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Background: We recently showed that striatal overexpression of brain derived neurotrophic factor (BDNF) by adeno-associated viral (AAV) vector exacerbated L-DOPA-induced dyskinesia (LID) in 6-OHDA-lesioned rats. An extensive sprouting of striatal serotonergic terminals accompanied this effect, accounting for the increased susceptibility to LID. Objective: We set to investigate whether the BDNF effect was restricted to LID, or extended to dyskinesia induced by direct D1 receptor agonists. Methods: Unilaterally 6-OHDA-lesioned rats received a striatal injection of an AAV vector to induce BDNF or GFP overexpression. Eight weeks later, animals received daily treatments with a low dose of SKF82958 (0.02 mg/kg s.c.) and development of dyskinesia was evaluated. At the end of the experiment, D1 and D3 receptors expression levels and D1 receptor-dependent signaling pathways were measured in the striatum. Results: BDNF overexpression induced significant worsening of dyskinesia induced by SKF82958 compared to the GFP group and increased the expression of D3 receptor at striatal level, even in absence of pharmacological treatment; by contrast, D1 receptor levels were not affected. In BDNF-overexpressing striata, SKF82958 administration resulted in increased levels of D1–D3 receptors co-immunoprecipitation and increased phosphorylation levels of Thr34 DARPP-32 and ERK1/2. Conclusion: Here we provide evidence for a functional link between BDNF, D3 receptors and D1–D3 receptor close interaction in the augmented susceptibility to dyskinesia in 6-OHDA-lesioned rats. We suggest that D1–D3 receptors interaction may be instrumental in driving the molecular alterations underlying the appearance of dyskinesia; its disruption may be a therapeutic strategy for treating dyskinesia in PD patients. [ABSTRACT FROM AUTHOR]

Attention deficit/hyperactivity disorder (ADHD) is characterized by inattention, impulsivity, and motor hyperactivity. Several lines of research support a crucial role for the dopamine transporter (DAT) gene in this psychiatric disease. Consistently, the most commonly prescribed medications in ADHD treatment are stimulant drugs, known to preferentially act on DAT. Recently, a knock-in mouse [DAT-cocaine insensitive (DAT-CI)] has been generated carrying a cocaine-insensitive DAT that is functional but with reduced dopamine uptake function. DAT-CI mutants display enhanced striatal extracellular dopamine levels and basal motor hyperactivity. Herein, we showed that DAT-CI animals present higher striatal dopamine turnover, altered basal phosphorylation state of dopamine and cAMP-regulated phosphoprotein 32 kDa (DARPP32) at Thr75 residue, but preserved D2 receptor (D2R) function. However, although we demonstrated that striatal D1 receptor (D1R) is physiologically responsive under basal conditions, its stimulus-induced activation strikingly resulted in paradoxical electrophysiological, behavioral, and biochemical responses. Indeed, in DAT-CI animals, (1) striatal LTP was completely disrupted, (2) R-(+)-6-chloro-7,8-dihydroxy-l-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF 81297) treatment induced paradoxical motor calming effects, and (3) SKF 81297 administration failed to increase cAMP/protein kinase A (PKA)/DARPP32 signaling. Such biochemical alteration selectively affected dopamine D1Rs since haloperidol, by blocking the tonic inhibition of D2R, unmasked a normal activation of striatal adenosine A2A receptor-mediated cAMP/PKA/DARPP32 cascade in mutants. Most importantly, our studies highlighted that amphetamine, nomifensine, and bupropion, through increased striatal dopaminergic transmission, are able to revert motor hyperactivity of DAT-CI animals. Overall, our results suggest that the paradoxical motor calming effect induced by these drugs in DAT-CI mutants depends on selective aberrant phasic activation of D1R/cAM P/PKA/ DARPP32 signaling in response to increased striatal extracellular dopamine levels. [ABSTRACT FROM AUTHOR]

The article presents a study on how overexpression of human alpha-synuclein induces VGF early changes in both blood and brain of rats. Topics include information on peptides containing the C-terminal end (LHRP) of the rat VGF protein; axon terminals of the substantia nigra (SN) of unilateral 6-hydroxydopamine lesioned; and information on early stage of nigrostriatal neurodegeneration.

