Activation of dopamine neurons is critical for aversive conditioning and prevention of generalized anxiety

Zweifel, Larry S.; Fadok, Jonathan P.; Argilli, Emmanuela; Garelick, Michael G.; Jones, Graham L.; Dickerson, Tavis M. K.; Allen, J. M.; Mizumori, Sheri J. Y.; Bonci, Antonello; Palmiter, Richard D.

doi:10.1038/nn.2808

Cited by 226 publications

(201 citation statements)

References 36 publications

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“…Furthermore, reduced dopaminergic signaling in the NAc is associated with emotional signs of nicotine withdrawal (Cryan et al, 2003;Paterson et al, 2007). Further confirmation that the mesolimbic dopaminergic system contributes to withdrawal from other addictive drugs would cohere with a growing body of literature demonstrating that it is also involved in a wide variety of aversive behaviors, including conditioned place aversion (Acquas et al, 1989;Calcagnetti and Schechter, 1991;Schechter and Meechan, 1994;Liu et al, 2008), fear conditioning (Borowski and Kokkinidis, 1996;Nader and LeDoux, 1999;Pezze and Feldon, 2004;Fadok et al, 2009;Muschamp et al, 2011), anxiety (Fride and Weinstock, 1988;Barrot et al, 2002;Barrot et al, 2005;Meloni et al, 2006;Rezayof et al, 2009;Richard and Berridge, 2011;Zweifel et al, 2011), intrinsic aversion to gustatory cues (Roitman et al, 2008), conditioned taste aversion Fenu et al, 2001), responses to stress (Geyer and Segal, 1974;Herman et al, 1982;Inglis and Moghaddam, 1999;Belda and Armario, 2009), and responses to nociceptive stimulation (Gear et al, 1999;Becerra et al, 2001;Barrot et al, 2002).…”

Section: Discussionmentioning

confidence: 91%

Increased Dopamine Receptor Activity in the Nucleus Accumbens Shell Ameliorates Anxiety during Drug Withdrawal

Radke¹,

Gewirtz

2012

Neuropsychopharmacol

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A number of lines of evidence suggest that negative emotional symptoms of withdrawal involve reduced activity in the mesolimbic dopamine system. This study examined the contribution of dopaminergic signaling in structures downstream of the ventral tegmental area to withdrawal from acute morphine exposure, measured as potentiation of the acoustic startle reflex. Systemic administration of the general dopamine receptor agonist apomorphine or a cocktail of the D1-like receptor agonist SKF82958 and the D2-like receptor agonist quinpirole attenuated potentiated startle during morphine withdrawal. This effect was replicated by apomorphine infusion into the nucleus accumbens shell. Finally, apomorphine injection was shown to relieve startle potentiation during nicotine withdrawal and conditioned place aversion to morphine withdrawal. These results suggest that transient activation of the ventral tegmental area mesolimbic dopamine system triggers the expression of anxiety and aversion during withdrawal from multiple classes of abused drugs.

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Section: Discussionmentioning

confidence: 91%

Increased Dopamine Receptor Activity in the Nucleus Accumbens Shell Ameliorates Anxiety during Drug Withdrawal

Radke¹,

Gewirtz

2012

Neuropsychopharmacol

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“…This behavior may reflect a relatively high level of anxiety as displayed by another cNR KO mouse line (Zweifel et al, 2011). In addition, 2 of 9 (ϳ20%) DATCre mice failed to perform the test, while for C57BL/6 mice the failure rate was ϳ2%.…”

Section: Acppb Effects In Conditional Nmda Receptor Knock-out Micementioning

confidence: 97%

Glycine Transporter-1 Inhibition Promotes Striatal Axon Sprouting via NMDA Receptors in Dopamine Neurons

