Blockade of ionotropic glutamatergic transmission in the ventral tegmental area reduces heroin reinforcement in rat.
BACKGROUND
While the role of the mesocorticolimbic (MCL) dopamine (DA) system in mediating the reinforcing properties of drugs of abuse has been well established, how and where other neurotransmitter systems interact to modify this system is less well understood.


OBJECTIVE
The present study sought to assess whether blockade of ionotropic glutamate receptors in the ventral tegmental area (VTA) would modulate heroin self-administration (SA) behavior in rats.


METHODS
The effects of systemic or regional administration of ionotropic glutamate receptor antagonists into the VTA on the maintenance of heroin SA were assessed. Rats were reinforced each time they responded on a lever with a single injection of intravenous heroin. To determine the specificity of their effects on heroin SA, the ability of these antagonists to modify locomotion and food-reinforced behavior was also examined.


RESULTS
Systemic or regional administration of the non-competitive NMDA antagonist dizocilpine into the VTA significantly increased the rate of heroin SA and shifted the heroin dose-response curve to the right. Similarly, when systemically administered, ketamine, another non-competitive NMDA antagonist, also increased the rate of heroin SA. However, when administered directly into the VTA, ketamine or AP5 [ D-(-)-2-amino-5-phosphonopentanoic acid, a competitive NMDA antagonist], dose-dependently blocked heroin SA. In contrast, 6,7-dinitroquinoxaline-2,3-dione (DNQX), an AMPA/kainate receptor antagonist, significantly increased heroin SA.


CONCLUSIONS
These data suggest that ionotropic glutamate receptors in the VTA, presumably by modulating MCL DA efferents and/or tegmental interneurons, modulate opiate reinforcement.
Xi
Zheng-Xiong
ZX
Department of Cell Biology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Stein
Elliot A
EA
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology; D003932:Heroin / Q000008:administration & dosage*; D007276:Injections, Intraventricular; D007649:Ketamine / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D008845:Microinjections; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism*; D012054:Reinforcement, Psychology; D012646:Self Administration; D013997:Time Factors; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects* / Q000502:physiology
D018691:Excitatory Amino Acid Antagonists; D011810:Quinoxalines; D017470:Receptors, Glutamate; C056723:FG 9041; D007649:Ketamine; D016291:Dizocilpine Maleate; D003932:Heroin; D015763:2-Amino-5-phosphonovalerate