Buspirone requires the intact nigrostriatal pathway to reduce the activity of the subthalamic nucleus via 5-HT1A receptors

Sagarduy, Ainhoa; Llorente, Javier; Miguélez, Cristina; Morera-Herreras, Teresa; Ruiz-Ortega, José Ángel; Ugedo, Luisa

doi:10.1016/j.expneurol.2015.12.005

Cited by 20 publications

(26 citation statements)

References 76 publications

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“…In striatum, which does not contain Glu interneurons, veratridine would stimulate only axon terminals, inducing a different pattern of discharge, insensitive to the useand frequency-dependent action of safinamide. GP and SNr also do not contain Glu interneurons; however, both GP and SNr receive massive glutamatergic projections from STN, and STN neurons discharge at much higher frequency (5-30 Hz) (Barraza et al, 2009;Sagarduy et al, 2016) than do pyramidal glutamatergic corticostriatal (and cortico-STN) neurons (1.7 Hz) (Degos et al, 2013), which might favor the use-dependent action of safinamide. Therefore, we can hypothesize that the Gluinhibiting action of safinamide on pallidal and nigral Glu release might be due to a preconditioning effect of safinamide on the excitability of tonically active STN neurons.…”

Section: Discussionmentioning

confidence: 99%

Safinamide Differentially Modulates In Vivo Glutamate and GABA Release in the Rat Hippocampus and Basal Ganglia

Morari

Brugnoli

Pisanò

et al. 2017

J Pharmacol Exp Ther

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Safinamide has been recently approved as an add-on to levodopa therapy for Parkinson disease. In addition to inhibiting monoamine oxidase type B, it blocks sodium channels and modulates glutamate (Glu) release in vitro. Since this property might contribute to the therapeutic action of the drug, we undertook the present study to investigate whether safinamide inhibits Glu release also in vivo and whether this effect is consistent across different brain areas and is selective for glutamatergic neurons. To this aim, in vivo microdialysis was used to monitor the spontaneous and veratridine-induced Glu and GABA release in the hippocampus and basal ganglia of naive, awake rats. Brain levels of safinamide were measured as well. To shed light on the mechanisms underlying the effect of safinamide, sodium currents were measured by patch-clamp recording in rat cortical neurons. Safinamide maximally inhibited the veratridine-induced Glu and GABA release in hippocampus at 15 mg/kg, which reached free brain concentrations of 1.89-1.37 M. This dose attenuated veratridine-stimulated Glu (but not GABA) release in subthalamic nucleus, globus pallidus, and substantia nigra reticulata, but not in striatum. Safinamide was ineffective on spontaneous neurotransmitter release. In vitro, safinamide inhibited sodium channels, showing a greater affinity at depolarized (IC = 8 M) than at resting (IC = 262 M) potentials. We conclude that safinamide inhibits in vivo Glu release from stimulated nerve terminals, likely via blockade of sodium channels at subpopulations of neurons with specific firing patterns. These data are consistent with the anticonvulsant and antiparkinsonian actions of safinamide and provide support for the nondopaminergic mechanism of its action.

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Section: Discussionmentioning

confidence: 99%

Safinamide Differentially Modulates In Vivo Glutamate and GABA Release in the Rat Hippocampus and Basal Ganglia

Morari

Brugnoli

Pisanò

et al. 2017

J Pharmacol Exp Ther

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“…The basal firing rate was recorded for 300 s and at least 150 s after each systemic drug dose. For local administration, a calibrated pipette glued adjacent to a recording micropipette was filled with buspirone 0.25 M dissolved in Dulbecco's buffered saline solution (NaCl 136.9 mM; KCl 2.7 mM; NaH 2 PO 4 8.1 mM; KH 2 PO 4 1.5 mM; MgCl 2 0.5 mM; and CaCl 2 0.9 mM, pH 7.4) as previously performed by Sagarduy et al (2016). Local buspirone injection in the SNr was applied with pressure pulses (50–150 ms) using a Picospritzer™ II (General Valve Corporation, Fairfield, NJ, USA).…”

Section: Methodsmentioning

confidence: 99%

“…When investigating the possible effect of antidyskinetic drugs, it is important to take into account the results collected in animal models of Parkinson's disease that reveal the structural and functional changes in the 5‐HT system induced by DA depletion and/or chronic administration of l ‐DOPA (see review Vegas‐Suarez et al, 2019). In this regard, we have observed that buspirone, a 5‐HT 1A receptor partial agonist, inhibits neuronal activity in the subthalamic nucleus in control rats but has no effect after DA depletion (Sagarduy et al, 2016). Another study found that it efficiently improves the behavioural score and reduces certain molecular changes associated with l ‐DOPA‐induced dyskinesia (Azkona et al, 2014).…”

Section: Introductionmentioning

confidence: 98%

6‐Hydroxydopamine lesion and levodopa treatment modify the effect of buspirone in the substantia nigra pars reticulata

