Using zebrafish (Danio rerio) as a model organism, we studied metabolomic markers of β-blocker neurotoxicity (propranolol, metoprolol, bisoprolol) and the relationships between neurotransmitter disturbances (dopamine, epinephrine, choline, cortisol) and their effects. Propranolol produced the most pronounced changes: significant increases in cortisol and epinephrine and decreases in dopamine and serotonin levels. Metoprolol caused a moderate increase in cortisol while elevating serotonin, suggesting a more balanced pharmacological profile. Bisoprolol had virtually no effect on cortisol or monoamine levels but increased the concentrations of choline, glycine, and glutamate. Differences in neurometabolic effects of β-blockers were identified: propranolol demonstrated a strong neurotoxic potential, consistent with its depressive side effects in humans; metoprolol showed an intermediate effect; while bisoprolol did not affect CNS. Zebrafish exhibited high sensitivity to neurochemical shifts, making this model valuable for preclinical drug neurotoxicity assessment.

Levodopa-induced dyskinesia (LID) is a debilitating complication of Parkinson's disease therapy. Emerging evidence suggests that the cerebellum is involved via cerebello -thalamo-striatal pathways.We first performed dual viral tracing to confirm cerebello-thalamo-striatal connectivity in a unilateral 6- hydroxydopamine rat model of LID. We then compared the efficacy of two cerebellar continuous theta burst stimulation (cTBS) protocols: a 2block protocol (14 days) and an intensified 3block protocol (10 days). Behavioral outcomes were assessed using the abnormal involuntary movement scale (AIMs). Local field potentials were recorded from the cerebellar dentate nucleus (DN) to characterize oscillatory variations. Striatal FosB expression was quantified as the molecular endpoint. Viral tracing confirmed the anatomical connectivity from the DN to the dorsolateral striatum via the parafascicular thalamus. Both the two protocols alleviated orolingual dyskinesia, with the 3block cTBS protocol demonstrated superior therapeutic efficacy (p < 0.001). Electrophysiological analysis revealed that LID was associated with reduced δ-band power and enhanced low-γ power in DN. Notably, cTBS normalized these aberrant oscillatory patterns by increasing δ power and decreasing pathological low-γ activity. The magnitude of δ power was negatively correlated with orolingual AIMs scores (r = -0.467, p = 0.021), whereas low-γ power was positively correlated with total dyskinesia severity (r = 0.551, p = 0.005) and orolingual AIMs scores (r = 0.581, p = 0.003). At the molecular level, cTBS normalized pathologically elevated striatal FosB expression in LID rats (p < 0.001). Collectively, these findings suggest that long-term cerebellar cTBS selectively ameliorates orolingual dyskinesia by modulating the cerebello-thalamo-striatal circuit.

L-DOPA-induced dyskinesia (LID) remains the most challenging complication of dopamine replacement therapy in Parkinson's disease, correlated with maladaptive plasticity within corticostriatal circuits. Perineuronal nets (PNNs), extracellular matrix structures enwrapping mainly parvalbumin interneurons (PV-INs), are key regulators of neuronal stability and plasticity, yet their contribution to LID is unknown. Using a unilateral 6-hydroxydopamine rat model of Parkinsonism followed by chronic L-DOPA administration, we quantified PNN-PV associations by Wisteria floribunda agglutinin (WFA) and PV immunolabeling across striatal and motor cortical territories. Dopamine loss markedly reduced PNN density and intensity in the dorsolateral striatum (DLS), which only partially recovered after L-DOPA. In LID, canonical WFA[+]/PV[+] cells remained low, whereas non-canonical WFA[-]/PV[+] populations expanded in both DLS and M1 motor cortex (M1), indicating region-specific remodeling toward a high-plasticity state. To assess causality, we used Chondroitinase ABC (ChABC) for PNN degradation. DLS-targeted ChABC exacerbated abnormal involuntary movements and increased local PV density, while M1-ChABC had no behavioral effect but altered PV metrics within the DLS-M1 axis. These findings identify the DLS as a critical node where PNN fragility amplifies dyskinesia, highlight a functional coupling between striatal and cortical PNN-PV remodeling, and suggest that stabilizing extracellular matrix integrity could mitigate maladaptive plasticity underlying LID.

