Dopamine Agonist Cotreatment Alters Neuroplasticity and Pharmacology of Levodopa-Induced Dyskinesia.

BACKGROUND: Current models of levodopa (L-dopa)-induced dyskinesia (LID) are obtained by treating dopamine-depleted animals with L-dopa. However, patients with LID receive combination therapies that often include dopamine agonists. OBJECTIVE: Using 6-hydroxydopamine-lesioned rats as a model, we aimed to establish whether an adjunct treatment with the D2/3 agonist ropinirole impacts on patterns of LID-related neuroplasticity and drug responses. METHODS: Different regimens of L-dopa monotreatment and L-dopa-ropinirole cotreatment were compared using measures of hypokinesia and dyskinesia. Striatal expression of ∆FosB and angiogenesis markers were studied immunohistochemically. Antidyskinetic effects of different drug categories were investigated in parallel groups of rats receiving either L-dopa monotreatment or L-dopa combined with ropinirole. RESULTS: We defined chronic regimens of L-dopa monotreatment and L-dopa-ropinirole cotreatment inducing overall similar abnormal involuntary movement scores. Compared with the monotreatment group, animals receiving the L-dopa-ropinirole combination exhibited an overall lower striatal expression of ∆FosB with a distinctive compartmental distribution. The expression of angiogenesis markers and blood-brain barrier hyperpermeability was markedly reduced after L-dopa-ropinirole cotreatment compared with L-dopa monotreatment. Moreover, significant group differences were detected upon examining the response to candidate antidyskinetic drugs. In particular, compounds modulating D1 receptor signaling had a stronger effect in the L-dopa-only group, whereas both amantadine and the selective NMDA antagonist MK801 produced a markedly larger antidyskinetic effect in L-dopa-ropinirole cotreated animals. CONCLUSIONS: Cotreatment with ropinirole altered LID-related neuroplasticity and pharmacological response profiles. The impact of adjuvant dopamine agonist treatment should be taken into consideration when investigating LID mechanisms and candidate interventions in both clinical and experimental settings. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Ropinirole Cotreatment Prevents Perivascular Glial Recruitment in a Rat Model of L-DOPA-Induced Dyskinesia.

Dopamine replacement therapy for Parkinson's disease is achieved using L-DOPA or dopamine D2/3 agonists, such as ropinirole. Here, we compare the effects of L-DOPA and ropinirole, alone or in combination, on patterns of glial and microvascular reactivity in the striatum. Rats with unilateral 6-hydroxydopamine lesions were treated with therapeutic-like doses of L-DOPA (6 mg/kg), an equipotent L-DOPA-ropinirole combination (L-DOPA 3 mg/kg plus ropinirole 0.5 mg/kg), or ropinirole alone. Immunohistochemistry was used to examine the reactivity of microglia (ionized calcium-binding adapter molecule 1, IBA-1) and astroglia (glial fibrillary acidic protein, GFAP), as well as blood vessel density (rat endothelial cell antigen 1, RECA-1) and albumin extravasation. L-DOPA monotreatment and L-DOPA-ropinirole cotreatment induced moderate-severe dyskinesia, whereas ropinirole alone had negligible dyskinetic effects. Despite similar dyskinesia severity, striking differences in perivascular microglia and astroglial reactivity were found between animals treated with L-DOPA vs. L-DOPA-ropinirole. The former exhibited a marked upregulation of perivascular IBA-1 cells (in part CD68-positive) and IBA-1-RECA-1 contact points, along with an increased microvessel density and strong perivascular GFAP expression. None of these markers were significantly upregulated in animals treated with L-DOPA-ropinirole or ropinirole alone. In summary, although ropinirole cotreatment does not prevent L-DOPA-induced dyskinesia, it protects from maladaptive gliovascular changes otherwise associated with this disorder, with potential long-term benefits to striatal tissue homeostasis.

Distinctive Effects of D1 and D2 Receptor Agonists on Cortico-Basal Ganglia Oscillations in a Rodent Model of L-DOPA-Induced Dyskinesia.

