Mechanism and Time Course of Cocaine-Induced Long-Term Potentiation in the Ventral Tegmental Area

Abstract

Synaptic plasticity in the ventral tegmental area (VTA) has been implicated in the acquisition of a drug-dependent state. Even a single exposure to cocaine in naive animals is sufficient to trigger sustained changes on VTA glutamatergic synapses that resemble activitydependent long-term potentiation (LTP) in other brain regions. However, an insight into its time course and mechanisms of action is limited. Here, we show that cocaine acts locally within the VTA to induce an LTP-like enhancement of AMPA receptor-mediated transmission that is not detectable minutes after drug exposure but is fully expressed within 3 h. This cocaine-induced LTP appears to be mediated via dopamine D 5 receptor activation of NMDA receptors and to require protein synthesis. Increased levels of high-conductance GluR1-containing AMPA receptors at synapses are evident at 3 h after cocaine exposure. Furthermore, our data suggest that cocaineinduced LTP might share the same molecular substrates for expression with activity-dependent LTP induced in the VTA by a spiketiming-dependent (STD) protocol, because we observed that STD LTP is significantly reduced or not inducible in VTA neurons previously exposed to cocaine in vivo or in vitro.

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

“…48 Of particular importance to the present discussion is the finding that the prominence of GluA2-containing AMPARs in a drug-naive state is replaced by increased expression of the GluA2-lacking variant of AMPARs following exposure to a psychostimulant drug. 36,37 Together, these findings suggest that increased Ca 2+ permeability and conductance of GluA2-lacking AMPA receptors are essential factors in the sensitized response to a psychostimulant drug challenge. If this change in AMPAR subtype is a critical step in the modification of glutamatergic synapses on DA neurons in the VTA required for the encoding of associations between contextual stimuli and drug reward, it follows that interference with regulated endocytosis of GluA2-containing AMPARs by Tat-GluA2 3Y is an ideal tool to prevent the ascendency of drug-related memories.…”

Prenatal Stress Exposure Increases the Excitation of Dopamine Neurons in the Ventral Tegmental Area and Alters Their Reponses to Psychostimulants

“…For example, enhancing the expression in GluR2-lacking AMPARs in the VTA DA neurons leads to increased sensitivity to drug reward (Carlezon et al, 2000), whereas blocking glutamate receptors in the VTA during psychostimulant pre-exposure prevents enhanced psychostimulant self-administration (Suto et al, 2003). Exposure to psycho-stimulants, ethanol, or stress leads to augmented AMPA receptor function and greater glutamate synaptic strength in VTA DA neurons (Argilli et al, 2008;Bellone and Luscher, 2006;Borgland et al, 2004;Chen et al, 2008;Churchill et al, 1999;Fitzgerald et al, 1996;Ortiz et al, 1995;Saal et al, 2003;Stuber et al, 2008;Ungless et al, 2001;Zhang et al, 1997). Therefore, increased glutamate neurotransmission might contribute to PSE-induced overexcitation/depolarization block in VTA DA neurons and mediate the increased responding to psychostimulants and addiction risk.…”

GABA Site Agonist Gaboxadol Induces Addiction-Predicting Persistent Changes in Ventral Tegmental Area Dopamine Neurons But Is Not Rewarding in Mice or Baboons

“…Similar glutamatergic transmission occurs in VTA DA neurons during cue-reward learning when dopamine neurons start to respond to reward-predicting cues instead of to actual reward (Stuber et al, 2008). Underlying mechanisms of the plasticity include formation of new GluA2-subunit-lacking AMPA receptors at the synaptic sites (Ungless et al, 2001;Borgland et al, 2004;Argilli et al, 2008) and a reduction of NMDA receptor activity (Mameli et al, 2011).…”