Serotonin (5-HT) plays a key role in the pathophysiology of psychotic disorders, presumably through a modulation of dopamine (DA) transmission. Reduction of 5-HT signaling has been suggested to enhance dopaminergic responses in animal models of psychosis. An intriguing naturalistic strategy to reduce 5-HT brain content is afforded by the dietary restriction to its precursor, l-tryptophan (TRP). We investigated the impact of a TRP-deficient diet in rats on the prepulse inhibition of the startle (PPI), a measure of sensorimotor gating which is typically impaired by psychotomimetic substances. After either short-term (6 h) or long-term (14 days) TRP deprivation, rats were tested for startle reflex and PPI. Moreover, we assessed the impact of both TRP deprivation regimens on PPI reduction induced by the psychotomimetic substance d-amphetamine (AMPH). Both TRP-deficient regimens failed to significantly affect PPI responses. However, chronic, but not short-term, TRP-deficient diet induced a significant sensitization to the effects of AMPH (1.25–2.5 mg/kg, subcutaneous). The enhanced predisposition to PPI disruption elicited by prolonged TRP deprivation was completely reversed 24 h after reinstatement of TRP in the diet, as well as pretreatment with antipsychotic drugs haloperidol (0.1 mg/kg, intraperitoneal) and clozapine (5 mg/kg, intraperitoneal), which exert their therapeutic action mostly through blockade of DA D2 receptors. The present results confirm and extend previous findings on the impact of serotonergic signaling in the modulation of DA transmission in schizophrenia and point to chronic TRP deprivation as a potential model of environmental manipulation that may produce a sensitization to psychotic-like symptoms induced by dopaminergic activation. [ABSTRACT FROM AUTHOR]

Abstract: Appearance of dyskinesia is a common problem of long-term Levodopa (L-DOPA) treatment in Parkinson''s disease (PD) patients and represents a major limitation for the pharmacological management of the motor symptoms in the advanced stages of disease. An increasing body of evidence points to dopamine released as a false neurotransmitter from the striatal serotonin terminals as the main pre-synaptic determinant of L-DOPA-induced dyskinesia. Here we review the animal experimental and human clinical data in support of this view, which point to the serotonin system as a promising target for anti-dyskinetic therapy in PD patients under L-DOPA medication. [Copyright &y& Elsevier]

Clinical trials in patients with Parkinson's disease have shown that transplants of fetal mesencephalic dopamine neurons can form a new functional innervation of the host striatum, but the clinical benefits have been highly variable: some patients have shown substantial recovery in motor function, whereas others have shown no improvement and even a worsening in the 3,4-dihydroxyphenyl-L-alanine (L-DOPA)-induced dyskinetic side effects. Differences in the composition of the grafted cell preparation may contribute to these discrepancies. In particular, the number of serotonin neurons contained in the graft can vary greatly depending on the dissection of the fetal tissue. Importantly, serotonin neurons have the ability to store and release dopamine, formed from exogenously administered L-DOPA. Here, we have evaluated the effect of transplants containing serotonin neurons, or a mixture of dopamine and serotonin neurons, on L-DOPA-induced dyskinesias in 6-hydroxydopamine-lesioned animals. As expected, dopamine neuron-rich grafts induced functional recovery, accompanied by a 60% reduction in L-DOPA-induced dyskinesia that developed gradually over the first 10 weeks. Rats with serotonin-rich grafts with few dopamine neurons, in contrast, showed a progressive worsening of their L-DOPA-induced dyskinesias over time, and no functional improvement. The antidyskinetic effect of dopamine-rich grafts was independent of the number of serotonin neurons present. We conclude that serotonin neurons in the grafts are likely to have a detrimental effect on L-DOPA-induced dyskinesias in cases in which the grafts contain no or few dopamine neurons. [ABSTRACT FROM AUTHOR]

