Sustained Impairment of α2A-Adrenergic Autoreceptor Signaling Mediates Neurochemical and Behavioral Sensitization to Amphetamine

Doucet, Édith; Bobadilla, Ana-Clara; Houades, Vanessa; Lanteri, Christophe; Godeheu, G.; Lanfumey, Laurence; Sara, Susan J.; Tassin, Jean‐Pol

doi:10.1016/j.biopsych.2012.11.029

Cited by 21 publications

(16 citation statements)

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“…Increased DA tone is an established theory behind many models of drug addiction (65)(66)(67). However, a recent study highlights the key role of noradrenergic autoreceptor signaling in the persistent modifications induced by repeated drug administration (68). NE terminals can release DA, perhaps under conditions where dopamine ␤-hydroxylase located in vesicles of NE terminals is saturated (69).…”

Section: Discussionmentioning

confidence: 99%

A Role for p38 Mitogen-activated Protein Kinase-mediated Threonine 30-dependent Norepinephrine Transporter Regulation in Cocaine Sensitization and Conditioned Place Preference

Padmanabhan

Kamalakkannan

Damaj

et al. 2015

Journal of Biological Chemistry

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Background: Cocaine-activated p38 MAPK-mediated norepinephrine transporter (NET) threonine 30 phosphorylation up-regulates NET. Results: p38 MAPK inhibition and TAT-NET-Thr 30 peptide blocks cocaine-mediated NET up-regulation and cocaine-induced locomotor sensitization and conditioned place preference (CPP). Conclusion: Blockade of p38 MAPK-mediated Thr30 -dependent NET regulation attenuates cocaine-induced locomotor sensitization, CPP, and CPP reinstatement. Significance: Regulation of NET plays a mechanistic role in cocaine-mediated behaviors.

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Section: Discussionmentioning

confidence: 99%

A Role for p38 Mitogen-activated Protein Kinase-mediated Threonine 30-dependent Norepinephrine Transporter Regulation in Cocaine Sensitization and Conditioned Place Preference

Padmanabhan

Kamalakkannan

Damaj

et al. 2015

Journal of Biological Chemistry

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“…Our data suggest that blockade of α2A-adrenergic receptor can increase the level of NE in the PVN. In vivo dialysate measured by microdialysis showed α2A-adrenergic receptor agonist clonidine decreased the level of NE in the prefrontal cortex (Doucet et al, 2013), LC and cingulate cortex (Mateo et al, 2001), which also indicate that NE release might be highly dependent on the α2A-adrenergic receptors. Hence, the anomaly of α 2A -ARs maybe a physiopathology mechanism to trigger depressive disorder through direct or indirect effects to the secretion of NE in the PVN and the firing of LC noradrenergic neurons (Aoki et al, 1994; Nörenberg et al, 1997; Lee et al, 1998; Guiard et al, 2008; Wang et al, 2009).…”

Section: Discussionmentioning

confidence: 97%

Effects of α2A Adrenoceptors on Norepinephrine Secretion from the Locus Coeruleus during Chronic Stress-Induced Depression

Wang

et al. 2017

Front. Neurosci.

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Chronic stressors can often lead to the development of psychological disorders, such as depression and anxiety. The locus coeruleus (LC) is a stress sensitive brain region located in the pons, with noradrenergic neurons that project to the hypothalamus, especially the paraventricular nucleus (PVN) of the hypothalamus. The purpose of this paper is to better understand how alpha 2A-adrenoceptors (α2A-ARs) and LC-hypothalamus noradrenergic system participate in the pathophysiological mechanism of depression. In vivo norepinephrine (NE) release in the PVN triggered by electrical stimulation in the LC was detected with carbon fiber electrodes in depression model of rats induced by chronic unpredictable mild stress (CUMS). Also, the extracellular level of NE in the PVN was measured by microdialysis in vivo without any stimulation in the LC. The alpha 2-adrenoceptor (α2-AR) antagonist yohimbine and α2A-ARs antagonist BRL-44408 maleate were systemically administered to rats to determine the effects of α2A-ARs on NE release in the PVN. The peak value of elicited NE release signals in the PVN induced by electrical stimulation in the LC in the CUMS rats were lower than that in the control rats. The extracellular levels of NE in the PVN of the CUMS rats were significantly less than that of the control rats. Intraperitoneal injection of yohimbine or BRL-44408 maleate significantly potentiated NE release in the PVN of the CUMS rats. The CUMS significantly increased protein expression levels of α2A-AR in the hypothalamus, and BRL-44408 maleate significantly reversed the increase of α2A-AR protein expression levels in the CUMS rats. Our results suggest that the CUMS could significantly facilitate the effect of α2-adrenoceptor-mediated presynaptic inhibition and decrease the release of NE in the PVN from LC. Blockade of the inhibitory action of excessive α2A-adrenergic receptors in the CUMS rats could increase the level of NE in the PVN, which is effective in the treatment of depressive disorders.

