Nucleus accumbens AGS3 expression drives ethanol seeking through Gβγ

Bowers, M. Scott; Hopf, F. Woodward; Chou, Jonathan; Guillory, Anitra M.; Chang, Shao-Ju; Janak, Patricia H.; Bonci, Antonello; Diamond, Ivan

doi:10.1073/pnas.0706999105

Cited by 77 publications

(102 citation statements)

References 59 publications

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“…Further, the nucleus accumbens also contributes to increased alcohol seeking that is observed during abstinence, i.e., incubation of alcohol seeking. For example, Bowers et al (2008) showed a region-specific increase in the expression of a novel G-protein modulator AGS3 in the nucleus accumbens core during abstinence from operant ethanol self-administration. Local knockdown of AGS3 reduced the increase in alcohol seeking, normally seen in abstinence, to pre-abstinence levels (Bowers et al, 2008).…”

Section: Alcoholmentioning

confidence: 99%

Compulsive drug use and its neural substrates

Lesscher

Vanderschuren²

2012

Reviews in the Neurosciences

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Drug addiction is a chronic relapsing brain disease, characterized by compulsive drug use. Despite the fact that drug addiction affects millions of people worldwide, treatments for this disorder are limited in number and efficacy. In our opinion, understanding the neural underpinnings of drug addiction would open new avenues for the development of innovative treatments for this disorder. Based on an awareness that drug use and drug reward do not equal drug addiction, there has been increasing interest in developing animal models of addiction that mimick the loss of control over drug use more closely than existing models aimed at studying drug reward. The present review provides an overview of animal studies of compulsive drug use and the neural mechanisms involved. First, the employed models are summarized, with a particular emphasis on models of escalation of drug use and resistance to punishment. Next, we discuss mechanisms within the (ventral and dorsal) striatum and (central) amygdala that have recently been implicated in the compulsive seeking and taking of alcohol and cocaine. The studies discussed here provide a promising line of research that will advance our knowledge of the neural circuits involved in the self-destructive behavior that characterizes drug addiction.

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Section: Alcoholmentioning

confidence: 99%

Compulsive drug use and its neural substrates

Lesscher

Vanderschuren²

2012

Reviews in the Neurosciences

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“…This finding contrasts with reports of decreased mGluR 2/3 functional activity following chronic involuntary cocaine exposure (Ghasemzadeh et al, 2009;Xi et al, 2002), and decreased [ 35 S]GTPgS binding in the CeA of rats with a history of short-access cocaine self-administration typically not associated with the development of physical dependence (Hao et al, 2010). The molecule AGS3, a modulator of G-protein signaling that sequesters Gia and therefore inhibits functional coupling of mGluR 2/3 , has been shown to be upregulated in the PFC and NAc of rats with a history of several weeks of home-cage ethanol self-administration (Bowers et al, 2008). The present data revealed no dependence-associated effects in [ 35 S]GTPgS binding of the PFC or NAc tissue samples, indicating that the induction of ethanol dependence by vapor inhalation produced physiological changes distinct from those obtained in models of home-cage consumption that do not induce physical dependence and overt signs of withdrawal.…”

Section: Effects Of Ly379268 On Locomotor Activity and Responding Maimentioning

confidence: 99%

Enhanced Sensitivity to Attenuation of Conditioned Reinstatement by the mGluR2/3 Agonist LY379268 and Increased Functional Activity of mGluR2/3 in Rats with a History of Ethanol Dependence

