Association of Low Striatal Dopamine D           <sub>2</sub>           Receptor Availability With Nicotine Dependence Similar to That Seen With Other Drugs of Abuse

Fehr, Christoph; Yakushev, Igor; Hohmann, Nina; Buchholz, Hans‐Georg; Landvogt, Christian; Deckers, Hanna; Eberhardt, Alexandra; Kläger, Marie; Smolka, Michael N.; Scheurich, Armin; Dielentheis, Thomas F.; Schmidt, Lutz; Rösch, Frank; Bartenstein, Peter; Gründer, Gerhard; Schreckenberger, Mathias

doi:10.1176/appi.ajp.2007.07020352

Cited by 198 publications

(166 citation statements)

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“…These results doubly dissociate the role of the D1R vs. D2R in nicotine motivation, such that the motivational response to withdrawal in dependent mice is D2R-mediated and acute nicotine motivation is D1R-mediated. These results are in line with previous studies showing that drug-dependent human subjects have marked decreases in D2R availability (34) and presumably in DA release (35), which is consistent with the hypothesis that a pattern of DA activity signals nicotine motivation and the present results showing that nicotine-dependent and -withdrawn mice have a decrease in tonic activity of VTA DA neurons. Furthermore, animal studies have shown that D1R antagonism blocks nicotine motivation in nondependent mice (36).…”

Section: Discussionsupporting

confidence: 93%

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: Discussionsupporting

confidence: 93%

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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“…We also examined D 2 receptor involvement in chronic nicotine withdrawal aversions. The DA D 2 receptor has been implicated in nicotine dependence (Fehr et al, 2008) and withdrawal (Laviolette et al, 2008). Our results show that acute aversive and chronic rewarding nicotine lead to opponent a-and bprocesses and that dopaminergic signaling, specifically at the D 2 receptor, mediates the opponent motivational process of chronic aversive but not acute rewarding nicotine.…”

Section: Introductionmentioning

confidence: 60%

Dopaminergic Signaling Mediates the Motivational Response Underlying the Opponent Process to Chronic but Not Acute Nicotine

Grieder

Sellings

Vargas‐Perez

et al. 2009

Neuropsychopharmacol

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The mesolimbic dopamine (DA) system is implicated in the processing of the positive reinforcing effect of all drugs of abuse, including nicotine. It has been suggested that the dopaminergic system is also involved in the aversive motivational response to drug withdrawal, particularly for opiates, however, the role for dopaminergic signaling in the processing of the negative motivational properties of nicotine withdrawal is largely unknown. We hypothesized that signaling at dopaminergic receptors mediates chronic nicotine withdrawal aversions and that dopaminergic signaling would differentially mediate acute vs dependent nicotine motivation. We report that nicotine-dependent rats and mice showed conditioned place aversions to an environment paired with abstinence from chronic nicotine that were blocked by the DA receptor antagonist a-flupenthixol (a-flu) and in DA D 2 receptor knockout mice. Conversely, a-flu pretreatment had no effect on preferences for an environment paired with abstinence from acute nicotine. Taken together, these results suggest that dopaminergic signaling is necessary for the opponent motivational response to nicotine in dependent, but not non-dependent, rodents. Further, signaling at the DA D 2 receptor is critical in mediating withdrawal aversions in nicotine-dependent animals. We suggest that the alleviation of nicotine withdrawal primarily may be driving nicotine motivation in dependent animals. Neuropsychopharmacology (2010) 35, 943-954;

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“…[ fallypride PET imaging study, nicotine-dependent smokers displayed signifi cantly less availability of D2/D3 receptors within the bilateral putamen, functionally covering parts of the dorsal striatum, compared to never-smoking subjects [83] .…”

Section: Pet Studies Of Postsynaptic Da Receptorsmentioning

confidence: 97%

“…labeled benzamide derivative that binds reversibly to D2 receptors [81] . In PET imaging with [ 18 F] FCP, Nader and colleagues [82] found that the baseline D2 receptor availability is negatively correlated with the rate of cocaine self-administration.[ fallypride PET imaging study, nicotine-dependent smokers displayed signifi cantly less availability of D2/D3 receptors within the bilateral putamen, functionally covering parts of the dorsal striatum, compared to never-smoking subjects [83] .[ 18 F] desmethoxyfallypride ([ 18 F] DMFP), another selective D2/D3 receptor antagonist, has also been developed and used to fi nd that a low availability of D2/3 receptors in the ventral striatum and adjacent putamen is associated with a high level of craving for alcohol [33] .For the D1 receptor, [ 11 C] NNC 112, a new benzazepine [(+)-8-chloro-5-(7-benzofuranyl)-7-hydroxy-3-methyl-2,3,4,5-tetra-hydro-lH-3-benzazepine], has been reported to be a useful PET radioligand for the quantitation of D1 receptors in humans [84] , and its D1 receptor selectivity has recently been re-evaluated [85] . With PET and the radiotracer [ 11 C] NNC 112, Martinez et al [86] found no difference between cocaine abusers and normal controls.…”

