Adenosine receptor blockade reverses hypophagia and enhances locomotor activity of dopamine-deficient mice

Kim, Douglas S.; Palmiter, Richard D.

doi:10.1073/pnas.252753799

Cited by 47 publications

(37 citation statements)

References 37 publications

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“…4,24 Adenosine receptors are colocalized as heteromers with dopaminergic D2 receptors, inhibiting effects of dopaminergic transmission. 25,26 Numerous animal studies have found motor improvement in toxin-induced models of PD, 27 in dopamine-deficient mice, 28 and in drug-induced parkinsonism 29 with caffeine. Caffeine may also increase bioavailability and prolong the clinical effect of levodopa 30 (note that the clinical effect of caffeine may persist even after levodopa levels decline, suggesting that the D2 receptor interactions are also important).…”

Section: Caffeine and Edsmentioning

confidence: 99%

Caffeine for treatment of Parkinson disease

et al. 2012

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Objective: Epidemiologic studies consistently link caffeine, a nonselective adenosine antagonist, to lower risk of Parkinson disease (PD). However, the symptomatic effects of caffeine in PD have not been adequately evaluated. Methods:We conducted a 6-week randomized controlled trial of caffeine in PD to assess effects upon daytime somnolence, motor severity, and other nonmotor features. Patients with PD with daytime somnolence (Epworth Ͼ10) were given caffeine 100 mg twice daily ϫ3 weeks, then 200 mg twice daily ϫ3 weeks, or matching placebo. The primary outcome was the Epworth Sleepiness Scale score. Secondary outcomes included motor severity, sleep markers, fatigue, depression, and quality of life. Effects of caffeine were analyzed with Bayesian hierarchical models, adjusting for study site, baseline scores, age, and sex.Results: Of 61 patients, 31 were randomized to placebo and 30 to caffeine. On the primary intention-to-treat analysis, caffeine resulted in a nonsignificant reduction in Epworth Sleepiness Scale score (Ϫ1.71 points; 95% confidence interval [CI] Ϫ3.57, 0.13). However, somnolence improved on the Clinical Global Impression of Change (ϩ0.64; 0.16, 1.13, intention-to-treat), with significant reduction in Epworth Sleepiness Scale score on per-protocol analysis (Ϫ1.97; Ϫ3.87, Ϫ0.05). Caffeine reduced the total Unified Parkinson's Disease Rating Scale score (Ϫ4.69 points; Ϫ7.7, Ϫ1.6) and the objective motor component (Ϫ3.15 points; Ϫ5.50, Ϫ0.83).Other than modest improvement in global health measures, there were no changes in quality of life, depression, or sleep quality. Adverse events were comparable in caffeine and placebo groups. Conclusions:Caffeine provided only equivocal borderline improvement in excessive somnolence in PD, but improved objective motor measures. These potential motor benefits suggest that a larger long-term trial of caffeine is warranted.

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Section: Caffeine and Edsmentioning

confidence: 99%

Caffeine for treatment of Parkinson disease

et al. 2012

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“…Because DD mice are hypoactive and will not engage in some behaviors at all, we trained groups of DD mice after injection with caffeine (15 mg/kg), which restores locomotor activity independently of DA signaling (32). Caffeine-treated DD mice were injected with L-Dopa (30 mg/kg) before behavioral testing to determine whether learning had occurred but could not be expressed without DA signaling.…”

Section: Experimental Paradigmmentioning

confidence: 99%

Restriction of dopamine signaling to the dorsolateral striatum is sufficient for many cognitive behaviors

Darvas

Palmiter

2009

Proc. Natl. Acad. Sci. U.S.A.