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“…Guanabenz/guanfacine is preferential for a2a, but clonidine and dexmedetomidine have equal affinity at a2 subtypes (Gobert et al, 1998). a2AR antagonists include yohimbine, efaroxan, BRL-44408 (2-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-2,3-dihydro-1-methyl-1H-isoindole), dexefaroxan, idazoxan, and atipamezole (Dickinson et al, 1988;Villegier et al, 2003;Juhila et al, 2005;Jimenez-Rivera et al, 2006;Doucet et al, 2013). Yohimbine and atipamezole show equal affinities at all three receptor subtypes, but atipamezole has a 200-fold greater selectivity than yohimbine for the a2AR over the a1AR (Schwartz and Clark, 1998).…”

Section: Pharmacologic Compounds Targeting Adrenergic Receptorsmentioning

confidence: 99%

“…Antagonism of a2AR, on the other hand, which facilitates NE transmission by blocking autoreceptor function, increased both acute stimulant-induced locomotion (Dickinson et al, 1988;Villegier et al, 2003;Jimenez-Rivera et al, 2006) and sensitized responses (Doucet et al, 2013) in mice and rats. Conversely, the a2AR agonist clonidine, which suppresses NE release via autoreceptor stimulation, produced a decreased acute response to cocaine (Vanderschuren et al, 2003;JimenezRivera et al, 2006) and prevented amphetamine sensitization (Doucet et al, 2013).…”

Section: Stimulant-induced Locomotor Activitymentioning

confidence: 99%

“…Conversely, the a2AR agonist clonidine, which suppresses NE release via autoreceptor stimulation, produced a decreased acute response to cocaine (Vanderschuren et al, 2003;JimenezRivera et al, 2006) and prevented amphetamine sensitization (Doucet et al, 2013). None of these studies provided evidence for the neuroanatomical substrates mediating these a2AR responses.…”

Section: Stimulant-induced Locomotor Activitymentioning

confidence: 99%

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Adrenaline Rush: The Role of Adrenergic Receptors in Stimulant-Induced Behaviors

Schmidt

Weinshenker

2014

Mol Pharmacol

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Psychostimulants, such as cocaine and amphetamines, act primarily through the monoamine neurotransmitters dopamine (DA), norepinephrine, and serotonin. Although stimulant addiction research has largely focused on DA, medication development efforts targeting the dopaminergic system have thus far been unsuccessful, leading to alternative strategies aimed at abating stimulant abuse. Noradrenergic compounds have shown promise in altering the behavioral effects of stimulants in rodents, nonhuman primates, and humans. In this review, we discuss the contribution of each adrenergic receptor (AR) subtype (a1, a2, and b) to five stimulant-induced behaviors relevant to addiction: locomotor activity, conditioned place preference, anxiety, discrimination, and self-administration. AR manipulation has diverse effects on these behaviors; each subtype profoundly influences outcomes in some paradigms but is inconsequential in others. The functional neuroanatomy and intracellular signaling mechanisms underlying the impact of AR activation/blockade on these behaviors remain largely unknown, presenting a new frontier for research on psychostimulant-AR interactions.

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Sustained Impairment of α2A-Adrenergic Autoreceptor Signaling Mediates Neurochemical and Behavioral Sensitization to Amphetamine

Cited by 21 publications

References 45 publications

A Role for p38 Mitogen-activated Protein Kinase-mediated Threonine 30-dependent Norepinephrine Transporter Regulation in Cocaine Sensitization and Conditioned Place Preference

A Role for p38 Mitogen-activated Protein Kinase-mediated Threonine 30-dependent Norepinephrine Transporter Regulation in Cocaine Sensitization and Conditioned Place Preference

Effects of α2A Adrenoceptors on Norepinephrine Secretion from the Locus Coeruleus during Chronic Stress-Induced Depression

Adrenaline Rush: The Role of Adrenergic Receptors in Stimulant-Induced Behaviors

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