Kufahl

Martin‐Fardon

Weiss

2011

Neuropsychopharmacol

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Recent findings implicate group II metabotropic glutamate receptors (mGluR 2/3 ) in the reinforcing and dependence-inducing actions of ethanol and identify these receptors as treatment targets for alcoholism. Here, we investigated the effects of mGLuR 2/3 activation on conditioned reinstatement in rats with different ethanol-dependence histories and examined dependence-associated changes in the functional activity of mGluR 2/3 . Following ethanol self-administration training and conditioning procedures, rats were made ethanol dependent, using ethanol vapor inhalation, under three conditions: a single intoxication and withdrawal episode (SW), repeated cycles of intoxication and withdrawal (RW), or no intoxication (CTRL). At 1 week after removal from ethanol vapor, self-administration resumed until stable baseline performance was reached, followed by extinction of operant responding and reinstatement tests. Post-withdrawal self-administration was increased in the RW group, but all groups showed conditioned reinstatement. The mGluR 2/3 agonist LY379268 dose -dependently reduced reinstatement in all groups, but was more effective at low doses in the SW and RW groups. The highest dose of LY379268 tested reduced spontaneous locomotor activity and operant responding maintained by a non-drug reinforcer, without differences among groups. The heightened sensitivity to the effects of LY379268 in rats with an ethanol-dependence history was therefore specific to behavior motivated by ethanol-related stimuli. Both the SW and RW groups showed elevated [35 S]GTPgS binding in the central nucleus of the amygdala (CeA) and bed nucleus of stria terminalis (BNST), relative to the CTRL group. The findings implicate changes in mGluR 2/3 functional activity as a factor in ethanol dependence and support treatment target potential of mGlu 2/3 receptors for craving and relapse prevention.

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“…As per procedures adapted from prior reports (Bowers et al, 2008), rats were water deprived during shaping that began with two, 15 h, fixed ratio one sessions (FR1) for 10% sucrose (w/v) in 20% EtOH (v/v). After these sessions, 1-2 h home cage water was allowed.…”

Section: Operant Etoh Self-administrationmentioning

confidence: 99%

“…Therefore, we hypothesized that NAcore astrocytes contribute to the motivation to self-administer EtOH after 3 weeks abstinence. To begin evaluating this hypothesis, ethanol selfadministration by formerly abstinent rats was provoked by a compound cue that was previously associated with EtOH availability (Bowers et al, 2008). The cue mimics EtOH-associated olfactory, auditory, and visual stimuli that contribute to the 'first drink' phenomenon.…”

Section: Astrocyte Densitymentioning

confidence: 99%

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Rat Nucleus Accumbens Core Astrocytes Modulate Reward and the Motivation to Self-Administer Ethanol after Abstinence

Bull

Freitas

Zou

et al. 2014

Neuropsychopharmacol

124

106

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Our understanding of the active role that astrocytes play in modulating neuronal function and behavior is rapidly expanding, but little is known about the role that astrocytes may play in drug-seeking behavior for commonly abused substances. Given that the nucleus accumbens is critically involved in substance abuse and motivation, we sought to determine whether nucleus accumbens astrocytes influence the motivation to self-administer ethanol following abstinence. We found that the packing density of astrocytes that were expressing glial fibrillary acidic protein increased in the nucleus accumbens core (NAcore) during abstinence from EtOH selfadministration. No change was observed in the nucleus accumbens shell. This increased NAcore astrocyte density positively correlated with the motivation for ethanol. Astrocytes can communicate with one another and influence neuronal activity through gap-junction hemichannels. Because of this, the effect of blocking gap-junction hemichannels on the motivation for ethanol was examined. The motivation to self-administer ethanol after 3 weeks abstinence was increased following microinjection of gap-junction hemichannel blockers into the NAcore at doses that block both neuronal and astrocytic channels. In contrast, no effect was observed following microinjection of doses that are not thought to block astrocytic channels or following microinjection of either dose into the nucleus accumbens shell. Additionally, the motivation for sucrose after 3 weeks abstinence was unaffected by NAcore gap-junction hemichannel blockers. Next, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) were selectively expressed in NAcore astrocytes to test the effect of astrocyte stimulation. DREADD activation increased cytosolic calcium in primary astrocytes, facilitated responding for rewarding brain stimulation, and reduced the motivation for ethanol after 3 weeks abstinence. This is the first work to modulate drug-seeking behavior with astrocyte-specific DREADDs. Taken together, our findings demonstrate that NAcore astrocytes can shape the motivation to self-administer ethanol; suggesting that the development of ligands which selectively stimulate astrocytes may be a successful strategy to abate ethanol-seeking behavior.

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Nucleus accumbens AGS3 expression drives ethanol seeking through Gβγ

Cited by 77 publications

References 59 publications

Compulsive drug use and its neural substrates

Compulsive drug use and its neural substrates

Enhanced Sensitivity to Attenuation of Conditioned Reinstatement by the mGluR2/3 Agonist LY379268 and Increased Functional Activity of mGluR2/3 in Rats with a History of Ethanol Dependence

Rat Nucleus Accumbens Core Astrocytes Modulate Reward and the Motivation to Self-Administer Ethanol after Abstinence

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