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The striatum is a vital substrate for performance, procedural memory, and learning. The ventral and medial striatum are thought to be critical for acquisition of tasks while the dorsolateral striatum is important for performance and habitual enactment of skills. Evidence based on cortical, thalamic, and amygdaloid inputs to the striatum suggests a medio-lateral zonation imposed on the classical dorso-ventral distinction. We therefore investigated the functional significance of dopaminergic signaling in cognitive tasks by studying dopamine-deficient (DD) mice and mice with dopamine signaling restored to only the dorsolateral (DL) striatum by viral rescue (vrDD-DL mice). Whereas DD mice failed in all of the tasks examined here, vrDD-DL mice displayed intact discriminatory learning, object recognition, visuospatial learning and spatial memory. Acquisition of operant behavior for food rewards was delayed in vrDD-DL mice and their motivation in a progressive ratio experiments was reduced. Therefore, dopaminergic signaling in the dorsolateral striatum is sufficient for mice to learn several different cognitive tasks although the rate of learning some of them was reduced. These results indicate that dopaminergic signaling in the ventromedial striatum is not absolutely necessary for mastery of these behaviors, but may facilitate them.knockout ͉ learning ͉ memory ͉ tyrosine hydroxylase ͉ viral gene transfer M idbrain dopamine (DA) neurons mediate not only motor control, but also play a crucial role in many emotional and cognitive functions (1). DA projections from the ventral tegmental area (VTA) to the ventral striatum play a key role in reward, motivation, formation of Pavlovian associations and Pavlovian to instrumental transfer (2-5). DA projections from the substantia nigra pars compacta (SNc) to the dorsomedial striatum contribute to goal-directed operant learning and projections to the dorsolateral striatum contribute to stimulusresponse learning (6-8). It is widely accepted that the ventral striatum is essential for the acquisition of learned behavior, whereas the dorsolateral striatum is thought to be important for general performance, rather than acquisition of learning (9-11). Within this theoretical framework, the transition from goaldirected actions during early learning to stimulus-response controlled habits reflects a reallocation from ventral to dorsal striatal control over behavior (12,13). Recently, a spiraling mechanism has been proposed through which a cascade of serial connectivity linking the ventral striatum with progressively more dorsal regions of the striatum allows the ventral striatum to exert control, mediated by DA neurotransmission, over dorsal striatal processes (14,15).Based on the associations of cognitive and psychiatric symptoms with Parkinson's disease (PD) (16-18), the striatum is also thought to contribute to memory and visuospatial learning (19)(20)(21). In accordance with these observations, data from rodent models of PD indicate that the dorsal striatum contributes to various for...

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“…The potential therapeutic efficacy of adenosine A 2A receptor antagonists is further demonstrated by studies showing that the motor impairment caused by genetic inactivation of the dopamine D 2 receptor is counteracted by administration of KW-6002 [75]. In addition, caffeine enhances locomotion in mice made dopamine deficient by inactivating the gene coding for tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of catecholamines [162]. Studies performed in MPTP-treated monkeys show that the anti-parkinsonian effect of KW-6002, administered alone or together with dopaminomimetic drugs, is not accompanied by dyskinesia, even after several days of administration [110,160,161].…”

Section: Caffeine and Parkinson's Diseasementioning

confidence: 99%

“…Lack of behavioral sensitization is also observed following chronic administration of levodopa to A 2A knockout mice unilaterally lesioned with 6-OHDA [164]. In addition, coadministration of caffeine reduces the hyperlocomotor effect produced by levodopa in genetically altered, dopamine-deficient mice [162]. The idea that adenosine A 2A receptor antagonists possess antidyskinetic properties has been recently challenged by Lundblad et al [165].…”

Section: Caffeine and Parkinson's Diseasementioning

confidence: 99%

Caffeine as a psychomotor stimulant: mechanism of action

Fisone

Borgkvist

Usiello

2004

Cellular and Molecular Life Sciences (CMLS)

469

282

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The popularity of caffeine as a psychoactive drug is due to its stimulant properties, which depend on its ability to reduce adenosine transmission in the brain. Adenosine A(1) and A(2A) receptors are expressed in the basal ganglia, a group of structures involved in various aspects of motor control. Caffeine acts as an antagonist to both types of receptors. Increasing evidence indicates that the psychomotor stimulant effect of caffeine is generated by affecting a particular group of projection neurons located in the striatum, the main receiving area of the basal ganglia. These cells express high levels of adenosine A(2A) receptors, which are involved in various intracellular processes, including the expression of immediate early genes and regulation of the dopamine- and cyclic AMP-regulated 32-kDa phosphoprotein DARPP-32. The present review focuses on the effects of caffeine on striatal signal transduction and on their involvement in caffeine-mediated motor stimulation.

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Adenosine receptor blockade reverses hypophagia and enhances locomotor activity of dopamine-deficient mice

Abstract: A denosine accumulates extracellularly from breakdown of ATP released from synaptic vesicles and also diffuses across cell membranes through adenosine transporters (1).

Cited by 47 publications

References 37 publications

Caffeine for treatment of Parkinson disease

Caffeine for treatment of Parkinson disease

Restriction of dopamine signaling to the dorsolateral striatum is sufficient for many cognitive behaviors

Caffeine as a psychomotor stimulant: mechanism of action

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