The Distinct Role of Medium Spiny Neurons and Cholinergic Interneurons in the D<sub>2</sub>/A<sub>2A</sub>Receptor Interaction in the Striatum: Implications for Parkinson's Disease

Tozzi, Alessandro; Iure, Antonio de; Filippo, Massimiliano Di; Tantucci, Michela; Costa, Cinzia; Borsini, Franco; Ghiglieri, Veronica; Giampà, Carmela; Fusco, Francesca R.; Picconi, Barbara; Calabresi, Paolo

doi:10.1523/jneurosci.4082-10.2011

Cited by 139 publications

(139 citation statements)

References 61 publications

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“…In the striatum, adenosine A2A receptors (A2ARs) and D2Rs are colocalized (29) and form A2AR-D2R heteromers (30). The A2AR and D2R interact antagonistically, such that agonism of A2ARs decreases signaling at D2Rs (31) and antagonism of A2ARs increases signaling at D2Rs (30).…”

Section: Pharmacological Manipulations Of D1rs But Not D2rs Block Avementioning

confidence: 99%

“…The A2AR and D2R interact antagonistically, such that agonism of A2ARs decreases signaling at D2Rs (31) and antagonism of A2ARs increases signaling at D2Rs (30). If the specific pattern of activity at D2Rs is a key factor in mediating aversions to nicotine withdrawal, and colocalized A2ARs and D2Rs act antagonistically in the striatum (29,30), then genetic and pharmacological manipulation of A2ARs should also affect nicotine-withdrawal aversions in dependent animals. We examined the effect of A2AR manipulation on the conditioned aversive responses to acute nicotine and withdrawal from chronic nicotine in A2AR KO mice and WT mice pretreated with the A2AR agonist CGS21680 (0.1 mg/ kg) or the A2AR antagonist SCH58261 (0.5 mg/kg).…”

Section: Pharmacological Manipulations Of D1rs But Not D2rs Block Avementioning

confidence: 99%

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Phasic D1 and tonic D2 dopamine receptor signaling double dissociate the motivational effects of acute nicotine and chronic nicotine withdrawal

Grieder

George

Tan

et al. 2012

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

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Nicotine, the main psychoactive ingredient of tobacco smoke, induces negative motivational symptoms during withdrawal that contribute to relapse in dependent individuals. The neurobiological mechanisms underlying how the brain signals nicotine withdrawal remain poorly understood. Using electrophysiological, genetic, pharmacological, and behavioral methods, we demonstrate that tonic but not phasic activity is reduced during nicotine withdrawal in ventral tegmental area dopamine (DA) neurons, and that this pattern of signaling acts through DA D2 and adenosine A2A, but not DA D1, receptors. Selective blockade of phasic DA activity prevents the expression of conditioned place aversions to a single injection of nicotine in nondependent mice, but not to withdrawal from chronic nicotine in dependent mice, suggesting a shift from phasic to tonic dopaminergic mediation of the conditioned motivational response in nicotine dependent and withdrawn animals. Either increasing or decreasing activity at D2 or A2A receptors prevents the aversive motivational response to withdrawal from chronic nicotine, but not to acute nicotine. Modification of D1 receptor activity prevents the aversive response to acute nicotine, but not to nicotine withdrawal. This double dissociation demonstrates that the specific pattern of tonic DA activity at D2 receptors is a key mechanism in signaling the motivational effects experienced during nicotine withdrawal, and may represent a unique target for therapeutic treatments for nicotine addiction.negative reinforcement | place conditioning | burst firing | population activity | osmotic minipumps T obacco addiction is the leading avoidable cause of disease and premature death in North America (1). Of more than 3,000 chemicals present in tobacco smoke, nicotine is the main psychoactive ingredient responsible for tobacco addiction (2). Withdrawal from chronic nicotine is hypothesized to represent a powerful source of negative reinforcement that drives relapse and compulsive tobacco use (3); therefore, understanding the neurobiological substrates mediating the motivational properties of nicotine withdrawal is an important step in the development of new treatments for nicotine addiction. Current hypotheses suggest that nicotine withdrawal leads to a decrease in dopamine (DA) signaling in the brain (4) and that DA neurons exhibit two activity states, phasic and tonic, that mediate separate aspects of behavior (5-7).Nicotine acutely produces both aversive and positive motivational effects (8, 9) by activating the mesolimbic DA system (7, 10) as well as non-DAergic neural substrates (11,12). DA neurons exhibit burst-and population-firing activity that leads to phasic and tonic DA release, respectively (5-7). Burst-firing produces a fast and large phasic DA release that mainly activates postsynaptic DA D1 receptors (D1Rs), and population-firing produces a slower tonic DA release that mainly activates the higher affinity (13) DA D2 receptors (D2Rs) (5, 6). The phasic and tonic activities of DA neurons are though...

