Morphine releases glutamate through AMPA receptors in the ventral tegmental area: a microdialysis study in conscious rats

Abstract

Drug addiction has developed to a social illness. Changes in glutamate transmission have been recorded by the repeated administration of addictive drugs into VTA. In this investigation, In vivo microdialysis was used to study the effects of morphine on glutamate release from the ventral tegmentum area (VTA) in freely moving rats. Rats were anesthetized with chloral hydrate (350 mg/kg, i.p.) and placed in a Kopf stereotaxic apparatus. A vertical guide cannula was implanted through a burr hole and secured with dental cement held on the skull with small screws. The final co-ordinates for the tip of the microdialysis probe in right VTA relative to bregma were: anteroposterior (AP), 5.8; lateral (L), 0.5 and dorsoventral (DV), 9.0 according to atlas of Paxinos. One week after surgery, the microdialysis probe was inserted into the guide cannula and perfused with artificial cerebrospinal fluid (aCSF). After a 60 min wash out period, dialysate samples were collected in 20 min periods in vials and 20?m was used for glutamate HPLC analysis. Intraperitoneal (IP) injection of acute and repeated administration of morphine at increasing doses enhanced significantly glutamate release. Only a minor tolerance developed to this effect of morphine. AP-5 (2-amino-5-phosphonovaleric acid, 0.5 mg/kg i.p.), a NMDA receptor antagonist, given 20 min before each repeated morphine injection, did not have a significant effect on the stimulated glutamate release. Conversely, injection of CNQX (6-cyano-7-nitroquinnoxaline-2, 3-dione, 0.5 mg/kg i.p), an AMPA receptor antagonist, 20 min before each morphine dose was found to markedly inhibit morphine-induced glutamate release in the VTA. In all experiments, release of glutamate reduced by time. These results show for the first time that acute and repeated injection of morphine stimulates glutamate release in the conscious rat VTA via AMPA receptors.