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A critical evaluation of behavioral rodent models of motor impairment used for screening of antiparkinsonian activity: The case of adenosine A2A receptor antagonists
No full textAnimal models of motor dysfunction constitute the basis for the screening of new drugs with potential efficacy in diseases characterized by motor impairment, such as Parkinson’s Disease (PD). Taking adenosine A2A receptor antagonists as an example of a new class of drugs for PD, the review will examine the most utilized rodent models of motor impairment and the results reported in the literature with this class of drugs. The results obtained so far in rodent models of PD suggested that A2A receptor antagonists might have symptomatic therapeutic efficacy in PD. They may ameliorate initiation of movement, gait and muscle rigidity, sensorimotor integration deficits, and tremor. Moreover, A2A receptor antagonists when administered with a low sub-threshold dose of l-DOPA potentiated its efficacy. However, the clinical trials so far performed have evaluated their efficacy in the “ON/OFF” of PD patients with motor complications, showing a limited efficacy of this class of drug. Therefore, on one hand, animal models of PD might have a limited validity; on the other hand, clinical trials should explore the efficacy of A2A receptor antagonists on a broader range of parkinsonian conditions
Adenosine A2A receptor antagonists and Parkinson’s disease: state of the art and future directions
No full textAdenosine A(2A) receptors present in the central nervous system have been implicated in the modulation of motor functions. Accordingly, adenosine A(2A) receptor antagonists currently constitute an attractive non-dopaminergic option for use in the treatment of Parkinson's disease (PD). The highly enriched distributions of adenosine A(2A) receptors in striatopallidal neurons, and their ability to form functional heteromeric complexes with dopamine D(2) and metabotropic glutamate mGlu5 receptors, render A(2A) receptor antagonists of particular interest in the modulation of motor behavior, whilst at the same time displaying a low predisposition to inducing non-motor side effects. Furthermore, adenosine A(2A) receptor antagonists appear to exert a marked efficacy on PD tremor and in reducing the progress of underlying neurodegeneration and maladaptive neuroplasticity that complicates standard dopamine replacement treatments in PD. Finally, recent evidence has illustrated an improvement of cognitive function as well as enhancement of attention in rodents following administration of A(2A) receptor antagonists. This article is aimed at examining preclinical studies describing these findings as well as reports from clinical trials, in order to provide a comprehensive review of the evidence suggesting that this class of drugs may represent an advance in the treatment of PD
Adenosine A2A receptor antagonist treatment of Parkinson’s disease
Full text linkAdenosine A2A receptors have a unique cellular and regional distribution in the basal ganglia (BG)being particularly concentrated in areas richly
innervated by dopamine (DA) such as the caudate-putamen, otherwise called striatum, and the globus pallidus. Adenosine A2A and DA D2
receptors are capable of forming fucntional heteromeric complexes and are colocalised in striatopallidal neurons. Based on the peculiar
cellular and regional distribution of this receptor and in line with data showing that A2A receptor antagonists improve motor symptoms of
Parkinson's disease (PD) in animal models and in clinical trials, A2A receptor antagonists have emerged as an attractive non-dopaminergic
target to improve the motor deficits that characterise PD. Experimental data have also shown that A2A receptor antagonists are capable of
exerting a neuroprotective effect and do not induce neuroplasticity phenomena that complicate long-term dopaminergic treatments. The present
review will provide an updated summary of results reported in the literature concerning the biochemical characteristics and BG
distribution of A2A receptors. We subsequently aim to examine the effects of adenosine A2A antagonists in rodent and primate models of PD
and L-DOPA-induced dyskinesia. Finally, conclusive remarks will be made on the neuroprotective effects of A2A antagonists and on the translation
of adenosine A2A receptor antagonists in the treatment of PD
Subchronic-intermittent caffeine amplifies the motor effects of amphetamine in rats