The molecular basis of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID), one of the major hindrances in the current therapy for Parkinson's disease, is still unclear. We show that attenuation of cAMP signaling in the medium spiny neurons of the striatum, achieved by genetic inactivation of the dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), reduces LID. We also show that, in dyskinetic mice, sensitized cAMP/cAMP-dependent protein kinase/DARPP-32 signaling leads to phosphorylation/activation of the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). The increase in ERK1/2 phosphorylation associated with dyskinesia results in activation of mitogen- and stress-activated kinase-1 (MSK-1) and phosphorylation of histone H3, two downstream targets of ERK involved in transcriptional regulation. In line with these observations, we found that c-Fos expression is abnormally elevated in the striata of mice affected by LID. Persistent enhancement of the ERK signaling cascade is implicated in the generation of LID. Thus, pharmacological inactivation of ERK1/2 achieved using SL327 (α[amino[(4-aminophenyl)thio]methylene]2-(trifluoromethyl)benzeneacetonitrile), an inhibitor of the mitogen-activated kinase/ERK kinase, MEK, during chronic L-DOPA treatment counteracts the induction dyskinesia. Together, these results indicate that a significant proportion of the abnormal involuntary movements developed in response to chronic L-DOPA are attributable to hyperactivation in striatal medium spiny neurons of a signaling pathway including sequential phosphorylation of DARPP-32, ERK1/2, MSK-1, and histone H3. [ABSTRACT FROM AUTHOR]

Abstract: The present study examined the effects of a tryptophan-deficient diet on behavioral and neurochemical response to amphetamine. A tryptophan-deficient diet (14 days) decreased striatal serotonin and 5-hydroxyindolacetic acid content in rats. Under the latter conditions, amphetamine increased dopamine efflux in striatum and nucleus accumbens and produced a greater increase in motor activity when compared to controls. These results indicate how response to psychostimulants might be altered in the presence of a tryptophan-deficient diet. [Copyright &y& Elsevier]

We explored possible differences in the peripheral and central pharmacokinetics ofl-DOPA as a basis for individual variation in the liability to dyskinesia. Unilaterally, 6-hydroxydopamine (6-OHDA) lesioned rats were treated chronically withl-DOPA for an induction and monitoring of abnormal involuntary movements (AIMs). Comparisons between dyskinetic and non-dyskinetic cases were then carried out with regard to plasma and striatall-DOPA concentrations, tissue levels of dopamine (DA), DA metabolites, and serotonin. After a single intraperitoneal injection ofl-DOPA, plasmal-DOPA concentrations did not differ between dyskinetic and non-dyskinetic animals, whereas peak levels ofl-DOPA in the striatal extracellular fluid were about fivefold larger in the former compared with the latter group. Interestingly, the time course of the AIMs paralleled the surge in striatall-DOPA levels. Intrastriatal infusion ofl-DOPA by reverse dialysis concentration dependently induced AIMs in all 6-OHDA lesioned rats, regardless of a previous priming for dyskinesia. Steady-state levels of DA and its metabolites in striatal and cortical tissue did not differ between dyskinetic and non-dyskinetic animals, indicating that the observed difference in motor response tol-DOPA did not depend on the extent of lesion-induced DA depletion. These results show that an elevation ofl-DOPA levels in the striatal extracellular fluid is necessary and sufficient for the occurrence of dyskinesia. Individual differences in the central bioavailability ofl-DOPA may provide a clue to the varying susceptibility to dyskinesia in Parkinson's disease. [ABSTRACT FROM AUTHOR]