Chronic administration of nicotine and nicotinic ligands have been shown to reduce levodopa-induced dyskinesia (LID) in rodents and primates. Due to its unique extra-striatal localisation and biochemical signalling properties, the α7 subtype of nicotinic acetylcholine receptors (nAChRs) may represent an important and unique target for drug development for the treatment of dyskinesia, particularly since positive allosteric modulator (PAM) at the α7 nAChRs subtype may provide an opportunity to reduce dyskinesia without side effects. In this study, we report on the anti-dyskinetic actions of a selective α7 PAM, PNU-120596 and compared its action to nicotine and other α7 nAChRs ligands. Unilaterally 6-OHDA lesioned female rats were primed with levodopa to display abnormal involuntary movements (AIMs) to model levodopa-induced dyskinesia. The effects of the α7 PAM, PNU-120596, an α7 agonist, PHA-543613 or the α7 antagonist, methyllycaconitine (MLA), as well as nicotine, a non-selective nAChR agonist were all examined on AIMs. Low doses of PNU-120596 and nicotine dose-dependently reduced AIMs, but combination of the PAM with nicotine produced only an additive effect which surprisingly, could not be demonstrated with the α7 agonist PHA-543613, while MLA dose-dependently reduced AIMS. The effects of PNU-120596 suggests that α7 PAMs may enhance the effect of basal acetylcholine on α7 receptors in the striatum and may provide a new avenue for the treatment of levodopa-induced dyskinesia. Reduction of AIMs by MLA suggests that the mechanism of AIMs reduction may involve the rapid desensitization of the α7 nAChRs subtype.

Clonidine is being increasingly prescribed in pediatric populations for behavioral conditions such as attention-deficit/hyperactivity disorder (ADHD), contributing to a rise in pediatric exposures and toxic ingestions. This article reviews the toxicokinetics, clinical presentation, and management of pediatric clonidine toxicity. Children under 5 years old account for the highest proportion of clonidine exposures, most of which are unintentional. Clonidine toxicity mimics an opioid toxidrome, often presenting with CNS depression, miosis, bradycardia, and hypotension. Diagnosis is primarily clinical. While supportive care remains the core component of treatment, naloxone may be beneficial in reversing CNS depression, though higher-than-standard doses are often required. Given the potential for delayed and prolonged toxicity, particularly with ingestion of transdermal patches, early recognition and intervention are critical. This review equips clinicians to understand, diagnose, and manage pediatric clonidine toxicity, emphasizing the importance of supportive care and consideration of naloxone for severe cases.

BackgroundLevodopa-induced dyskinesia (LID) in Parkinson's disease (PD) is linked to exaggerated gamma oscillations. Buspirone, a 5-HT1A receptor agonist, is a potent medication for psychiatric conditions, predominantly prescribed for anxiety treatment.ObjectiveThis study aims to investigate whether buspirone alleviates dyskinesia in LID rat and its effects on pathological oscillatory activity and cortico-striatal functional connectivity.MethodsWe collected motor behavior and electrophysiological data of cortico-striatal from Sham rats, unilateral 6-hydroxydopamine (6-OHDA)-lesioned PD model rats, and rats with LID. We further examined the behavioral and electrophysiological changes in LID rats following buspirone intervention.ResultsPD rats showed increased beta activity and aperiodic components at 10-50 Hz, while LID rats exhibited excessive gamma oscillations and aperiodic activity at 50-150 Hz. Additionally, gamma-band functional connectivity within the cortico-striatal circuit was significantly enhanced during on-state dyskinesia, when rats exhibited abnormal involuntary movements. Administration of buspirone effectively reduced dyskinesia severity, suppressed gamma activity, decreased aperiodic components (50-150 Hz), and disrupted gamma-band functional connectivity without compromising the antiparkinsonian effects of levodopa.ConclusionsExcessive gamma oscillations represent a key electrophysiological marker of dyskinesia. Altered gamma-band connectivity within the cortico-striatal network may contribute to its pathophysiology. Buspirone appears to be a promising candidate for the treatment of LID, potentially offering a novel therapeutic strategy.

