title: Modifications of the input currents on VTA dopamine neurons following acute versus chronic cocaine exposure.
abstract: Excitatory synapses on dopamine (DA) neurons in the ventral tegmental area (VTA) are modulated following exposure to various addictive drugs, including cocaine. Previously we have shown that cocaine affects GABA(A) receptor (GABA(A)R)-mediated neurotransmission in VTA DA neurons. This finding led us to reexamine the modulation of the excitatory synapse on these neurons in response to cocaine exposure, while the activity of GABA(A)R is uninterrupted. Using rat brain slices, evoked post synaptic currents (ePSC) were monitored and inhibitors of NMDA receptor (NMDAR) and AMPA receptor (AMPAR) were gradually added to inhibitors-free bath solution. Modifications in the efficacy of the excitatory synapses were evaluated by comparing AMPAR-mediated and NMDAR-mediated currents (AMPA/NMDA ratio). The lack of GABA(A)R inhibitors enabled us to examine parallel changes in the relation between GABA(A)R-mediated and NMDAR-mediated currents (GABA(A)/NMDA ratio). First, we found that AMPA/NMDA ratio measured under complete availability of GABA(A)R, is significantly higher than the ratio measured under GABA(A)R blockade. In addition, GABA(A)/NMDA ratio, but not AMPA/NMDA ratio, is augmented a few hours following in vitro acute cocaine exposure. When measured 24 h after in vivo single cocaine injection, no change in GABA(A)/NMDA ratio was observed, however, the AMPA/NMDA ratio was found to be significantly higher. Finally, a decrease in both ratios was detected in rats repeatedly injected with cocaine. Taken together, these results lead to a better understanding of the means by which cocaine modifies synaptic inputs on VTA DA neurons. The parallel changes in GABA(A)/NMDA ratio may suggest an interaction between inhibitory and excitatory neural systems.
authors.affiliation: Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Avner
authors.initials: A
authors.lastname: Michaeli
authors.forename: Henry
authors.initials: H
authors.lastname: Matzner
authors.forename: Tatyana
authors.initials: T
authors.lastname: Poltyrev
authors.forename: Rami
authors.initials: R
authors.lastname: Yaka
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D059290:Dopaminergic Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects* / Q000502:physiology
chemical_list: D018765:Dopamine Uptake Inhibitors; D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D003042:Cocaine