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

Radke, Anna K.; Gewirtz, Jonathan C.

doi:10.1038/npp.2012.97

Cited by 50 publications

(30 citation statements)

References 107 publications

(149 reference statements)

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“…Therefore, reduced EPN-to-LHb GABAergic transmission during withdrawal may increase the indirect inhibitory control of the EPN over dopamine neurons. Indeed, decreased activity of VTA dopamine neurons drives negative states 27,28 , and reduced dopamine signaling in the ventral striatum is associated with drug withdrawal symptoms and stress-induced relapse 29,30 .…”

Section: Discussionmentioning

confidence: 99%

Shifted pallidal co-release of GABA and glutamate in habenula drives cocaine withdrawal and relapse

Meye¹,

Soiza-Reilly²,

Smit³

et al. 2016

Nat Neurosci

134

151

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Cocaine withdrawal produces aversive states and vulnerability to relapse, hallmarks of addiction. The lateral habenula (LHb) encodes negative stimuli and contributes to aversive withdrawal symptoms. However, it remains unclear which inputs to LHb promote this and what the consequences are for relapse susceptibility. We report, using rabies-based retrolabeling and optogenetic mapping, that the entopeduncular nucleus (EPN, the mouse equivalent of the globus pallidus interna) projects to an LHb neuronal subset innervating aversion-encoding midbrain GABA neurons. EPN-to-LHb excitatory signaling is limited by GABAergic cotransmission. This inhibitory component decreases during cocaine withdrawal as a result of reduced presynaptic vesicular GABA transporter (VGAT). This shifts the EPN-to-LHb GABA/glutamate balance, disinhibiting EPN-driven LHb activity. Selective virally mediated VGAT overexpression at EPN-to-LHb terminals during withdrawal normalizes GABAergic neurotransmission. This intervention rescues cocaine-evoked aversive states and prevents stress-induced reinstatement, used to model relapse. This identifies diminished inhibitory transmission at EPN-to-LHb GABA/glutamate synapses as a mechanism contributing to the relapsing feature of addictive behavior.

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Section: Discussionmentioning

confidence: 99%

Shifted pallidal co-release of GABA and glutamate in habenula drives cocaine withdrawal and relapse

Meye¹,

Soiza-Reilly²,

Smit³

et al. 2016

Nat Neurosci

134

151

View full text Add to dashboard Cite

show abstract

“…A low-dopamine state of an animal is often correlated with negative affective signs such as anxiety and anhedonia (Radke and Gewirtz, 2012). The intensity of these symptoms increases with repeated drug exposure, eventually leading to dependence and a shift in hedonic set point to a more negative state (Koob and Le Moal, 1997; Koob, 2013).…”

Section: Discussionmentioning

confidence: 99%

Switch from excitatory to inhibitory actions of ethanol on dopamine levels after chronic exposure: Role of kappa opioid receptors

et al. 2016

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Acute ethanol exposure is known to stimulate the dopamine system; however, chronic exposure has been shown to downregulate the dopamine system. In rodents, chronic intermittent exposure (CIE) to ethanol also increases negative affect during withdrawal, such as, increases in anxiety- and depressive-like behavior. Moreover, CIE exposure results in increased ethanol drinking and preference during withdrawal. Previous literature documents reductions in CIE-induced anxiety-, depressive-like behaviors and ethanol intake in response to kappa opioid receptor (KOR) blockade. KORs are located on presynaptic dopamine terminals in the nucleus accumbens (NAc) and inhibit release, an effect which has been linked to negative affective behaviors. Previous reports show an upregulation in KOR function following extended CIE exposure; however it is not clear whether there is a direct link between KOR upregulation and dopamine downregulation during withdrawal from CIE. This study aimed to examine the effects of KOR modulation on dopamine responses to ethanol of behaving mice exposed to air or ethanol vapor in a repeated intermittent pattern. First, we showed that KORs have a greater response to an agonist after moderate CIE compared to air exposed mice using ex vivo fast scan cyclic voltammetry. Second, using in vivo microdialysis, we showed that, in contrast to the expected increase in extracellular levels of dopamine following an acute ethanol challenge in air exposed mice, CIE exposed mice exhibited a robust decrease in dopamine levels. Third, we showed that blockade of KORs reversed the aberrant inhibitory dopamine response to ethanol in CIE exposed mice while not affecting the air exposed mice demonstrating that inhibition of KORs “rescued” dopamine responses in CIE exposed mice. Taken together, these findings indicate that augmentation of dynorphin/KOR system activity drives the reduction in stimulated (electrical and ethanol) dopamine release in the NAc. Thus, blockade of KORs is a promising avenue for developing pharmacotherapies for alcoholism.

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“…Increased rates of acquisition (Carroll et al 2002), escalation, and reinstatement (Perry et al 2006) of cocaine self-administration in the HiS rats could be explained by a number of hypotheses, including increased sensitivity to reward (rats consume more drug because it is more rewarding), decreased sensitivity to reward (rats consume more drug to compensate for a reward deficit), a loss of control in reward seeking, or differences in the severity of withdrawal. Considering recent evidence that reward- and withdrawal-related behaviors require overlapping brain mechanisms (Radke et al 2011, Radke and Gewirtz 2012), more than one of these hypotheses may be true. While the current results cannot speak to whether HiS and LoS rats differ in reward-related mechanisms, they do suggest decreased withdrawal severity in the HiS line.…”

Section: Discussionmentioning

confidence: 99%

Cocaine withdrawal in rats selectively bred for low (LoS) versus high (HiS) saccharin intake

Radke

Zlebnik

Carroll

2015

Pharmacology Biochemistry and Behavior

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Cocaine use results in anhedonia during withdrawal, but it is not clear how this emotional state interacts with an individual's vulnerability for addiction. Rats selectively bred for high (HiS) or low (LoS) saccharin intake are a well-established model of drug abuse vulnerability, with HiS rats being more likely to consume sweets and drugs of abuse such as cocaine and heroin (Carroll et al. 2002) than LoS rats. This study examined whether the motivational consequences of cocaine withdrawal are differentially expressed in HiS and LoS rats. HiS and LoS rats were trained to respond for a sucrose reward on a progressive ratio (PR) schedule of reinforcement and breakpoints were measured during and after chronic, continuous exposure to cocaine (30 mg/kg/day). Cocaine, but not saline, treatment resulted in lower breakpoints for sucrose during withdrawal in LoS rats only. These results suggest anhedonia during withdrawal is more pronounced in the less vulnerable LoS rats. Fewer motivational deficits during withdrawal may contribute to drug vulnerability in the HiS line.

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

Cited by 50 publications

References 107 publications

Shifted pallidal co-release of GABA and glutamate in habenula drives cocaine withdrawal and relapse

Shifted pallidal co-release of GABA and glutamate in habenula drives cocaine withdrawal and relapse

Switch from excitatory to inhibitory actions of ethanol on dopamine levels after chronic exposure: Role of kappa opioid receptors

Cocaine withdrawal in rats selectively bred for low (LoS) versus high (HiS) saccharin intake

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