Schmitz¹,

Castagna²,

Mrejeru³

et al. 2013

J. Neurosci.

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NMDA receptor activity is involved in shaping synaptic connections throughout development and adulthood. We recently reported that brief activation of NMDA receptors on cultured ventral midbrain dopamine neurons enhanced their axon growth rate and induced axonal branching. To test whether this mechanism was relevant to axon regrowth in adult animals, we examined the reinnervation of dorsal striatum following nigral dopamine neuron loss induced by unilateral intrastriatal injections of the toxin 6-hydroxydopamine. We used a pharmacological approach to enhance NMDA receptor-dependent signaling by treatment with an inhibitor of glycine transporter-1 that elevates levels of extracellular glycine, a coagonist required for NMDA receptor activation. All mice displayed sprouting of dopaminergic axons from spared fibers in the ventral striatum to the denervated dorsal striatum at 7 weeks post-lesion, but the reinnervation in mice treated for 4 weeks with glycine uptake inhibitor was approximately twice as dense as in untreated mice. The treated mice also displayed higher levels of striatal dopamine and a complete recovery from lateralization in a test of sensorimotor behavior. We confirmed that the actions of glycine uptake inhibition on reinnervation and behavioral recovery required NMDA receptors in dopamine neurons using targeted deletion of the NR1 NMDA receptor subunit in dopamine neurons. Glycine transport inhibitors promote functionally relevant sprouting of surviving dopamine axons and could provide clinical treatment for disorders such as Parkinson's disease.

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“…The role of dopamine in aversive learning has been investigated primarily in the acquisition and maintenance of fear or avoidance learning (Iordanova et al, 2006;Rossato et al, 2009;Fadok et al, 2009;Zweifel et al, 2011;Pezze and Feldon, 2004). These studies have shown a requirement for dopamine signaling in some elements of aversive learning (Inoue et al, 2000), but evidence suggesting that dopamine directly encodes prediction error in aversive learning has been primarily correlative (Iordanova, 2009).…”

Section: Introductionmentioning

confidence: 99%

Activation of D1/5 Dopamine Receptors: A Common Mechanism for Enhancing Extinction of Fear and Reward-Seeking Behaviors

Abraham

Neve

Lattal

2016

Neuropsychopharmacol

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Dopamine is critical for many processes that drive learning and memory, including motivation, prediction error, incentive salience, memory consolidation, and response output. Theories of dopamine's function in these processes have, for the most part, been developed from behavioral approaches that examine learning mechanisms in appetitive tasks. A parallel and growing literature indicates that dopamine signaling is involved in consolidation of memories into stable representations in aversive tasks such as fear conditioning. Relatively little is known about how dopamine may modulate memories that form during extinction, when organisms learn that the relation between previously associated events is severed. We investigated whether fear and reward extinction share common mechanisms that could be enhanced with dopamine D1/5 receptor activation. Pharmacological activation of dopamine D1/5 receptors (with SKF 81297) enhanced extinction of both cued and contextual fear. These effects also occurred in the extinction of cocaine-induced conditioned place preference, suggesting that the observed effects on extinction were not specific to a particular type of procedure (aversive or appetitive). A cAMP/PKA biased D1 agonist (SKF 83959) did not affect fear extinction, whereas a broadly efficacious D1 agonist (SKF 83822) promoted fear extinction. Together, these findings show that dopamine D1/5 receptor activation is a target for the enhancement of fear or reward extinction.

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Activation of dopamine neurons is critical for aversive conditioning and prevention of generalized anxiety

Cited by 226 publications

References 36 publications

Increased Dopamine Receptor Activity in the Nucleus Accumbens Shell Ameliorates Anxiety during Drug Withdrawal

Increased Dopamine Receptor Activity in the Nucleus Accumbens Shell Ameliorates Anxiety during Drug Withdrawal

Glycine Transporter-1 Inhibition Promotes Striatal Axon Sprouting via NMDA Receptors in Dopamine Neurons

Activation of D1/5 Dopamine Receptors: A Common Mechanism for Enhancing Extinction of Fear and Reward-Seeking Behaviors

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