Pregnenolone for the treatment of L-DOPA-induced dyskinesia in Parkinson's disease.

Growing preclinical and clinical evidence highlights neurosteroid pathway imbalances in Parkinson's Disease (PD) and L-DOPA-induced dyskinesias (LIDs). We recently reported that 5α-reductase (5AR) inhibitors dampen dyskinesias in parkinsonian rats; however, unraveling which specific neurosteroid mediates this effect is critical to optimize a targeted therapy. Among the 5AR-related neurosteroids, striatal pregnenolone has been shown to be increased in response to 5AR blockade and decreased after 6-OHDA lesions in the rat PD model.

Serotonin/dopamine interaction in the induction and maintenance of L-DOPA-induced dyskinesia: An update.

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.

BDNF Overexpression Increases Striatal D3 Receptor Level at Striatal Neurons and Exacerbates D1-Receptor Agonist-Induced Dyskinesia.

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.

Essential fatty acids deficient diet modulates N-Acylethanolamide profile in rat's tissues.

No data are available on whether a diet deficient of the essential fatty acids is able to modulate tissue levels of endocannabinoids and congeners. Male rats fed for 12 weeks a diet deficient of essential fatty acids, palmitic and oleic acids (EFAD), replaced with saturated fatty acids (SAFA), showed lowered n-3 and n-6 PUFAs levels in plasma, liver and adipose tissue, with concomitant steep increase of oleic and mead acids, while in hypothalamus no changes in PUFA concentration were detected and only palmitoleic acid was found increased. We found a reduction of anandamide and palmitoylethanolamide in liver and brain, while oleoylethanolamide increased significantly in liver and adipose tissue, associated to a 50 % body weight decrease.

5alpha-reductase inhibitors dampen L-DOPA-induced dyskinesia via normalization of dopamine D1-receptor signaling pathway and D1-D3 receptor interaction.

Although 1-3,4-dihydroxyphenylalanine (L-DOPA) is the mainstay therapy for treating Parkinson's disease (PD), its long-term administration is accompanied by the development of motor complications, particularly L-DOPA induced dyskinesia (LID), that dramatically affects patients' quality of life. LID has consistently been related to an excessive dopamine receptor transmission, particularly at the down-stream signaling of the striatal D receptors (DR), resulting in an exaggerated stimulation of cAMP-dependent protein kinase and extracellular signal-regulated kinase (ERK) pathway. We previously reported that pharmacological blockade of 5alpha-reductase (5AR), the rate-limiting enzyme in neurosteroids synthesis, attenuates the severity of a broad set of behavioral alterations induced by DR and DR activation, without inducing extrapyramidal symptoms.

The 5-alpha reductase inhibitor finasteride reduces dyskinesia in a rat model of Parkinson's disease.

Levodopa-induced dyskinesia (LID) is a disabling motor complication occurring in Parkinson's disease patients (PD) after long-term l-DOPA treatment. Although its etiology remains unclear, there is accumulating evidence that LID relies on an excessive dopamine receptor transmission, particularly at the downstream signaling of D receptors. We previously reported that the pharmacological blockade of 5-alpha reductase (5AR), the rate limiting enzyme in neurosteroids synthesis, rescued a number of behavioral aberrations induced by D receptor-selective and non-selective agonists, without inducing extrapyramidal symptoms.

Modulation of serotonergic transmission by eltoprazine in L-DOPA-induced dyskinesia: Behavioral, molecular, and synaptic mechanisms.

L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias (LIDs) represent the main side effect of Parkinson's Disease (PD) therapy. Among the various pharmacological targets for novel therapeutic approaches, the serotonergic system represents a promising one. In experimental models of PD and in PD patients the development of abnormal involuntary movements (AIMs) and LIDs, respectively, is accompanied by the impairment of bidirectional synaptic plasticity in key structures such as striatum.

Effect of selective and non-selective serotonin receptor activation on L-DOPA-induced therapeutic efficacy and dyskinesia in parkinsonian rats.