L-DOPA-induced dyskinesia (LID) in Parkinson's disease has been linked to oscillatory neuronal activities in the cortico-basal ganglia network. We set out to examine the pattern of cortico-basal ganglia oscillations induced by selective agonists of D1 and D2 receptors in a rat model of LID. Local field potentials were recorded in freely moving rats using large-scale electrodes targeting three motor cortical regions, dorsomedial and dorsolateral striatum, external globus pallidus, and substantial nigra pars reticulata. Abnormal involuntary movements were elicited by the D1 agonist SKF82958 or the D2 agonist sumanirole, while overall motor activity was quantified using video analysis (DeepLabCut). Both SKF82958 and sumanirole induced dyskinesia, although with significant differences in temporal course, overall severity, and body distribution. The D1 agonist induced prominent narrowband oscillations in the high gamma range (70-110 Hz) in all recorded structures except for the nigra reticulata. Additionally, the D1 agonist induced strong functional connectivity between the recorded structures and the phase analysis revealed that the primary motor cortex (forelimb area) was leading a supplementary motor area and striatum. Following treatment with the D2 agonist, narrowband gamma oscillations were detected only in forelimb motor cortex and dorsolateral striatum, while prominent oscillations in the theta band occurred in the globus pallidus and nigra reticulata. Our results reveal that the dyskinetic effects of D1 and D2 receptor agonists are associated with distinct patterns of cortico-basal ganglia oscillations, suggesting a recruitment of partially distinct networks.

Non-dopaminergic approaches to the treatment of motor complications in Parkinson's disease.

Dopamine replacement therapy with l-DOPA is the most efficacious symptomatic treatment for Parkinson's disease, but its utility is limited by a development of motor fluctuations and abnormal involuntary movements (dyskinesia) in the majority of patients. These complications are attributed to the combined effects of dopaminergic degeneration and non-physiological reinstatement of dopamine transmission by the standard oral medications. There is substantial evidence that this altered state of dopamine transmission causes pathophysiological changes to a variety of non-dopaminergic neurotransmitter systems in the brain. This evidence has prompted an interest in developing drugs that target non-dopaminergic receptors for the purpose of improving l-DOPA-induced dyskinesia and/or motor fluctuations. We here review all the most important categories of non-dopaminergic targets that have been investigated so far, but with a particular focus on modulators of glutamatergic and serotonergic transmission, which continue to inspire significant efforts towards clinical translation. In particular, we discuss both the experimental rationale and the clinical experience thus far gained from studying 5-HT1A and 5-HT1B receptor agonists, NMDA and AMPA receptor antagonists, mGluR5 negative allosteric modulators, mGluR4 positive allosteric modulators, and adenosine A2a receptor antagonists. We also review compounds with complex pharmacological properties that are already used clinically or about to enter an advanced phase of clinical development (amantadine, safinamide, zonisamide, pridopidine, mesdopetam). We conclude with an outlook on possible directions to address unmet needs and improve the chance of successful translation in this therapeutic area.

Verification of multi-structure targeting in chronic microelectrode brain recordings from CT scans.

BACKGROUND: Large-scale microelectrode recordings offer a unique opportunity to study neurophysiological processes at the network level with single cell resolution. However, in the small brains of many experimental animals, it is often technically challenging to verify the correct targeting of the intended structures, which inherently limits the reproducibility of acquired data. NEW METHOD: To mitigate this problem, we have developed a method to programmatically segment the trajectory of electrodes arranged in larger arrays from acquired CT-images and thereby determine the position of individual recording tips with high spatial resolution, while also allowing for coregistration with an anatomical atlas, without pre-processing of the animal samples or post-imaging histological analyses. RESULTS: Testing the technical limitations of the developed method, we found that the choice of scanning angle influences the achievable spatial resolution due to shadowing effects caused by the electrodes. However, under optimal acquisition conditions, individual electrode tip locations within arrays with 250 µm inter-electrode spacing were possible to reliably determine. COMPARISON TO EXISTING METHODS: Comparison to a histological verification method suggested that, under conditions where individual wires are possible to track in slices, a 90% correspondence could be achieved in terms of the number of electrodes groups that could be reliably assigned to the same anatomical structure. CONCLUSIONS: The herein reported semi-automated procedure to verify anatomical targeting of brain structures in the rodent brain could help increasing the quality and reproducibility of acquired neurophysiological data by reducing the risk of assigning recorded brain activity to incorrectly identified anatomical locations. DATA AVAILABILITY: The tools developed in this study are freely available as a software package at: https://github.com/NRC-Lund/ct-tools.

