 mg/kg), the fatty acid amide hydrolase (FAAH) inhibitor cyclohexylcarbamic acid 3-carbamoylbiphenyl-3-yl ester (URB597; 0.03-0.3 mg/kg), the cannabinoid CB(1) receptor agonist (-)-cis-3-2-hydroxy-4-(1,1-dimethylheptyl) phenyl-trans-4-(3-hydroxypropyl)-cyclohexanol (CP55,940; 0.03-0.3 mg/kg) and the CB(1) receptor antagonist rimonabant (0.3-3 mg/kg) on immobility time in the forced swim test (FST) in rats. Moreover, the effects of AM404, CP55,940 and URB597 on the antidepressant-like activity of imipramine and citalopram in the FST were also examined. We found that AM404 (0.3-3 mg/kg), CP55,940 (0.1 mg/kg) and URB597 (0.1-0.3 mg/kg) reduced the immobility time of rats, while rimonabant (0.3-3 mg/kg) was inactive in this respect. We also observed that the anti-immobility effects of AM404 (1 mg/kg), CP55,940 (0.1 mg/kg) and URB597 (0.3 mg/kg), but not of imipramine (30 mg/kg), were blocked by rimonabant (3 mg/kg). In another set of experiments we showed that the inactive dose of AM404 (0.1 mg/kg) potentiated the effects of the inactive doses of imipramine (15 mg/kg) or citalopram (30 mg/kg), while CP55,940 (0.03 mg/kg) and URB597 (0.03 mg/kg) enhanced the effect of imipramine only. None of the drugs studied, given alone or in combination, increased the basal locomotor activity of rats. Our results indicate that activation of the eCB system induces antidepressant-like effects in the FST in rats, and that these effects are mediated by CB(1) receptors. Moreover, they also indicate that agents activating eCB transmission enhance the anti-immobility responses to antidepressant drugs.
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