Selective activation of 5-HT1 receptors has been shown to produce near to full suppression of L-DOPA-induced dyskinesia (LID) in animal models of Parkinson's disease; however, a reduction of the therapeutic effect of L-DOPA has been reported in several studies. Conversely, we recently found that increasing the serotonergic tone with chronic administration of the serotonin precursor 5-hydroxy-tryptophan (5-HTP) can reduce LID in 6-OHDA-lesioned rats, without affecting L-DOPA efficacy. To directly compare the effects of selective versus non-selective serotonin receptor activation, here we first tested different acute doses of the 5-HT1A/1B receptor agonist eltoprazine and 5-HTP on LID in order to identify doses of the individual compounds showing similar anti-dyskinetic efficacy in L-DOPA-primed dyskinetic rats.

Effect of serotonin transporter blockade on L-DOPA-induced dyskinesia in animal models of Parkinson's disease.

Serotonin transporter blockade with selective serotonin reuptake inhibitors (SSRIs) was recently shown to counteract L-DOPA-induced dyskinesia in 6-hydroxydopamine (6-OHDA)-lesioned rats. However, this effect has never been described in Parkinson's disease (PD) patients, despite that they often receive SSRIs for the treatment of depression. In the present study, we investigated the efficacy of the SSRI citalopram against dyskinesia in two experimental models of PD, the 6-OHDA-lesioned rat and 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-treated macaque.

Effect of memantine on L-DOPA-induced dyskinesia in the 6-OHDA-lesioned rat model of Parkinson's disease.

An increasing body of experimental evidence demonstrates that the glutamatergic system is involved in the genesis of l-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID). Indeed, the N-methyl-d-aspartate (NMDA) receptor antagonist amantadine is the only anti-dyskinetic compound used in patients, albeit with limited efficacy and side effects. In this study, we investigated the anti-dyskinetic properties of memantine, a non-competitive NMDA receptor antagonist in clinical use for the treatment of dementia, in the 6-hydroxy-dopamine (6-OHDA)-lesion rat model of Parkinson's disease.

The anti-dyskinetic effect of dopamine receptor blockade is enhanced in parkinsonian rats following dopamine neuron transplantation.

Graft-induced dyskinesia (GID) is a serious complication induced by dopamine (DA) cell transplantation in parkinsonian patients. We have recently shown that DA D2 receptor blockade produces striking blockade of dyskinesia induced by amphetamine in grafted 6-OHDA-lesioned rats, a model of GID. This study was designed to investigate whether blockade of DA D1 receptors could produce similar outcome, and to see whether the effect of these treatments in grafted rats was specific for dyskinesia induced by amphetamine, or could also influence L-DOPA-induced dyskinesia (LID).

5-Hydroxy-tryptophan for the treatment of L-DOPA-induced dyskinesia in the rat Parkinson's disease model.

The serotonin system has recently emerged as an important player in the appearance of L-DOPA-induced dyskinesia (LID) in experimental models of Parkinson's disease, as it provides an unregulated source of L-DOPA-derived dopamine release in the dopamine-depleted striatum. Accordingly, toxin lesion or pharmacological silencing of serotonin neurons suppressed LID in the rat and monkey models of Parkinson's disease. However, 5-HT1 receptor agonists were also found to partially reduce the therapeutic effect of L-DOPA.

Chronic tryptophan deprivation attenuates gating deficits induced by 5-HT(1A), but not 5-HT₂ receptor activation.

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-HT(1A) and 5-HT(2A) 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-HT(1A) and 5-HT(2A) expression and/or signaling.

Effects of tryptophan deficiency on prepulse inhibition of the acoustic startle in rats.

Rationale: 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).

Vitamin A deficiency affects neither frontocortical acetylcholine nor working memory.

