Interference with AMPA receptor endocytosis: effects on behavioural and neurochemical correlates of amphetamine sensitization in male rats

Choi, Fiona; Ahn, Soyon; Wang, Yu Tian; Phillips, Anthony G.

doi:10.1503/jpn.120257

Cited by 9 publications

(9 citation statements)

References 55 publications

(38 reference statements)

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“…In the current study, we provided evidence suggesting that this form of long-term depression involves clathrin-mediated endocytosis of AMPA receptors from postsynaptic membranes. Our observation that the GluR2 3Y peptide interferes with 1-Hz LTD expression in the NAc shell aligns with previous studies showing a similar inhibition of NMDAR-dependent low-frequency LTD by the same peptide (Brebner et al, 2005; Choi et al, 2013). Thus, we believe the underlying mechanism of 1Hz-LTD in the NAc remained consistent even as we transitioned to utilizing a different mouse strain throughout our investigation into the cell type-specific nature of this form of long-term synaptic plasticity.…”

Section: Discussionsupporting

confidence: 92%

“…Furthermore, we confirmed a bimodal distribution of the average “post-pairing” EPSC amplitudes (minutes 40–50 of electrophysiological recording) upon post-hoc analysis of those data from C57BL/6J mice (Figure 1B). To further characterize 1Hz-LTD of EPSCs in MSNs from the NAc shell of C57BL/6J mice, we obtained a peptide derived from the C-terminus of the AMPA receptor GluR2 subunit (denoted GluR2 3Y ) that inhibits clathrin-mediated AMPA receptor endocytosis and NMDAR-dependent LTD in the NAc (Brebner et al, 2005; Choi et al, 2013). Following pre-treatment of slices (45–120 minutes) with the active form of this “interference” peptide (10 μM), we did not observe 1-Hz LTD in NAc shell MSNs (108.68 ± 7.75% of baseline; n=5; student’s t test: p > 0.05 vs baseline).…”

Section: Resultsmentioning

confidence: 99%

“…The scrambled peptide, Tat-GluR2, comprised the same 9 amino acids in random sequence (VYKYGGYNE) and served as a control. These peptides have been documented to modulate GluR2 internalization and behavioral sensitization to psychostimulants previously (Brebner et al, 2005; Choi et al, 2013). The concentration selected (10 μM) was determined by the Wang lab in preliminary studies to maximally prevent AMPA internalization.…”

Section: Methodsmentioning

confidence: 99%

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Cell type-specific synaptic encoding of ethanol exposure in the nucleus accumbens shell

2014

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Synaptic alterations in the nucleus accumbens (NAc) are crucial for the aberrant reward-associated learning that forms the foundation of drug dependence. Altered glutamatergic synaptic plasticity, in particular, is thought to be a vital component of the neurobiological underpinnings of addictive behavior. The development of bacterial artificial chromosome-eGFP (enhanced green fluorescent protein) transgenic mice that express eGFP driven by endogenous D1 dopamine receptor (D1R) promoters has now allowed investigation of the cell type-specific synaptic modifications in the NAc in response to drugs of abuse. In this study, we used whole-cell ex vivo slice electrophysiology in Drd1-eGFP mice to investigate cell type-specific alterations in NAc synaptic plasticity following ethanol exposure. Electrophysiological recordings were made from eGFP-expressing medium spiny neurons (D1+ MSNs) and non-eGFP expressing (putative D2 receptor-expressing) (D1− MSNs) from the shell subregion of the NAc. We observed low frequency-induced long-term depression (1Hz-LTD) of α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA)-mediated excitatory postsynaptic currents (EPSCs) solely in D1+ MSNs. However, 24 hours following 4 consecutive days of in vivo chronic intermittent ethanol (CIE) vapor exposure, 1Hz-LTD was conversely observed only in D1− MSNs, and now absent in D1+ MSNs. Complete recovery of the baseline plasticity phenotype in both cell types required a full 2 weeks of withdrawal from CIE vapor exposure. Thus, we observed a cell type-specificity of synaptic plasticity in the NAc shell, as well as, a gradual recovery of the pre-ethanol exposure plasticity state following extended withdrawal. These changes highlight the adaptability of NAc shell MSNs to the effects of ethanol exposure and may represent critical neuroadaptations underlying the development of ethanol dependence.

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Cell type-specific synaptic encoding of ethanol exposure in the nucleus accumbens shell

2014

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“…These changes in excitatory synaptic strength are reflective of altered synaptic plasticity mechanisms. The expression of behavioural sensitisation to amphetamine is blocked by the administration of a GluA2 3Y peptide that acts to inhibit AMPAR endocytosis and synaptic plasticity (Brebner et al, 2005, Choi et al, 2014a.…”

Section: Psychostimulant Sensitisation and Glutamate Receptorsmentioning

confidence: 99%

“…Intra-cerebral microinjection of pharmacological antagonists or 'interference' peptides would allow us to determine whether these proteins and subsequent signalling pathways are contributing to synaptic plasticity mechanisms involved in MK-801-induced sensitisation. To determine whether the changes in excitatory synaptic strength are contributing to the expression of MK-801 sensitisation, techniques previously utilised in psychostimulant sensitisation research could be employed, such as optogenetic reversal (Pascoli et al, 2012) or administration of the GluA2 3Y peptide that acts to inhibit AMPAR endocytosis and synaptic plasticity (Brebner et al, 2005, Choi et al, 2014a.…”