Standard treatment for Parkinson's disease (PD) is dopamine replacement therapy with L-DOPA. However, chronic treatment often results in abnormal involuntary movements called L-DOPA-induced dyskinesia (LID). Prior evidence indicates that heightened striatal cholinergic tone may contribute to LID. Restoring cholinergic inhibition by targeting the inhibitory M4 muscarinic acetylcholine (ACh) receptor (M4) reduces LID in preclinical models. Although intrinsic striatal sources of ACh have been considered for their role in LID, extrinsic sources of ACh such as the pedunculopontine nucleus (PPN) have not been well investigated for their role in LID. Therefore, the current study employed hemiparkinsonian Long-Evans rats with a PPN-targeted cannula ipsilateral to 6-OHDA lesion. We examined the effect of local unilateral PPN infusion of M4 PAM VU0467154 on LID, motor performance, and c-fos expression within the PPN. It was expected that PPN infusion of VU0467154 would reduce LID, reduce L-DOPA's motor benefit, and globally reduce c-fos expression in the PPN. Contrary to our expectations, PPN infusion of M4 PAM did not significantly affect LID severity. Furthermore, M4 PAM did not alter L-DOPA-mediated motor improvement, and decreased c-fos expression specifically in PPN cholinergic neurons. These results suggest that local PPN ACh dynamics differ from those of the striatum. In the context of prior work, our results suggest that PPN cholinergic modulation or global PPN modulation may be a promising strategy for altering freezing of gait without decreasing motor benefit of L-DOPA and without increasing LID severity.

Chronic treatment with levodopa often leads to levodopa-induced dyskinesia (LID), around 40% of individuals are affected. Stigmasterol exhibits antioxidant, anti-inflammatory, and glutamate-antagonist properties, acting through AKT-1, VEGFR, and IL-6 to prevent neuronal death. This study investigates the STI potential to mitigate LID. Male Sprague Dawley rats were assigned to five groups (SHAM, 6-OHDA, LID, STI 10, STI 20), with n = 10. PD was induced by stereotaxic infusion of 6-OHDA (3 µg/µL × 2.5 µL) into the right medial forebrain bundle. After a 21-day recovery period, development of PD was confirmed through behavioral assessment, including APO-induced rotation, footprint analyses, and a stepping test assessment conducted over 7 days. Subsequently, the rats were treated with levodopa + carbidopa and stigmasterol (10/20 mg/Kg) orally for 28 days. Abnormal involuntary movements (AIMs) were assessed at intervals of 1, 14, 21, and 28th days to evaluate the effect of stigmasterol on LID. On day 28, rats were euthanized, and brain samples were analyzed for biochemical, and histopathological changes in the striatum and substantia nigra using nissl staining. STI treatment (10/20 mg/Kg) significantly decreased AIMS, MDA level, TNF-α, IL-1β, NF- kB, and NLRP3 and significantly increased GSH, SOD, catalase and dopamine levels. The histopathology assessment restored neurons in the striatum and substantia nigra of the brain. The result concludes that co-administration of stigmasterol (10/20 mg/Kg) with L-DOPA + carbidopa restores DA level, showing anti-inflammatory, anti-oxidant properties, and neuroprotective activity. Stigmasterol can therefore be administered as an adjuvant treatment to delay LID.

We aimed to elucidate morphological changes in striatonigral projection neurons in a rat model of levodopa-induced dyskinesia (LID). Male Wistar rats underwent unilateral 6-hydroxydopamine lesioning to establish a hemiparkinsonian model. At 8 weeks postoperatively, the rats were allocated to either the levodopa-treated group or the saline-treated control group. Behavioral abnormalities were quantified using the Abnormal Involuntary Movement (AIM) scores. We identified direct pathway neurons projecting to substantia nigra pars reticulata (SNr) by retrograde tracer injection. Dendritic spine morphology and the ultrastructure of synaptic terminals in SNr were assessed. The AIM scores increased along with levodopa treatment. Compared to control rats and the intact side of the LID model, the dendritic spine heads of striatonigral projection neurons were significantly enlarged, while spine density was reduced in the dopamine-denervated side of the LID model. Electron microscopic analysis revealed enlarged axon terminals and an increased number of synaptic vesicles in the dopamine-denervated side of SNr in levodopa-treated rats compared with those of the controls. Repeated levodopa administration induces morphological plasticity in striatonigral neurons, characterized by enlarged dendritic spine heads, reduced spine density, and enlarged synaptic terminals. These structural alterations likely contribute to enhanced GABAergic transmission in SNr and a reduced threshold for dyskinesia.