Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor

Ledent, Catherine; Vaugeois, Jean-Marie; Schiffmann, Serge N.; Pedrazzini, Thierry; Yacoubi, Malika El; Vanderhaeghen, Jean‐Jacques; Costentin, Jean; Heath, John K.; Vassart, Gilbert; Parmentier, Marc

doi:10.1038/41771

Cited by 840 publications

(649 citation statements)

References 24 publications

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“…Thus, BC1-deficient mice showed reduced exploratory behaviour in the barrier test, the open-field test and the complex-alley maze test, and were reluctant to enter open arms in the elevated plus-maze. Reduced exploratory behaviour may also be mediated by mechanisms regulating anxiety [6,23]. Importantly, observations in the laboratory on exploration and anxiety-related behaviour were confirmed by results from the semi-naturalistic outdoor studies.…”

Section: Bc1 Rna Modulates Expression Of Exploratory Behaviour But Nomentioning

confidence: 67%

Role of a neuronal small non-messenger RNA: behavioural alterations in BC1 RNA-deleted mice

Lewejohann

Skryabin

Sachser

et al. 2004

Behavioural Brain Research

139

102

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BC1 RNA is a small non-messenger RNA common in dendritic microdomains of neurons in rodents. In order to investigate its possible role in learning and behaviour, we compared controls and knockout mice from three independent founder lines established from separate embryonic stem cells. Mutant mice were healthy with normal brain morphology and appeared to have no neurological deficits. A series of tests for exploration and spatial memory was carried out in three different laboratories. The tests were chosen as to ensure that different aspects of spatial memory and exploration could be separated and that possible effects of confounding variables could be minimised. Exploration was studied in a barrier test, in an open-field test, and in an elevated plus-maze test. Spatial memory was investigated in a Barnes maze and in a Morris water maze (memory for a single location), in a multiple T-maze and in a complex alley maze (route learning), and in a radial maze (working memory). In addition to these laboratory tasks, exploratory behaviour and spatial memory were assessed under semi-naturalistic conditions in a large outdoor pen. The combined results indicate that BC1 RNA-deficient animals show behavioural changes best interpreted in terms of reduced exploration and increased anxiety. In contrast, spatial memory was not affected. In the outdoor pen, the survival rates of BC1-depleted mice were lower than in controls. Thus, we conclude that the neuron-specific non-messenger BC1 RNA contributes to the aptive modulation of behaviour.

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Section: Bc1 Rna Modulates Expression Of Exploratory Behaviour But Nomentioning

confidence: 67%

Role of a neuronal small non-messenger RNA: behavioural alterations in BC1 RNA-deleted mice

Lewejohann

Skryabin

Sachser

et al. 2004

Behavioural Brain Research

139

102

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“…In spite of these di erences, our data con®rm an important role for A 2a receptors in vascular tone regulation, and suggest that the systemic response mediated by these receptors is prevalently linked to the release of NO, probably from endothelial cells. The role of endothelial receptors in the response to adenosine was previously suggested by the evidence from Nees (1989) blood pressure was, in fact, observed in A 2a receptor gene knockout-mice (Ledent et al, 1997).…”

Section: Discussionmentioning

confidence: 78%

Adenosine‐mediated hypotension in in vivo guinea‐pig: receptors involved and role of NO

