Calcium-permeable AMPA Receptors in the VTA and Nucleus Accumbens After Cocaine Exposure: When, How, and Why?

Overview

Journal Front Mol Neurosci

Specialty Molecular Biology

Date 2012 Jul 4

PMID 22754497

Citations 137

Authors

Marina E Wolf

Kuei Y Tseng

Affiliations

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Abstract

In animal models of drug addiction, cocaine exposure has been shown to increase levels of calcium-permeable AMPA receptors (CP-AMPARs) in two brain regions that are critical for motivation and reward-the ventral tegmental area (VTA) and the nucleus accumbens (NAc). This review compares CP-AMPAR plasticity in the two brain regions and addresses its functional significance. In VTA dopamine neurons, cocaine exposure results in synaptic insertion of high conductance CP-AMPARs in exchange for lower conductance calcium-impermeable AMPARs (CI-AMPARs). This plasticity is rapid in onset (hours), GluA2-dependent, and can be observed with a single cocaine injection. Whereas it is short-lived after experimenter-administered cocaine, it persists for months after cocaine self-administration. In addition to strengthening synapses and altering Ca(2+) signaling, CP-AMPAR insertion alters subsequent induction of plasticity at VTA synapses. However, CP-AMPAR insertion is unlikely to mediate the increased DA cell activity that occurs during early withdrawal from cocaine exposure. Metabotropic glutamate receptor 1 (mGluR1) exerts a negative influence on CP-AMPAR accumulation in the VTA. Acutely, mGluR1 stimulation elicits a form of LTD resulting from CP-AMPAR removal and CI-AMPAR insertion. In medium spiny neurons (MSNs) of the NAc, extended access cocaine self-administration is required to increase CP-AMPAR levels. This is first detected after approximately a month of withdrawal and then persists. Once present in NAc synapses, CP-AMPARs mediate the expression of incubation of cue-induced cocaine craving. The mechanism of their accumulation may be GluA1-dependent, which differs from that observed in the VTA. However, similar to VTA, mGluR1 stimulation removes CP-AMPARs from MSN synapses. Loss of mGluR1 tone during cocaine withdrawal may contribute to CP-AMPAR accumulation in the NAc. Thus, results in both brain regions point to the possibility of using positive modulators of mGluR1 as treatments for cocaine addiction.

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References

Post R, Weiss S, Pert A . The role of context and conditioning in behavioral sensitization to cocaine. Psychopharmacol Bull. 1987; 23(3):425-9. View

Bellone C, Mameli M, Luscher C . In utero exposure to cocaine delays postnatal synaptic maturation of glutamatergic transmission in the VTA. Nat Neurosci. 2011; 14(11):1439-46. DOI: 10.1038/nn.2930. View

Ferrario C, Goussakov I, Stutzmann G, Wolf M . Withdrawal from cocaine self-administration alters NMDA receptor-mediated Ca2+ entry in nucleus accumbens dendritic spines. PLoS One. 2012; 7(8):e40898. PMC: 3411692. DOI: 10.1371/journal.pone.0040898. View

Anderson S, Famous K, Sadri-Vakili G, Kumaresan V, Schmidt H, Bass C . CaMKII: a biochemical bridge linking accumbens dopamine and glutamate systems in cocaine seeking. Nat Neurosci. 2008; 11(3):344-53. DOI: 10.1038/nn2054. View

Lu W, Monteggia L, Wolf M . Repeated administration of amphetamine or cocaine does not alter AMPA receptor subunit expression in the rat midbrain. Neuropsychopharmacology. 2001; 26(1):1-13. DOI: 10.1016/S0893-133X(01)00272-X. View

Schenk S, Snow S . Sensitization to cocaine's motor activating properties produced by electrical kindling of the medial prefrontal cortex but not of the hippocampus. Brain Res. 1994; 659(1-2):17-22. DOI: 10.1016/0006-8993(94)90858-3. View