Abstract: The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) exerts a multifaceted function in the modulation of information processing, through the activation of multiple receptor families. In particular, stimulation of 5-HT1A and 5-HT2A receptors leads to sensorimotor gating impairments and perceptual perturbations. Previous evidence has shown that chronic deprivation of l-tryptophan (TRP), the precursor of 5-HT, results in marked reductions of 5-HT brain levels, as well as neuroplastic alterations in 5-HT1A and 5-HT2A expression and/or signaling. Building on these premises, in the present study we tested whether a prolonged TRP deprivation may differentially impact the roles of these receptors in the regulation of the prepulse inhibition (PPI) of the acoustic startle reflex, a dependable index of gating. Male Sprague-Dawley rats were fed for 14 days with either a regimen with negligible TRP content (TR−) or the same diet supplemented of TRP (TR+). At the end of this schedule, rats were treated with the prototypical 5-HT1A receptor agonist 8-OH-DPAT (62.5–250μg/kg, subcutaneous, s.c.) or the 5-HT2 receptor agonist DOI (0.25–1mg/kg, s.c.). Notably, the PPI deficits induced by 8-OH-DPAT in TR− rats were significantly milder than those observed in their TR+ counterparts; these effects were fully prevented by the 5-HT1A antagonist WAY-100135 (10mg/kg, intraperitoneal). Conversely, TRP deprivation did not affect the PPI-disrupting properties of DOI. These findings suggest that prolonged 5-HT depletion attenuates the influence of 5-HT1A, but not 5-HT2 receptors on sensorimotor gating, confirming the distinct mechanisms of these two targets in PPI regulation. [Copyright &y& Elsevier]

Abstract: 5-HT1 receptor agonists have been shown to reduce abnormal involuntary movements (AIMs) in the rat and monkey models of l-DOPA-induced dyskinesia. Different mechanisms have been proposed to underlie this effect. Activation of pre-synaptic 5-HT1 receptors has been suggested to inhibit dysregulated release of dopamine from the serotonin terminals, and thus, abnormal activation of striatal dopamine receptors. Activation of post-synaptic 5-HT1 receptors expressed in non-serotonergic neurons in different brain areas, by contrast, has been shown to result in decreased glutamate and GABA release, which may also contribute to the antidyskinetic effect. To unveil the relative contribution of these mechanisms, we have investigated the effect of increasing doses of 5-HT1A and 5-HT1B receptor agonists on AIMs induced by either l-DOPA or apomorphine. In contrast to l-DOPA-induced AIMs, which were dampened already at low doses of 5-HT1 agonists, reduction of apomorphine-induced AIMs required higher doses. Removal of the serotonin innervation suppressed l-DOPA-induced AIMs, but neither affected apomorphine-induced AIMs nor the inhibiting effect of 5-HT1 agonists on AIMs induced by the direct dopamine agonist, suggesting that such effect is independent on activation of pre-synaptic 5-HT1 receptors. [Copyright &y& Elsevier]

Parkinson's disease (PD) is characterized by motor symptoms due to loss of brain dopamine and non-motor symptoms, including gastrointestinal disorders. Although there is no cure for PD, symptomatic treatments are available. L-Dopa is the gold standard PD therapy, but most patients develop dyskinesias (LID), which are challenging to manage. Amantadine is recognized as the most effective drug for LID, but its adverse effects limit the use in patients. Here we review how 5α-reductase inhibitors (5ARIs), drugs used to treat benign prostatic hyperplasia and alopecia, exhibit beneficial effects in PD animal models. 5ARIs show neuroprotective properties in brain and gut dopaminergic systems, and reduce dyskinesias in rodent model of PD. Additionally, the 5ARI finasteride dampened dopaminergic-induced drug gambling in PD patients. Neuroprotection and antidyskinetic activities of 5ARIs in animal models of PD suggest their potential repurposing in men with PD to address gut dysfunction, protect brain DA and inhibit dyskinesias., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Ample evidence suggests that the serotonergic system plays a major role in several aspects of Parkinson's disease. In this review, we focus on the interplay between dopamine and serotonin in the appearance of L-DOPA-induced dyskinesia (LID), the most troublesome side effect of L-DOPA therapy. Indeed, while this drug exerts significant amelioration of motor symptoms during the first few years of treatment, eventually, most of patients experience dyskinesias, which limit the use of L-DOPA in advanced stages of disease. Here, we present the mechanisms underlying LID and the role of serotonin neurons, review preclinical and clinical data, and discuss possible therapeutic strategies., (Copyright © 2021 Elsevier B.V. All rights reserved.)