Drug-Driven AMPA Receptor Redistribution Mimicked by Selective Dopamine Neuron Stimulation

Abstract

BackgroundAddictive drugs have in common that they cause surges in dopamine (DA) concentration in the mesolimbic reward system and elicit synaptic plasticity in DA neurons of the ventral tegmental area (VTA). Cocaine for example drives insertion of GluA2-lacking AMPA receptors (AMPARs) at glutamatergic synapes in DA neurons. However it remains elusive which molecular target of cocaine drives such AMPAR redistribution and whether other addictive drugs (morphine and nicotine) cause similar changes through their effects on the mesolimbic DA system.Methodology / Principal FindingsWe used in vitro electrophysiological techniques in wild-type and transgenic mice to observe the modulation of excitatory inputs onto DA neurons by addictive drugs. To observe AMPAR redistribution, post-embedding immunohistochemistry for GluA2 AMPAR subunit was combined with electron microscopy. We also used a double-floxed AAV virus expressing channelrhodopsin together with a DAT Cre mouse line to selectively express ChR2 in VTA DA neurons. We find that in mice where the effect of cocaine on the dopamine transporter (DAT) is specifically blocked, AMPAR redistribution was absent following administration of the drug. Furthermore, addictive drugs known to increase dopamine levels cause a similar AMPAR redistribution. Finally, activating DA VTA neurons optogenetically is sufficient to drive insertion of GluA2-lacking AMPARs, mimicking the changes observed after a single injection of morphine, nicotine or cocaine.Conclusions / SignificanceWe propose the mesolimbic dopamine system as a point of convergence at which addictive drugs can alter neural circuits. We also show that direct activation of DA neurons is sufficient to drive AMPAR redistribution, which may be a mechanism associated with early steps of non-substance related addictions.

Opiate-Induced Molecular and Cellular Plasticity of Ventral Tegmental Area and Locus Coeruleus Catecholamine Neurons

“…As with cocaine and other abused drugs, a single injection of morphine was found to increase the ratio of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)toN-methyl-D-asparticacid(NMDA) excitatory postsynaptic currents (EPSCs) 24 hours after administration, consistent with long-term potentiation (LTP) of glutamatergic synapses onto DA neurons (Saal et al 2003). Recently, it has also been reported that acute morphine induces AMPAR receptor (AMPAR) redistribution in VTA in a manner similar to cocaine, specifically an insertion of GluA2-lacking AMPARs (Brown et al 2010). Brown et al observed an increased rectification index and increased cytoplasmic GluA2 AMPAR in response to acute morphine, an effect that is recapitulated by direct stimulation of DA neurons in VTA using selective channelrhodposin 2 expression (Brown et al 2010), directly implicating DA activity/signaling within VTA to glutamatergic regulation.…”

Cocaine Evokes Projection-Specific Synaptic Plasticity of Lateral Habenula Neurons

“…This implies a potential role of DA signaling in triggering cocaine-evoked adaptations in the LHb (Kowski et al, 2009;Shen et al, 2012). In the VTA, cocaine triggers synaptic plasticity via its action on the DA transporter (Brown et al, 2010a). Therefore, cocaine may lead to a surge in DA in LHb, which may account for the cellular mechanism triggering the synaptic potentiation onto LHb neurons.…”

Interactions of Cathinone NPS with Human Transporters and Receptors in Transfected Cells

“…For example, SERT knockout mice exhibit greater rewarding effects of cocaine in the conditioned place preference paradigm compared with wildtype mice (Sora et al, 2001). More sophisticated genetic models with a triple amino acid mutation in the DAT gene showed that DAT inhibition is necessary for cocaine-induced conditioned place preference (O'Neill et al, 2014) and cocaine-evoked synaptic plasticity (Brown et al, 2010). Clinical studies that assess pharmacological interactions between a psychostimulant and receptor-selective antagonists or well-characterized transporter ligands shed light on specific molecular target mediating subjective effects and acute toxicity in humans.…”