Henry D, Greene M, White F . Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: repeated administration. J Pharmacol Exp Ther. 1989; 251(3):833-9. View

Finch D . Neurophysiology of converging synaptic inputs from the rat prefrontal cortex, amygdala, midline thalamus, and hippocampal formation onto single neurons of the caudate/putamen and nucleus accumbens. Hippocampus. 1996; 6(5):495-512. DOI: 10.1002/(SICI)1098-1063(1996)6:5<495::AID-HIPO3>3.0.CO;2-I. View

Sun X, Wolf M . Nucleus accumbens neurons exhibit synaptic scaling that is occluded by repeated dopamine pre-exposure. Eur J Neurosci. 2009; 30(4):539-50. DOI: 10.1111/j.1460-9568.2009.06852.x. View

10.

Kerchner G, Nicoll R . Silent synapses and the emergence of a postsynaptic mechanism for LTP. Nat Rev Neurosci. 2008; 9(11):813-25. PMC: 2819160. DOI: 10.1038/nrn2501. View

11.

Pascoli V, Turiault M, Luscher C . Reversal of cocaine-evoked synaptic potentiation resets drug-induced adaptive behaviour. Nature. 2011; 481(7379):71-5. DOI: 10.1038/nature10709. View

12.

Brown T, Lee B, Mu P, Ferguson D, Dietz D, Ohnishi Y . A silent synapse-based mechanism for cocaine-induced locomotor sensitization. J Neurosci. 2011; 31(22):8163-74. PMC: 3286116. DOI: 10.1523/JNEUROSCI.0016-11.2011. View

13.

Mameli M, Halbout B, Creton C, Engblom D, Parkitna J, Spanagel R . Cocaine-evoked synaptic plasticity: persistence in the VTA triggers adaptations in the NAc. Nat Neurosci. 2009; 12(8):1036-41. DOI: 10.1038/nn.2367. View

14.

Bockaert J, Perroy J, Becamel C, Marin P, Fagni L . GPCR interacting proteins (GIPs) in the nervous system: Roles in physiology and pathologies. Annu Rev Pharmacol Toxicol. 2010; 50:89-109. DOI: 10.1146/annurev.pharmtox.010909.105705. View

15.

Meredith G, Baldo B, Andrezjewski M, Kelley A . The structural basis for mapping behavior onto the ventral striatum and its subdivisions. Brain Struct Funct. 2008; 213(1-2):17-27. PMC: 2556127. DOI: 10.1007/s00429-008-0175-3. View

16.

Brown M, Bellone C, Mameli M, Labouebe G, Bocklisch C, Balland B . Drug-driven AMPA receptor redistribution mimicked by selective dopamine neuron stimulation. PLoS One. 2011; 5(12):e15870. PMC: 3013137. DOI: 10.1371/journal.pone.0015870. View

17.

Ho S, Chen C, Liu T, Chang H, Liou J . Protein kinase mζ is necessary for cocaine-induced synaptic potentiation in the ventral tegmental area. Biol Psychiatry. 2011; 71(8):706-13. DOI: 10.1016/j.biopsych.2011.10.031. View

18.

Goto Y, Grace A . Dopamine-dependent interactions between limbic and prefrontal cortical plasticity in the nucleus accumbens: disruption by cocaine sensitization. Neuron. 2005; 47(2):255-66. DOI: 10.1016/j.neuron.2005.06.017. View

19.

Liu S, Zukin R . Ca2+-permeable AMPA receptors in synaptic plasticity and neuronal death. Trends Neurosci. 2007; 30(3):126-34. DOI: 10.1016/j.tins.2007.01.006. View

20.

Olive M . Metabotropic glutamate receptor ligands as potential therapeutics for addiction. Curr Drug Abuse Rev. 2009; 2(1):83-98. PMC: 2717506. DOI: 10.2174/1874473710902010083. View