Vitamin A is quite often implicated in supporting acetylcholine synthesis. Choline acetyltransferase, the enzyme promoting acetylcholine synthesis, and the vesicular acetylcholine transporter are modulated by retinoic acid treatment. This paper illustrates the effect of vitamin A deprivation on acetylcholine content in the hippocampus, striatum and prefrontal cortex of rats, brain regions containing retinoid acid receptors.

Tryptophan-deficient diet increases the neurochemical and behavioral response to amphetamine.

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.

Augmented cocaine-induced accumbal dopamine efflux, motor activity and place preference in rats fed with a tryptophan-deficient diet.

In the present study we demonstrate that consumption of a tryptophan-deficient diet for a period of 14 days decreased the striatal serotonin and 5-hydroxyindolacetic acid tissue content in rats, whereas the level of dopamine remained unchanged. Under this condition of diminished serotonergic tone, a challenge dose of cocaine (10mg/kg, i.p.

Role of striatal L-DOPA in the production of dyskinesia in 6-hydroxydopamine lesioned rats.

We explored possible differences in the peripheral and central pharmacokinetics of L-DOPA as a basis for individual variation in the liability to dyskinesia. Unilaterally, 6-hydroxydopamine (6-OHDA) lesioned rats were treated chronically with L-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 striatal L-DOPA concentrations, tissue levels of dopamine (DA), DA metabolites, and serotonin.

Vitamin A deficiency induces motor impairments and striatal cholinergic dysfunction in rats.

Vitamin A and its derivatives, retinoids, are involved in the regulation of gene expression by binding two nuclear receptor families, retinoic acid receptors and retinoid X receptors. Retinoid receptors are highly expressed in the striatum, revealing an involvement of this system in the control of movement as demonstrated by previous observations in knockout mice. To further assess the role of retinoids in adult striatal function, the present study investigated the effect of vitamin A deprivation on rat motor activity and coordination, the rate of synthesis and release of dopamine, the functioning of D1 and D2 receptors and their expression in the striatum.

Biphasic effects of ethanol on acetylcholine release in the rat prefrontal cortex.

Low doses of ethanol (0.5 g/kg i.p.

Vitamin A deficiency produces spatial learning and memory impairment in rats.

Vitamin A and its derivatives (retinoids) play important roles in many physiological processes. The recent finding of high levels of cellular retinol-binding protein type 1 immunoreactivity, cellular retinoic acid-binding protein type 1 immunoreactivity and the presence of nuclear retinoid receptors in the central nervous system of adult rodents suggests that retinoids may carry out important roles in the adult brain. In consideration of the role of the hippocampus in spatial learning and memory we evaluated the effect of vitamin A deprivation in adult rats on these functions.

Bidirectional modulation of spatial working memory by ethanol.

Background: It is common knowledge that ethanol causes cognitive and memory impairments. Although these deficits are attributed to its central depressant properties, ethanol has biphasic effects and at low doses can produce excitatory actions.

Methods: Here we examined whether ethanol could have biphasic effects on performance in a delayed alternation task in a T-maze, a behavioral test of working memory.

Intravenous versus oral initial load of propafenone for conversion of recent-onset atrial fibrillation in the emergency room: a randomized trial.

Background: Non-valvular paroxysmal atrial fibrillation is a common clinical condition associated with a high risk of thromboembolism and hemodynamic problems which increase with the duration of arrhythmia. Therefore, even if arrhythmia ceases spontaneously within 24 hours in about half of the patients, a higher early conversion rate is desirable. Propafenone either by intravenous or oral load has been shown effective in conversion to sinus rhythm.

Hippocampal acetylcholine release correlates with spatial learning performance in freely moving rats.

To assess the activity of septohippocampal cholinergic neurons during the learning of a radial-arm maze task we measured changes in extracellular acetylcholine levels in the hippocampus by means of the vertical microdialysis technique. During the 12 days spent learning the spatial task the extracellular concentration of acetylcholine in the hippocampus was monitored while rats performed the test. One week before radial-arm maze training a guide cannula was implanted unilaterally in the hippocampus.