Cocaine exposure reorganizes cell type– and input-specific connectivity in the nucleus accumbens

MacAskill, Andrew F.; Cassel, John M; Carter, Adam G.

doi:10.1038/nn.3783

Cited by 153 publications

(222 citation statements)

References 57 publications

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“…Repeated noncontingent cocaine exposure increases the strength of BLA inputs specifically to D1 MSNs in the medial NAshell (MacAskill et al, 2014). In line with this finding, withdrawal from cocaine self-administration leads to incubation and results in insertion of the GluA2-lacking AMPAR in the BLA-to-NAshell pathway .…”

Section: B Nucleus Accumbens Shellsupporting

confidence: 66%

“…In the latter case, the potentiation was specific to input onto D1 MSNs. In contrast, repeated noncontingent cocaine injection followed by a short (3-day) withdrawal resulted in depression of vHPC input onto D1 MSNs (MacAskill et al, 2014). This depression is mediated by presynaptic and postsynaptic mechanisms.…”

Section: A Long-term Synaptic Plasticitymentioning

confidence: 85%

“…Thus, recent research has focused on the synaptic changes occurring in the BLA-NAc synapses after drug exposure. MacAskill et al (2014) found that the number of BLA connections with NAc D1-MSNs, but not D2-MSNs, was increased after repeated noncontingent cocaine injections. In the incubation model, on the other hand, these synapses show postsynaptic changes .…”

Section: A Long-term Synaptic Plasticitymentioning

confidence: 89%

See 2 more Smart Citations

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

et al. 2016

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Section: B Nucleus Accumbens Shellsupporting

confidence: 66%

Section: A Long-term Synaptic Plasticitymentioning

confidence: 85%

Section: A Long-term Synaptic Plasticitymentioning

confidence: 89%

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The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

et al. 2016

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“…Strengthened synaptic transmission has been detected in multiple limbic projections to the NAc after withdrawal from cocaine self-administration, and the behavioral roles of these projection-specific adaptations has started to be explored (Britt et al, 2012;Lee et al, 2013;Suska et al, 2013;Ma et al, 2014;MacAskill et al, 2014;Pascoli et al, 2014). The present study reveals that NAc afferents from nontraditional limbic regions are also targeted by cocaine experience.…”

Section: Circuitry Consequencesmentioning

confidence: 62%

Cocaine-Induced Synaptic Alterations in Thalamus to Nucleus Accumbens Projection

Neumann

Wang

Yan

et al. 2016

Neuropsychopharmacol

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Exposure to cocaine induces addiction-associated behaviors partially through remodeling neurocircuits in the nucleus accumbens (NAc). The paraventricular nucleus of thalamus (PVT), which projects to the NAc monosynaptically, is activated by cocaine exposure and has been implicated in several cocaine-induced emotional and motivational states. Here we show that disrupting synaptic transmission of select PVT neurons with tetanus toxin activated via retrograde trans-synaptic transport of cre from NAc efferents decreased cocaine selfadministration in rats. This projection underwent complex adaptations after self-administration of cocaine (0.75 mg/kg/infusion; 2 h/d × 5 d, 1 d overnight training). Specifically, 1d after cocaine self-administration, we observed increased levels of AMPA receptor (AMPAR)-silent glutamatergic synapses in this projection, accompanied by a decreased ratio of AMPAR-to-NMDA receptor (NMDAR)-mediated EPSCs. Furthermore, the decay kinetics of NMDAR EPSCs was significantly prolonged, suggesting insertion of new GluN2B-containing NMDARs to PVT-to-NAc synapses. After 45-d withdrawal, silent synapses within this projection returned to the basal levels, accompanied by a return of the AMPAR/NMDAR ratio and NMDAR decay kinetics to the basal levels. In amygdala and infralimbic prefrontal cortical projections to the NAc, a portion of cocaine-generated silent synapses becomes unsilenced by recruiting calcium-permeable AMPARs (CP-AMPARs) after drug withdrawal. However, the sensitivity of PVT-to-NAc synapses to CP-AMPAR-selective antagonists was not changed after withdrawal, suggesting that CP-AMPAR trafficking is not involved in the evolution of cocaine-generated silent synapses within this projection. Meanwhile, the release probability of PVT-to-NAc synapses was increased after short-and long-term cocaine withdrawal. These results reveal complex and profound alterations at PVT-to-NAc synapses after cocaine exposure and withdrawal.

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“…In contrast, for the activated responses, DEP20 significantly modulated more pSPNs than other cell types [ 2 (3) ϭ 9.8, P ϭ 0.019; Table 4]. We note that these activated pSPNs could be either D1ϩ or D2ϩ expressing cells and that they might have different sensitivities to appetite suppressants (MacAskill et al 2014). The remaining 36 neurons were unaffected.…”

Section: Electrophysiologymentioning

confidence: 89%

D1 and D2 antagonists reverse the effects of appetite suppressants on weight loss, food intake, locomotion, and rebalance spiking inhibition in the rat NAc shell

Kalyanasundar

Pérez

Luna

et al. 2015

Journal of Neurophysiology

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R. D1 and D2 antagonists reverse the effects of appetite suppressants on weight loss, food intake, locomotion, and rebalance spiking inhibition in the rat NAc shell. J Neurophysiol 114: 585-607, 2015. First published May 13, 2015 doi:10.1152/jn.00012.2015.-Obesity is a worldwide health problem that has reached epidemic proportions. To ameliorate this problem, one approach is the use of appetite suppressants. These compounds are frequently amphetamine congeners such as diethylpropion (DEP), phentermine (PHEN), and bupropion (BUP), whose effects are mediated through serotonin, norepinephrine, and dopaminergic pathways. The nucleus accumbens (NAc) shell receives dopaminergic inputs and is involved in feeding and motor activity. However, little is known about how appetite suppressants modulate its activity. Therefore, we characterized behavioral and neuronal NAc shell responses to shortterm treatments of DEP, PHEN, and BUP. These compounds caused a transient decrease in weight and food intake while increasing locomotion, stereotypy, and insomnia. They evoked a large inhibitory imbalance in NAc shell spiking activity that correlated with the onset of locomotion and stereotypy. Analysis of the local field potentials (LFPs) showed that all three drugs modulated beta, theta, and delta oscillations. These oscillations do not reflect an aversive-malaise brain state, as ascertained from taste aversion experiments, but tracked both the initial decrease in weight and food intake and the subsequent tolerance to these drugs. Importantly, the appetite suppressant-induced weight loss and locomotion were markedly reduced by intragastric (and intra-NAc shell) infusions of dopamine antagonists SCH-23390 (D1 receptor) or raclopride (D2 receptor). Furthermore, both antagonists attenuated appetite suppressant-induced LFP oscillations and partially restored the imbalance in NAc shell activity. These data reveal that appetite suppressant-induced behavioral and neuronal activity recorded in the NAc shell depend, to various extents, on dopaminergic activation and thus point to an important role for D1/D2-like receptors (in the NAc shell) in the mechanism of action for these anorexic compounds.

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Cocaine exposure reorganizes cell type– and input-specific connectivity in the nucleus accumbens

Cited by 153 publications

References 57 publications

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

Cocaine-Induced Synaptic Alterations in Thalamus to Nucleus Accumbens Projection

D1 and D2 antagonists reverse the effects of appetite suppressants on weight loss, food intake, locomotion, and rebalance spiking inhibition in the rat NAc shell

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