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Section: Pharmacological Manipulations Of D1rs But Not D2rs Block Avementioning

confidence: 99%

Section: Pharmacological Manipulations Of D1rs But Not D2rs Block Avementioning

confidence: 99%

Phasic D1 and tonic D2 dopamine receptor signaling double dissociate the motivational effects of acute nicotine and chronic nicotine withdrawal

Grieder

George

Tan

et al. 2012

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

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“…A 1 and A 2A receptors are expressed in the brain, with A 2A being primarily localized to the dorsal striatum, nucleus accumbens, olfactory tubercle, and external globus pallidus (GPe) (Schwarzschild et al, 2006). In the striatum, A 2A receptors are co-localized with dopamine D 2 receptors, the peptide enkephalin, and the metabotropic glutamate receptor 5 (mGluR5), with which they functionally interact in dendrites and spines of medium spiny striatopallidal neurons within the indirect pathway of the basal ganglia (Fuxe et al, 2003(Fuxe et al, , 2007a(Fuxe et al, , b, 2010aTanganelli et al, 2004;Kachroo et al, 2005;Simola et al, 2008;Agnati et al, 2010;Tozzi et al, 2011) (Figure 1). D 2 and A 2A receptors have opposite effects on the activity of striatal neurons (Ferré et al, 1997).…”

Section: Non-dopaminergic Therapiesmentioning

confidence: 99%

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

Smith

Wichmann

Factor

et al. 2011

Neuropsychopharmacol

194

137

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The demonstration that dopamine loss is the key pathological feature of Parkinson's disease (PD), and the subsequent introduction of levodopa have revolutionalized the field of PD therapeutics. This review will discuss the significant progress that has been made in the development of new pharmacological and surgical tools to treat PD motor symptoms since this major breakthrough in the 1960s. However, we will also highlight some of the challenges the field of PD therapeutics has been struggling with during the past decades. The lack of neuroprotective therapies and the limited treatment strategies for the nonmotor symptoms of the disease (ie, cognitive impairments, autonomic dysfunctions, psychiatric disorders, etc.) are among the most pressing issues to be addressed in the years to come. It appears that the combination of early PD nonmotor symptoms with imaging of the nigrostriatal dopaminergic system offers a promising path toward the identification of PD biomarkers, which, once characterized, will set the stage for efficient use of neuroprotective agents that could slow down and alter the course of the disease.

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“…In a recent paper published in The Journal of Neuroscience, Tozzi et al (2011) provide a model of D 2 R-dependent eCBmediated LTD that could potentially reconcile the aforementioned studies. The main feature of the Tozzi et al (2011) model is the involvement of the adenosine A 2A receptors (A 2A Rs), which are highly enriched in the striatum and tightly counteract D 2 Rs at multiple levels (Schiffmann et al, 2007).…”

mentioning

confidence: 71%

“…This leaves an important question unanswered: how does a postsynaptically initiated, D 2 R-dependent phenomenon induce LTD in all MSNs if D 2 Rs are expressed in only a subset of these neurons? Recent studies have attempted to address this question (Wang et al, 2006;Kreitzer and Malenka, 2007;Tozzi et al, 2011). Wang et al (2006) suggested that the relevant D 2 Rs mediating striatal LTD were those expressed in cholinergic interneurons that, despite their low abundance (Ͻ5%), project to virtually all MSNs.…”

mentioning

confidence: 99%

Toward a Model of Retrograde Regulation of Striatal Synaptic Depression: Figure 1.

Bertran‐Gonzalez¹,

Napier²

2011

J. Neurosci.

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The Distinct Role of Medium Spiny Neurons and Cholinergic Interneurons in the D₂/A_2AReceptor Interaction in the Striatum: Implications for Parkinson's Disease

Cited by 139 publications

References 61 publications

Phasic D1 and tonic D2 dopamine receptor signaling double dissociate the motivational effects of acute nicotine and chronic nicotine withdrawal

Phasic D1 and tonic D2 dopamine receptor signaling double dissociate the motivational effects of acute nicotine and chronic nicotine withdrawal

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

Toward a Model of Retrograde Regulation of Striatal Synaptic Depression: Figure 1.

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The Distinct Role of Medium Spiny Neurons and Cholinergic Interneurons in the D2/A2AReceptor Interaction in the Striatum: Implications for Parkinson's Disease

Cited by 139 publications

References 61 publications

Phasic D1 and tonic D2 dopamine receptor signaling double dissociate the motivational effects of acute nicotine and chronic nicotine withdrawal

Phasic D1 and tonic D2 dopamine receptor signaling double dissociate the motivational effects of acute nicotine and chronic nicotine withdrawal

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

Toward a Model of Retrograde Regulation of Striatal Synaptic Depression: Figure 1.

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The Distinct Role of Medium Spiny Neurons and Cholinergic Interneurons in the D₂/A_2AReceptor Interaction in the Striatum: Implications for Parkinson's Disease