Activation of D₂-like receptors in rat ventral tegmental area inhibits cocaine-reinstated drug-seeking behavior.
Relapse is a hallmark of cocaine addiction. Cocaine-induced neuroplastic changes in the mesocorticolimbic circuits critically contribute to this phenomenon. Pre-clinical evidence indicates that relapse to cocaine-seeking behavior depends on activation of dopamine neurons in the ventral tegmental area. Thus, blocking such activation may inhibit relapse. Because the activity of dopamine neurons is regulated by D₂-like autoreceptors expressed on somatodendritic sites, this study, using the reinstatement model, aimed to determine whether activation of D₂-like receptors in the ventral tegmental area can inhibit cocaine-induced reinstatement of extinguished cocaine-seeking behavior. Rats were trained to self-administer i.v. cocaine (0.25 mg/infusion) under a modified fixed-ratio 5 schedule. After such behavior was well learned, rats went through extinction training to extinguish cocaine-seeking behavior. The effect of quinpirole, a selective D₂-like receptor agonist microinjected into the ventral tegmental area, on cocaine-induced reinstatement was then assessed. Quinpirole (0-3.2 μg/side) dose-dependently decreased cocaine-induced reinstatement and such effects were reversed by the selective D₂-like receptor antagonist eticlopride when co-microinjected with quinpirole into the ventral tegmental area. The effect appeared to be specific to the ventral tegmental area because quinpirole microinjected into the substantia nigra had no effect. Because D₂-like receptors are expressed on rat ventral tegmental area dopamine neurons projecting to the pre-frontal cortex and nucleus accumbens, our data suggest that these dopamine circuits may play a critical role in cocaine-induced reinstatement. The role of potential changes in D₂-like receptors and related signaling molecules of dopamine neurons in the vulnerability to relapse was discussed.
Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Yueqiang
Y
Xue
Jeffery D
JD
Steketee
George V
GV
Rebec
Wenlin
W
Sun
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D003216:Conditioning, Operant; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D005108:Extinction, Psychological / Q000187:drug effects; D008297:Male; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D012008:Recurrence; D012646:Self Administration; D019966:Substance-Related Disorders / Q000517:prevention & control; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D018491:Dopamine Agonists; D017448:Receptors, Dopamine D2; D019257:Quinpirole; D003042:Cocaine
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