ABSTRACT
The striatum is a brain area implicated in the pharmacological action of drugs of abuse. Adenosine A2A receptors (A2ARs) 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 A2ARs. We found that synaptic transmission was depressed in corticostriatal slices after perfusion with cocaine (10 µM). This effect was reduced by the A2AR antagonist ZM241385 and almost abolished in striatal A2AR-knockout mice (mice lacking A2ARs in striatal neurons, stA2ARKO). The effect of cocaine on synaptic transmission was also prevented by the protein tyrosine phosphatases (PTPs) inhibitor sodium orthovanadate (Na3VO4). 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 stA2ARKO. 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 A2ARs modulate cocaine-induced synaptic depression in the striatum and highlight the potential role of PTPs and specifically STEP in the effects of cocaine.
Subject(s)
Cocaine/pharmacology , Corpus Striatum/drug effects , Dopamine Uptake Inhibitors/pharmacology , Protein Tyrosine Phosphatases, Non-Receptor/metabolism , Receptor, Adenosine A2A/metabolism , Synaptic Transmission/drug effects , Animals , Cerebral Cortex/cytology , Corpus Striatum/cytology , Enzyme Inhibitors/pharmacology , Gene Expression Regulation/drug effects , Humans , In Vitro Techniques , Inhibitory Postsynaptic Potentials/drug effects , Inhibitory Postsynaptic Potentials/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Neural Pathways/physiology , Neurons/drug effects , Neurons/ultrastructure , Receptor, Adenosine A2A/genetics , Synaptosomes/drug effects , Synaptosomes/metabolism , Vanadates/pharmacologyABSTRACT
The mechanisms responsible for vascular autoregulation in the brain during changes in mean arterial blood pressure are ambiguous. Potentially, adenosine, a purine nucleoside and potent vasodilator, may be involved as earlier studies have documented an increase in brain adenosine concentrations with cerebral ischemia and hypotension. Consequently, we tested the hypothesis that adenosine is involved in vasodilatation during hypotension within the autoregulatory range (>50 mm Hg) by exposing adenosine 2a receptor (A2aR) knockout and wild type (WT) mice to short (2 to 5 mins) periods of hypotension. We found that autoregulation was significantly (P<0.05) impaired by 29% in A2a knockout mice as compared with WT animals. Furthermore, the A2R antagonist (A2a>A2b:10-85>1), ZM-241385, in a dose (1, 5, 10 mg/kg, intraperitoneally)-related manner, attenuated autoregulation in WT mice. In knockout mice treated with ZM-2413585 (5 and 10 mg/kg), autoregulation was further impaired indicating that A2b receptors also participated in cerebral vasodilatation. Treatment with dipyridamole (1.0 mg/kg) that increases extracellular concentrations of adenosine improved autoregulation in the A2aR knockout mice. We would conclude that adenosine through both A2a and A2b receptors is involved in physiologic vascular regulation during hypotension even within the autoregulatory range.
