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

Grieder, Taryn E.; Sellings, Laurie H. L.; Vargas‐Perez, Hector; Ting‐A‐Kee, Ryan; Siu, Eric; Tyndale, Rachel F.; Kooy, Derek van der

doi:10.1038/npp.2009.198

Cited by 37 publications

(88 citation statements)

References 70 publications

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“…We suggest that phasic DA activity at D1Rs mediates acute nicotine aversions, whereas tonic DA activity at D2Rs (and indirectly, A2ARs) mediates aversions to withdrawal from chronic nicotine. Rodents experiencing spontaneous withdrawal from chronic nicotine show a CPA to a withdrawal-paired environment in place-conditioning paradigms (20,33). Similarly, previously drugnaive mice given a single aversive dose of nicotine will show a CPA to the nicotine-paired environment (20).…”

Section: Discussionmentioning

confidence: 99%

“…Withdrawal from nicotine has been hypothesized to represent a powerful source of negative reinforcement (20,23) that drives relapse and compulsive tobacco use (2, 3). Therefore, understanding the neurobiological substrates mediating the motivational properties of withdrawal from chronic nicotine is an important step in the development of new treatments for nicotine addiction.…”

Section: Discussionmentioning

confidence: 99%

“…Pharmacological blockade of DA activity at receptors attenuates the expression of food (19) and drug motivation (20,21) in place-conditioning paradigms. Interestingly, pharmacological activation of DA receptors (DARs) also prevents food motivation (19) and conditioned place aversions (CPAs) to morphine withdrawal (21).…”

Section: Activation or Blockade Of Da Receptors Prevents The Expressimentioning

confidence: 99%

“…We hypothesized that a specific pattern of signaling at DARs could mediate nicotine withdrawal, and thus that either pharmacologically increasing or decreasing activity at DARs would prevent CPAs to nicotine withdrawal. Mice given chronic nicotine (7 mg·kg·d) were subjected to place-conditioning during spontaneous withdrawal (20) after pretreatment with vehicle, the DAR agonist apomorphine (2.5 mg/kg), or the DAR antagonist α-flupenthixol (0.8 mg/kg). A one-way ANOVA showed a significant effect of pharmacological pretreatment (F 2,42 = 17.1, P < 0.05) (Fig.…”

Section: Activation or Blockade Of Da Receptors Prevents The Expressimentioning

confidence: 99%

“…We next directly investigated the specific patterns of DA neuron firing that mediate the motivational response to nicotine withdrawal. Using defined criteria to measure phasic bursting activity and tonic population activity of DA neurons (18, 22), we measured tonic and phasic VTA DA activity with in vivo extracellular single-unit recordings in saline control, previously drug-naive given acute nicotine (1.5 mg/kg), nicotine dependent (3.14 mg·kg·d), and nicotine-dependent and spontaneously withdrawn rats (20,23). Analysis of tonic DA neuron activity with one-way ANOVA revealed a significant effect of drug treatment (F 3,35 = 9.7, P < 0.05) (Fig.…”

Section: Activation or Blockade Of Da Receptors Prevents The Expressimentioning

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: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Activation or Blockade Of Da Receptors Prevents The Expressimentioning

confidence: 99%

Section: Activation or Blockade Of Da Receptors Prevents The Expressimentioning

confidence: 99%

Section: Activation or Blockade Of Da Receptors Prevents The Expressimentioning

confidence: 99%

See 3 more Smart Citations

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 Vapor Method to Induce Nicotine Dependence in Rodents

Kallupi

George

2017

CP Neuroscience

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Nicotine, the main addictive component of tobacco, induces potentiation of brain stimulation reward, increases locomotor activity and induces conditioned place preference. Nicotine cessation produces a withdrawal syndrome that can be relieved by nicotine replacement therapy. In the last decade, the market for electronic cigarettes has flourished, especially among adolescents. The nicotine vaporizer or electronic nicotine delivery system is a battery-operated device that simulates the experience of tobacco smoking without inhaling smoke. The device is designed to be an alternative for conventional cigarettes that emits vaporized nicotine that is inhaled by the user. This report describes a procedure to vaporize nicotine in the air to produce blood nicotine levels in rodents that are clinically relevant to those that are observed in humans and produce dependence. We also describe how to construct the apparatus to deliver nicotine vapor in a stable, reliable, and consistent manner and how to analyze air for nicotine content.

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