Editors' ChoiceNeuroscience

An Addictive Switch

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Sci. Signal.  26 Nov 2013:
Vol. 6, Issue 303, pp. ec290
DOI: 10.1126/scisignal.2004944

Cocaine is a highly addictive drug, and synaptic changes in the mesolimbic region of the brain are associated with a single exposure. In particular, there is a switch in the glutamate receptors such that after cocaine exposure there is an increase in the ratio of AMPA receptor–mediated to N-methyl-D-aspartate (NMDA) receptor–mediated excitation, which involves the insertion of calcium-permeable AMPA receptors into the synapse (see Huang et al.). NMDA receptors and AMPA receptors are both activated by glutamate, but their pharmacological and electrophysiological properties depend on their subunit composition. Yuan et al. compared the calcium signaling (by imaging) and electrophysiological properties of excitatory glutamatergic synapses onto dopaminergic neurons of the ventral tegmental area (VTA) of mice injected once with saline or cocaine. In slice preparations from cocaine-injected animals, specific pharmacological inhibitors indicated that NMDA-mediated excitatory postsynaptic potentials were selectively blocked by an inhibitor of receptors containing the GluN2B subunit but that this had no effect on calcium signaling, indicating that the calcium signal was predominantly mediated by the change in the AMPA receptor composition. Pharmacological evidence indicated that the NMDA receptors in the cocaine-injected mice contained the GluN2B subunit, whereas those of the saline-injected mice contained the GluN2A subunit. However, the lack of calcium permeability of the NMDA receptors suggested that an additional subunit switch had occurred such that the receptors contained the GluN3 subunit, which is normally only present during development. Indeed, slices from GluN3-knockout mice did not exhibit the change in either NMDA receptor or AMPA receptor properties in response to a single injection of cocaine. Addition of an agonist of the metabotropic glutamate receptor mGluR1 (a G protein–coupled receptor coupled to Gαq) to slice preparations from cocaine-injected mice reversed the cocaine-induced changes in electrophysiological and pharmacological properties in both the AMPA receptors and NMDA receptors. The reversal of the cocaine-induced changes in NMDA receptor electrophysiological properties by mGluR1 stimulation was blocked (i) by buffering intracellular calcium or depleting endoplasmic reticulum calcium stores, (ii) by inhibiting the inositol 3-phosphate (IP3) receptor or the interaction of scaffolding proteins Shank3 and Homer that mediate its recruitment to the synapse, or (iii) by inhibiting mTOR (mammalian target of rapamycin). Thus, cocaine induces receptor switching in both NMDA and AMPA receptors, and the AMPA receptor switch depends on the NDMA receptor switch. Furthermore, signaling through mGluR1 can reverse these changes through a pathway involving mTOR, suggesting that protein synthesis is necessary for full restoration of synaptic behavior.

T. Yuan, M. Mameli, E. C. O’ Connor, P. N. Dey, C. Verpelli, C. Sala, I. Perez-Otano, C. Lüscher, C. Bellone, Expression of cocaine-evoked synaptic plasticity by GluN3A-containing NMDA receptors. Neuron 80, 1025–1038 (2013). [PubMed]

Y. H. Huang, O. M. Schlüter, Y. Dong, An unusual suspect in cocaine addiction. Neuron 80, 835–836 (2013). [PubMed]