Cortico-Striatal Oscillations Are Correlated to Motor Activity Levels in Both Physiological and Parkinsonian Conditions.

Oscillatory neural activity in the cortico-basal ganglia-thalamocortical (CBGTC) loop is associated with the motor state of a subject, but also with the availability of modulatory neurotransmitters. For example, increased low-frequency oscillations in Parkinson's disease (PD) are related to decreased levels of dopamine and have been proposed as biomarkers to adapt and optimize therapeutic interventions, such as deep brain stimulation. Using neural oscillations as biomarkers require differentiating between changes in oscillatory patterns associated with parkinsonism vs. those related to a subject's motor state. To address this point, we studied the correlation between neural oscillatory activity in the motor cortex and striatum and varying degrees of motor activity under normal and parkinsonian conditions. Using rats with bilateral or unilateral 6-hydroxydopamine lesions as PD models, we correlated the motion index (MI)-a measure based on the physical acceleration of the head of rats-to the local field potential (LFP) oscillatory power in the 1-80 Hz range. In motor cortices and striata, we observed a robust correlation between the motion index and the oscillatory power in two main broad frequency ranges: a low-frequency range [5.0-26.5 Hz] was negatively correlated to motor activity, whereas a high-frequency range [35.0-79.9 Hz] was positively correlated. We observed these correlations in both normal and parkinsonian conditions. In addition to these general changes in broad-band power, we observed a more restricted narrow-band oscillation [25-40 Hz] in dopamine-denervated hemispheres. This oscillation, which seems to be selective to the parkinsonian state, showed a linear frequency dependence on the concurrent motor activity level. We conclude that, independently of the parkinsonian condition, changes in broad-band oscillatory activities of cortico-basal ganglia networks (including changes in the relative power of low- and high-frequency bands) are closely correlated to ongoing motions, most likely reflecting he operations of these neural circuits to control motor activity. Hence, biomarkers based on neural oscillations should focus on specific features, such as narrow frequency bands, to allow differentiation between parkinsonian states and physiological movement-dependent circuit modulation.

The 5-HT3 receptor antagonist ondansetron potentiates the effects of the acetylcholinesterase inhibitor donepezil on neuronal network oscillations in the rat dorsal hippocampus.

Cognitive impairments in Alzheimer's disease (AD) have been associated with alterations in neuronal oscillatory activity, of which hippocampal theta and gamma oscillations are essential for the coordination of neuronal networks during cognitive functions. Cognitive deterioration in AD is delayed by symptomatic treatment with donepezil and other acetylcholinesterase inhibitors (AChEIs). However, the efficacy of symptomatic monotherapy is insufficient. Combining 5-HT receptor antagonists with AChEIs represents a promising new approach for symptomatic treatment of AD. The selective 5-HT3 receptor antagonist ondansetron decreases the activity of interneurons with a concomitant increase in the activity of pyramidal neurons in the hippocampus of freely moving rats. Additionally, 5-HT3 receptor antagonism modulates acetylcholine release in rat cortex and hippocampus. We investigated the effects of ondansetron alone and in combination with donepezil on hippocampal oscillations using in vivo electrophysiology. Neuronal network oscillations were recorded in the dorsal hippocampus during electrical stimulation of the brainstem pedunculopontine tegmental nucleus in urethane-anaesthetised rats. In addition, potential pharmacokinetic interactions between donepezil and ondansetron were assessed. Ondansetron alone did not affect hippocampal network oscillations. Donepezil dose-dependently increased hippocampal theta and gamma power during PPT stimulation. Ondansetron (0.3 mg/kg, i.v.) potentiated theta and gamma responses to 0.2 mg/kg donepezil and prolonged theta and gamma responses to 0.3 mg/kg donepezil. These effects could not be attributed to pharmacokinetic interactions between the compounds. This study demonstrates that ondansetron potentiates the effects of donepezil on elicited neuronal oscillations and suggests that 5-HT3 receptor antagonists may be beneficial as adjunctive therapy to AChEIs for the symptomatic treatment of cognitive deficits in AD.