Section: Future Directionsmentioning

confidence: 99%

Neural mechanisms of MK-801 induced sensitisation

Lefevre¹

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Behavioural sensitisation describes the progressive and enduring augmentation of a drug-induced response that develops with repeated exposure. Sensitisation is a putative mechanism in the pathophysiology of drug addiction and neuropsychiatric disorders such as schizophrenia. In rodents, drug-induced behavioural sensitisation has been described for several different drug classes. The neural mechanisms underpinning behavioural sensitisation to most drugs of abuse share similarities, such as NMDA receptor (NMDAR) activation, although not all use the same mechanism of action.The NMDAR antagonist MK-801 can inhibit sensitisation to other drugs of abuse. However, MK-801 also produces behavioural sensitisation to its own hyperlocomotor inducing effects, suggesting that MK-801 sensitisation has a distinctive mechanism of action.The overall aim of my thesis was to investigate the neural mechanisms of behavioural sensitisation to MK-801 in rats. First, I established the effect of drug dose, environmental context, length of withdrawal period and rat strain on the ability of repeated intermittent MK-801 administration to induce behavioural sensitisation. MK-801-induced sensitisation was shown to be dependent on the dose of MK-801, length of withdrawal period and the rat strain. Sensitisation however was not modulated by the environmental context in which MK-801 administration occurred.In the established sensitisation paradigm, a functional and molecular analysis of the nucleus accumbens of rats sensitised to MK-801 was undertaken. Ex vivo slice electrophysiology revealed a decrease in the excitatory synaptic strength in the nucleus accumbens of rats sensitised to MK-801. An LC-MS/MS proteomics approach demonstrated that proteins altered by MK-801 sensitisationwere predominately related to functions including calcium signalling and mitochondrial dysfunction.I also probed the role of corticosterone signalling using a pharmacological and physiological approach. Pharmacological antagonism of the glucocorticoid receptor with RU486 was found to facilitate behavioural sensitisation to MK-801, potentially through its augmenting effect on MK-801 induced corticosterone levels. Following on from this experiment, I showed that pharmacological antagonism of the stress-related kappa opioid receptor with nor-Binaltorphimine did not have the same effect as RU486. Lastly, I also used LY354740, a pharmacological agonist of the metabotropic glutamate receptors, as a preliminary investigation into the role of glutamatergic transmission. Stimulation of these receptors however was without effect on MK-801 sensitisation.ii Using a range of approaches I have elucidated some of the neural mechanisms and adaptations associated with behavioural sensitisation to MK-801. These results predominately show that sensitisation to MK-801 differs from the mechanism of sensitisation to other drugs of abuse. This model could prove useful for studying the role of NMDARs in the pathophysiology of drug addiction and schizophrenia.iii

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Do Alcohol-Related AMPA-Type Glutamate Receptor Adaptations Promote Intake?

Hopf

Mangieri

2018

The Neuropharmacology of Alcohol

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Ionotropic glutamate receptors (AMPA, NMDA, and kainate receptors) play a central role in excitatory glutamatergic signaling throughout the brain. As a result, functional changes, especially long-lasting forms of plasticity, have the potential to profoundly alter neuronal function and the expression of adaptive and pathological behaviors. Thus, alcohol-related adaptations in ionotropic glutamate receptors are of great interest, since they could promote excessive alcohol consumption, even after long-term abstinence. Alcohol- and drug-related adaptations in NMDARs have been recently reviewed, while less is known about kainate receptor adaptations. Thus, we focus here on functional changes in AMPARs, tetramers composed of GluA1-4 subunits. Long-lasting increases or decreases in AMPAR function, the so-called long-term potentiation or depression, have widely been considered to contribute to normal and pathological memory states. In addition, a great deal has been learned about the acute regulation of AMPARs by signaling pathways, scaffolding and auxiliary proteins, intracellular trafficking, and other mechanisms. One important common adaptation is a shift in AMPAR subunit composition from GluA2-containing, calcium-impermeable AMPARs (CIARs) to GluA2-lacking, calcium-permeable AMPARs (CPARs), which is observed under a broad range of conditions including intoxicant exposure or intake, stress, novelty, food deprivation, and ischemia. This shift has the potential to facilitate AMPAR currents, since CPARs have much greater single-channel currents than CIARs, as well as faster AMPAR activation kinetics (although with faster inactivation) and calcium-related activity. Many tools have been developed to interrogate particular aspects of AMPAR signaling, including compounds that selectively inhibit CPARs, raising exciting translational possibilities. In addition, recent studies have used transgenic animals and/or optogenetics to identify AMPAR adaptations in particular cell types and glutamatergic projections, which will provide critical information about the specific circuits that CPARs act within. Also, less is known about the specific nature of alcohol-related AMPAR adaptations, and thus we use other examples that illustrate more fully how particular AMPAR changes might influence intoxicant-related behavior. Thus, by identifying alcohol-related AMPAR adaptations, the specific molecular events that underlie them, and the cells and projections in which they occur, we hope to better inform the development of new therapeutic interventions for addiction.

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Interference with AMPA receptor endocytosis: effects on behavioural and neurochemical correlates of amphetamine sensitization in male rats

Cited by 9 publications

References 55 publications

Cell type-specific synaptic encoding of ethanol exposure in the nucleus accumbens shell

Cell type-specific synaptic encoding of ethanol exposure in the nucleus accumbens shell

Neural mechanisms of MK-801 induced sensitisation

Do Alcohol-Related AMPA-Type Glutamate Receptor Adaptations Promote Intake?

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