Nieri¹,

Martinotti²,

Calderone³

et al. 2001

British J Pharmacology

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1 Adenosine produced a biphasic lowering of the mean BP with a drastic bradycardic e ect at the highest doses. The ®rst phase hypotensive response was signi®cantly reduced by the nitric oxide (NO) synthase inhibitor L-NAME. 2 The A 2a /A 2b agonist NECA produced hypotensive and bradycardic responses similar to those elicited by adenosine, which were not signi®cantly modi®ed by the A 2b antagonist enprofylline. 3 The A 2a agonist CGS 21680 did not signi®cantly in¯uence basal HR while induced a hypotensive response antagonized by the A 2a selective antagonist ZM 241385, and reduced by both L-NAME and the guanylate cyclase inhibitor methylene blue. 4 The A 1 agonist R-PIA showed a dose-dependent decrease in BP with a drastic decrease in HR at the highest doses. The A 1 selective antagonist DPCPX signi®cantly reduced the bradycardic activity and also the hypotensive responses obtained with the lowest doses while it increased those obtained with the highest ones. 5 The A 1 /A 3 agonist APNEA, in the presence of the xanthinic non-selective antagonist 8-pSPT, maintained a signi®cant hypotensive, but not bradycardic, activity, not abolished by the histamine antagonist diphenhydramine. 6 The selective A 3 agonist IB-MECA revealed a weak hypotensive and bradycardic e ect, but only at the highest doses. 7 In conclusion, in the systemic cardiovascular response to adenosine two major components may be relevant: an A 2a -and NO-mediated hypotension, and a bradycardic e ect with a consequent hypotension, via atypical A 1 receptors. Finally, an 8-pSPT-resistant hypotensive response not attributable to A 3 receptor-stimulation or to release of histamine by mastocytes or other immune cells was observed. IntroductionFour classes of membrane surface adenosine receptors are described, de®ned A 1 , A 2a , A 2b and A 3 , through which the nucleoside in¯uences many functions in humans and other animals (Ralevic & Burnstock, 1998). As far as the cardiovascular system is concerned, adenosine slows heart rate (HR) and atrioventricular conduction and antagonizes the cardio-stimulatory e ects of catecholamines via cardiac A 1 receptors in di erent mammals (Belardinelli et al., 1989;Olsson & Pearson, 1990). An increase in blood pressure (BP) and HR has been described in rats and in cats via central A 1 receptors (St Lambert et al., 1994; SilvaCarvalho et al., 1993). In contrast, a dose-related decrease in BP and HR is observed after microinjection of adenosine into the caudal nucleus of tractus solitarii in the rat (Lo et al., 1998).As regards a direct e ect on blood vessels, A 1 purinoceptors mediate vasodilation in the porcine coronary artery (Merkel et al., 1992) but they are involved, on the contrary, in vasoconstrictor responses, i.e. in the rat kidney (Jackson, 1991), in guinea-pig pulmonary artery and aorta (Biaggioni et al., 1989;Stoggall & Shaw, 1990) and in hamster skin (Stojanov & Proctor, 1990;Proctor & Stojanov, 1991).Moreover, a signi®cant role of A 1 receptors in the regulation of BP also appears to be linked to a prejunction...

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“…Furthermore, mice lacking A2AR (Chen et al, 1999;Ledent et al, 1997) have been shown to demonstrate reduced sensitivity to the hypnotic effects of alcohol, increased alcohol consumption, and reduced alcohol-withdrawal seizures (El Yacoubi et al, 2001;Naassila et al, 2002). As a result, antagonism of A2AR signaling could be useful in the treatment of alcohol withdrawal symptoms; however, since inhibition of A2AR also results in increased alcohol consumption, the mechanisms through which the A2AR mediates each of these effects should be further delineated to identify a more specific therapeutic approach.…”

Section: Adenosine Receptor Signaling In Ethanol Drinkingmentioning

confidence: 99%

Adenosine Signaling in Striatal Circuits and Alcohol Use Disorders

Nam

Bruner

Choi

2013

Molecules and Cells

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Adenosine signaling has been implicated in the pathophysiology of alcohol use disorders and other psychiatric disorders such as anxiety and depression. Numerous studies have indicated a role for A1 receptors (A1R) in acute ethanol-induced motor incoordination, while A2A receptors (A2AR) mainly regulate the rewarding effect of ethanol in mice. Recent findings have demonstrated that dampened A2AR-mediated signaling in the dorsomedial striatum (DMS) promotes ethanol-seeking behaviors. Moreover, decreased A2AR function is associated with decreased CREB activity in the DMS, which enhances goal-oriented behaviors and contributes to excessive ethanol drinking in mice. Interestingly, caffeine, the most commonly used psychoactive substance, is known to inhibit both the A1R and A2AR. This dampened adenosine receptor function may mask some of the acute intoxicating effects of ethanol. Furthermore, based on the fact that A2AR activity plays a role in goal-directed behavior, caffeine may also promote ethanol-seeking behavior. The A2AR is enriched in the striatum and exclusively expressed in striatopallidal neurons, which may be responsible for the regulation of inhibitory behavioral control over drug rewarding processes through the indirect pathway of the basal ganglia circuit. Furthermore, the antagonistic interactions between adenosine and dopamine receptors in the striatum also play an integral role in alcoholism and addiction-related disorders. This review focuses on regulation of adenosine signaling in striatal circuits and the possible implication of caffeine in goal-directed behaviors and addiction.

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Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor

Cited by 840 publications

References 24 publications

Role of a neuronal small non-messenger RNA: behavioural alterations in BC1 RNA-deleted mice

Role of a neuronal small non-messenger RNA: behavioural alterations in BC1 RNA-deleted mice

Adenosine‐mediated hypotension in in vivo guinea‐pig: receptors involved and role of NO

Adenosine Signaling in Striatal Circuits and Alcohol Use Disorders

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