Vegas-Suárez

Pisanò

Requejo

et al. 2020

British J Pharmacology

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Background and Purpose l‐DOPA‐induced dyskinesia (LID) is considered a major complication in the treatment of Parkinson's disease (PD). Buspirone (5‐HT1A partial agonist) have shown promising results in the treatment of PD and LID, however no 5‐HT‐based treatment has been approved in PD. The present study was aimed to investigate how the substantia nigra pars reticulata (SNr) is affected by buspirone and whether it is a good target to study 5‐HT antidyskinetic treatments. Experimental Approach Buspirone was studied using in vivo single‐unit, electrocorticogram, local field potential recordings along with microdialysis and immunohistochemistry in naïve/sham, 6‐hydroxydopamine (6‐OHDA)‐lesioned or 6‐OHDA‐lesioned and l‐DOPA‐treated (6‐OHDA/l‐DOPA) rats. Key Results Local buspirone inhibited SNr neuron activity in all groups. However, systemic buspirone reduced burst activity in 6‐OHDA‐lesioned rats (with or without l‐DOPA treatment), whereas 8‐OH‐DPAT, a full 5‐HT1A agonist induced larger inhibitory effects in sham animals. Neither buspirone nor 8‐OH‐DPAT markedly modified the low‐frequency oscillatory activity in the SNr or synchronization within the SNr with the cortex. In addition, local perfusion of buspirone increased GABA and glutamate release in the SNr of naïve and 6‐OHDA‐lesioned rats but no effect in 6‐OHDA/l‐DOPA rats. In the 6‐OHDA/l‐DOPA group, increased 5‐HT transporter and decreased 5‐HT1A receptor expression was found. Conclusions and Implications The effects of buspirone in SNr are influenced by dopamine loss and l‐DOPA treatment. The present results suggest that the regulation of burst activity of the SNr induced by DA loss may be a good target to test new drugs for the treatment of PD and LID.

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“…This results in inhibition of serotonergic neurotransmission [2]. The drug in addition has a weak affinity for 5-HT 2 receptors and act as an antagonist at dopamine D-2, D-3 and D-4 receptors [3][4][5]. In animal models of pain, buspirone exerted analgesic action increasing the threshold to thermal, electrical, chemogenic, and visceral pain.…”

Section: Introductionmentioning

confidence: 99%

“…There is also a decrease in hepatic 5 In this study, our aim was to investigate the possible modulatory effect of buspirone on the development of hepatic injury caused by CCl 4 . The latter is a widely used industrial solvent which is known to cause heptotoxicity in humans and rodents.…”

Section: Introductionmentioning

confidence: 99%

The 5-HT1A Agonist Buspirone Decreases Liver Oxidative Stress and Exerts Protective Effect Against CCl4– Toxicity

Abdel-Salam¹,

Shaffie²,

Mohammed³

et al. 2017

JECT

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We aimed to study the effect of buspirone, an anxiolytic drug and 5-HT1A agonist on liver injury induced by carbon tetrachloride (CCl4) in rats. Rats were orally treated with CCl4 (2.8 mL/kg in olive oil) along with buspirone at 10, 20 or 30 mg/kg once daily starting with CCl4 and for one week thereafter. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) as well as alkaline phosphatase (ALP) activities were determined in the serum. Markers of oxidative stress: lipid peroxidation (malondialdehyde; MDA), reduced glutathione (GSH), nitric oxide (nitrite/nitrate) levels were measured in the liver. Moreover, paraoxonase 1 activity was determined in the liver and serum. The administration of CCl4 led to significant increases in serum ALT, AST, and ALP activities. Results showed that there were significantly increased hepatic MDA, nitrite and decreased GSH levels. PON1 activity decreased both in the liver and serum, respectively. The immunohistochemical investigations using anti-caspase-3 antibody revealed that CCl4 caused apoptosis to many hepatocytes. DNA studies showed that CCl4 caused hypoploidy in hepatocytes. Rats treated with 20-30 mg/kg buspirone showed significant decrease in serum ALT and AST by 19.5-34.3% and 24.2-31.4%, respectively. Serum ALP decreased by 21.7% after 30 mg/kg buspirone. In the liver, the higher dose of the drug resulted in decreased MDA (by 15.8%), decreased nitric oxide (17.4%) and increased GSH (by 20.1%). Significantly increased serum PON1 activity by 43.9-53.5% was observed after treatment with 20-30 mg/kg buspirone. On histopathologic examination of liver sections, there was mild protective effect for the drug at 30 mg/kg. Sections stained with anti- caspase- 3 confirmed the results obtained from histopathological examination. Moreover, buspirone given at 30 mg/kg resulted in an increase in % of cells containing normal values of DNA. These results indicate that buspirone decreases liver oxidative stress and exerts protective effect against CCl4- toxicity. The study thus indicates more beneficial effects of buspirone as an anxiolytic drug and that the drug could be used safely in patients with liver disease.

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Buspirone requires the intact nigrostriatal pathway to reduce the activity of the subthalamic nucleus via 5-HT1A receptors

Cited by 20 publications

References 76 publications

Safinamide Differentially Modulates In Vivo Glutamate and GABA Release in the Rat Hippocampus and Basal Ganglia

Safinamide Differentially Modulates In Vivo Glutamate and GABA Release in the Rat Hippocampus and Basal Ganglia

6‐Hydroxydopamine lesion and levodopa treatment modify the effect of buspirone in the substantia nigra pars reticulata

The 5-HT1A Agonist Buspirone Decreases Liver Oxidative Stress and Exerts Protective Effect Against CCl4– Toxicity

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