Cocaine-Induced Changes of Synaptic Transmission in the Striatum are Modulated by Adenosine A2A Receptors and Involve the Tyrosine Phosphatase STEP

Abstract

The striatum is a brain area implicated in the pharmacological action of drugs of abuse. Adenosine A 2A receptors (A 2A Rs) are highly expressed in the striatum and mediate, at least in part, cocaine-induced psychomotor effects in vivo. Here we studied the synaptic mechanisms implicated in the pharmacological action of cocaine in the striatum and investigated the influence of A 2A Rs. We found that synaptic transmission was depressed in corticostriatal slices after perfusion with cocaine (10 mM). This effect was reduced by the A 2A R antagonist ZM241385 and almost abolished in striatal A 2A R-knockout mice (mice lacking A 2A Rs in striatal neurons, stA 2A RKO). The effect of cocaine on synaptic transmission was also prevented by the protein tyrosine phosphatases (PTPs) inhibitor sodium orthovanadate (Na 3 VO 4 ). In synaptosomes prepared from striatal slices, we found that the activity of striatal-enriched protein tyrosine phosphatase (STEP) was upregulated by cocaine, prevented by ZM241385, and absent in synaptosomes from stA 2A RKO. The role played by STEP in cocaine modulation of synaptic transmission was investigated in whole-cell voltage clamp recordings from medium spiny neurons of the striatum. We found that TAT-STEP, a peptide that renders STEP enzymatically inactive, prevented cocaine-induced reduction in AMPA-and NMDA-mediated excitatory post-synaptic currents, whereas the control peptide, TAT-myc, had no effect. These results demonstrate that striatal A 2A Rs modulate cocaine-induced synaptic depression in the striatum and highlight the potential role of PTPs and specifically STEP in the effects of cocaine.

Cocaine and Amphetamine Induce Overlapping but Distinct Patterns of AMPAR Plasticity in Nucleus Accumbens Medium Spiny Neurons

“…In addition, mGluR activation has been shown to induce rapid translation of striatal-enriched protein tyrosine phosphatase (STEP), which also downregulates AMPAR surface expression and may actively maintain endocytosis rates (Luscher and Huber, 2010;Zhang et al, 2008). Acute exposure to both amphetamine and cocaine alters phosphorylation of STEP in striatal regions and inactivation of STEP prevents cocaineinduced reductions in AMPAR-mediated currents in MSNs (Chiodi et al, 2014;Sun et al, 2007;Tashev et al, 2009;Valjent et al, 2005). However, the degree to which alterations in STEP activity may occur in response to psychostimulant re-exposure is unknown.…”

Adenosine STEPs on synaptic function

“…In an earlier paper, these investigators (Chiodi et al, ) found that activation of the G protein coupled A 2A R activates STEP leading to a reduction in striatal field potential amplitude (i.e., an increase in synaptic depression). The reduction in field potential amplitude can be blocked by D 2 R antagonists, A 2A R antagonists, non‐selective protein tyrosine phosphatase inhibitors, or calcineurin inhibitors.…”

“…Likewise, knockout of the mouse A 2A R also prevented the cocaine‐induced reduction in striatal field potential amplitude. When recording whole‐cell currents from medium spiny neurons in the dorsal striatum, Chiodi et al () observed that cocaine reduced AMPA‐ and NMDA‐mediated excitatory post‐synaptic currents. The cocaine‐induced reduction in excitatory post‐synaptic currents was blocked with a A 2A R antagonist or STEP substrate trapping mutant, TAT‐STEP, illustrating the important role of A 2A R and STEP in this pathway that leads to synaptic depression.…”

“…Chiodi et al () found FK506, a calcineurin inhibitor, blocks the synaptic depression. Since calcineurin is calcium‐dependent, the authors examined how an A 2A R agonist (CGS21680) would affect intracellular calcium in human SH‐SY5Y cells (Mallozzi et al, ).…”

Discovery of Novel Striatal‐enriched Protein Tyrosine Phosphatase Inhibitors Through Structure‐based Virtual Screening

“…9-11 STEP is also associated with the negative regulation of extracellular regulated kinase (ERK), which is a member of the MAPK family and functions critically in synaptic strengthening. In addition, it was shown that cocaine administration led to increase STEP activity in the striatum, which resulted in synaptic depression in that brain area, 17,18 suggesting that STEP inhibitors can be used to treat or mitigate symptoms caused by cocaine abuse. 11 Consistently, a dramatic upregulation of ERK activity was observed in a ptpn5 knockout mouse model.…”