No full textCaffeine, the most widely consumed psychostimulant drug, acutely stimulates motor behaviour and enhances dopamine agonists actions whilst chronically it induces tolerance to either caffeine- or dopamine agonist-induced motor activating effects. The present study examined whether subchronic caffeine administration (15 mg/kg, on alternate days for 14 days) induces enduring modifications in caffeine- and amphetamine-mediated motor activity. To this end, motor activation and rotational behaviour stimulated by either caffeine or D-amphetamine (0.5, 2 mg/kg), given 3 days after the last caffeine administration, were evaluated in neurologically intact and unilaterally 6-hydroxydopamine-lesioned rats respectively. Subchronic caffeine resulted in an increase in caffeine-induced motor and turning behaviour. Furthermore, caffeine pretreatment potentiated the motor effects of amphetamine in both intact and 6-hydroxydopamine-lesioned rats. These results suggest that subchronic caffeine treatment results in an enhancement of its motor stimulant effects, rather than in tolerance, and induces neuroadaptive facilitatory changes in dopamine transmissio
Pharmacological therapy of Parkinson's disease: current options and new avenues
No full textParkinson's disease is a neurodegenerative pathology which affects the dopaminergic neurons in the mesencephalon, leading to a progressive and relentless motor disability and to non-motor symptoms of different severity. The aim of this review is to summarize the features of drugs currently used in the pharmacotherapy of Parkinson's disease, with a look at their beneficial effects and limitations. Drugs acting on dopamine transmission, as L-DOPA, direct dopaminergic agonists, inhibitors for either the MAO or COMT enzymes and drugs acting on neurotransmitters other than dopamine (e.g. acetylcholine, glutamate) will be covered. Investigational drugs currently under examination for their therapeutic potential in Parkinson's disease and recent patents which may be relevant to the field will be also discusse
Caffeine consumption and changes in the function of dopaminergic transmission: evidence of a hyperdopaminergic state in rats subchronically treated with caffeine
No full textThe existence of extensive interactions between the psychostimulant caffeine and the dopaminergic transmission has been clearly demonstrated
by means of both neurochemical and behavioral experiments. In light of the fact that caffeine is widely consumed and considering the major role
played by dopamine in mediating important physiological functions, such as movement, learning and emotional control, elucidating the features
of such an interaction appears as an issue of great interest. This chapter summarizes evidence previously obtained in a rat model of
subchronic caffeine administration demonstrating the capability of caffeine in triggering a hyperfunctional state involving the
dopaminergic transmission in the corpus striatum which is manifested at both the behavioral and the neurochemical level. In particular,
subchronic caffeine administration was found to promote the development of both sensitization to the motor stimulant effects of caffeine itself
and cross-sensitization to those of amphetamine. Next to this, different neuroadaptive phenomena , which involve persistent changes in
receptors'density and affinity state as well as enduring modifications in immediate early gene expression, but not dopamine release, were
observed in striatal regions of rats sensitized to caffeine. The relevance of these findings to the possible mechanisms underlying
caffeine-dopamine interactions is discussed
Role of adenosine A2A receptors in motor control: relevance to Parkinson’s disease and dyskinesia
No full textAdenosine is an endogenous purine nucleoside that regulates several physiological functions, at the central and peripheral levels. Besides, adenosine has emerged as a major player in the regulation of motor behavior. In fact, adenosine receptors of the A2A subtype are highly enriched in the caudate–putamen, which is richly innervated by dopamine. Moreover, several studies in experimental animals have consistently demonstrated that the pharmacological antagonism of A2A receptors has a facilitatory influence on motor behavior. Taken together, these findings have envisaged A2A receptors as a promising target for symptomatic therapies aimed at ameliorating motor deficits. Accordingly, A2A receptor antagonists have been extensively studied as new agents for the treatment of Parkinson’s disease (PD), the epitome of motor disorders. In this review, we provide an overview of the effects that adenosine A2A receptor antagonists elicit in rodent and primate experimental models of PD, with regard to the counteraction of motor deficits as well as to manifestation of dyskinesia and motor fluctuations. Moreover, we briefly present the results of clinical trials of A2A receptor antagonists in PD patients experiencing motor fluctuations, with particular regard to dyskinesia. Finally, we discuss the interaction between A2A receptor antagonists and serotonin receptor agonists, since combined administration of these drugs has recently emerged as a new potential therapeutic strategy in the treatment of dyskinesia
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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