mentioning

confidence: 99%

Brain dopaminergic system changes in drug addiction: a review of positron emission tomography findings

et al. 2014

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Dopamine (DA) is considered crucial for the rewarding effects of drugs of abuse, but its role in addiction remains unclear. Positron emission tomography (PET) is the fi rst technology used for in vivo measurement of components of the dopaminergic system in the human brain. In this article, we review the major fi ndings from PET imaging studies on the involvement of DA in drug addiction, including presynaptic DA synthesis, vesicular monoamine transporter 2, the DA transporter, and postsynaptic DA receptors. These results have corroborated the role of DA in addiction and increased the understanding of its underlying mechanisms.Keywords: dopamine; dopaminergic system; drug addiction; positron emission tomography ·Review· Brain Dopaminergic System Dopamine (DA) is a catecholamine neurotransmitter in the nervous system. It has many functions in the brain, including punishment, reward, voluntary movement, mood, attention, motivation, sleep, working memory, and learning [1] .DA is synthesized by the hydroxylation and decarboxylation of L-tyrosine in DA neurons and, before being released into the synapse in response to an action potential, it is stored within presynaptic vesicles (Fig. 1). The action of DA occurs by binding to postsynaptic DA receptors, resulting in the formation of second messengers. There are fi ve subtypes of DA receptors, which can be grouped into two classes or families: D1-like and D-2 like [1,2] . The D1-like receptor family comprises the D1 and D5 receptors, encoded by genes with no introns, acting by way of Gs-proteins and activating adenylyl cyclase, thus increasing cAMP production [3,4] .The D2-like receptor family comprises the D2, D3, and D4 receptors, encoded by genes containing introns. D2-like receptors act via Gi-proteins, inhibit adenylyl cyclase activity, and thus decrease cAMP activity [3,5] .The action of DA in the synapse is terminated primarily by reuptake to the presynaptic membrane through the dopamine transporter (DAT) [6] . Otherwise, DA is partially removed by oxidation by monoamine oxidase orcatechol-O-methyltransferase in the synaptic cleft (Fig. 1).T h e d o p a m i n e r g i c n e u r o n s , w h o s e p r i m a r y neurotransmitter is DA, interconnect many areas of the brain to form a system which originates in the substantia nigra (SN) pars compacta, ventral tegmental area (VTA), and hypothalamus. The dopaminergic system is typically divided into four major pathways: mesocortical (from the VTA to the frontal cortex), mesolimbic (from the VTA to the nucleus accumbens), nigrostriatal (from the SN to the striatum), and tuberoinfundibular (from the hypothalamus to the pituitary gland). The mesostriatal and mesocortical pathways are currently recognized to contribute most to drug addiction [7] . Neurosci Bull October 1, 2014, 30(5): 765-776 766 Drug AddictionThe term addiction is derived from the Latin verb addicere, which referred to the Roman court action of binding a person to another. From the 17th century, addiction has been used to refer to psychoactive substances (...

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Association of Low Striatal Dopamine D ₂ Receptor Availability With Nicotine Dependence Similar to That Seen With Other Drugs of Abuse

Cited by 198 publications

References 45 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

Dopaminergic Signaling Mediates the Motivational Response Underlying the Opponent Process to Chronic but Not Acute Nicotine

Brain dopaminergic system changes in drug addiction: a review of positron emission tomography findings

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Association of Low Striatal Dopamine D 2 Receptor Availability With Nicotine Dependence Similar to That Seen With Other Drugs of Abuse

Cited by 198 publications

References 45 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

Dopaminergic Signaling Mediates the Motivational Response Underlying the Opponent Process to Chronic but Not Acute Nicotine

Brain dopaminergic system changes in drug addiction: a review of positron emission tomography findings

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Product

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Association of Low Striatal Dopamine D ₂ Receptor Availability With Nicotine Dependence Similar to That Seen With Other Drugs of Abuse