Endogenous kappa-opioid receptor systems regulate mesoaccumbal dopamine dynamics and vulnerability to cocaine.
Genetic and pharmacological approaches were used to examine kappa-opioid receptor (KOR-1) regulation of dopamine (DA) dynamics in the nucleus accumbens and vulnerability to cocaine. Microdialysis revealed that basal DA release and DA extraction fraction (Ed), an indirect measure of DA uptake, are enhanced in KOR-1 knock-out mice. Analysis of DA uptake revealed a decreased Km but unchanged Vmax in knock-outs. Knock-out mice exhibited an augmented locomotor response to cocaine, which did not differ from that of wild-types administered a behavioral sensitizing cocaine treatment. The ability of cocaine to increase DA was enhanced in knock-outs, whereas c-fos induction was decreased. Although repeated cocaine administration to wild types produced behavioral sensitization, knock-outs exhibited no additional enhancement of behavior. Administration of the long-acting KOR antagonist nor-binaltorphimine to wild-type mice increased DA dynamics. However, the effects varied with the duration of KOR-1 blockade. Basal DA release was increased whereas Ed was unaltered after 1 h blockade. After 24 h, release and Ed were increased. The behavioral and neurochemical effects of cocaine were enhanced at both time points. These data demonstrate the existence of an endogenous KOR-1 system that tonically inhibits mesoaccumbal DA neurotransmission. Its loss induces neuroadaptations characteristic of "cocaine-sensitized" animals, indicating a critical role of KOR-1 in attenuating responsiveness to cocaine. The increased DA uptake after pharmacological inactivation or gene deletion highlights the plasticity of mesoaccumbal DA neurons and suggests that loss of KOR-1 and the resultant disinhibition of DA neurons trigger short- and long-term DA transporter adaptations that maintain normal DA levels, despite enhanced release.
Chefer
Vladimir I
VI
Integrative Neuroscience Section, Behavioral Neurosciences Branch, National Institute on Drug Abuse/Intramural Research Program, Baltimore, Maryland 21224.
Czyzyk
Traci
T
Department of Neuroscience and Cell Biology, Center for Advanced Biotechnology and Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854.
Bolan
Elizabeth A
EA
Integrative Neuroscience Section, Behavioral Neurosciences Branch, National Institute on Drug Abuse/Intramural Research Program, Baltimore, Maryland 21224.
Moron
Jose
J
Integrative Neuroscience Section, Behavioral Neurosciences Branch, National Institute on Drug Abuse/Intramural Research Program, Baltimore, Maryland 21224.
Pintar
John E
JE
Department of Neuroscience and Cell Biology, Center for Advanced Biotechnology and Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854.
Shippenberg
Toni S
TS
Integrative Neuroscience Section, Behavioral Neurosciences Branch, National Institute on Drug Abuse/Intramural Research Program, Baltimore, Maryland 21224.
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western / Q000379:methods; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003042:Cocaine / Q000008:administration & dosage*; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D016014:Linear Models; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis / Q000379:methods; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D017711:Nonlinear Dynamics; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000172:deficiency / Q000502:physiology*; D013997:Time Factors; D014316:Tritium / Q000378:metabolism
D018765:Dopamine Uptake Inhibitors; D017874:Immediate-Early Proteins; D017473:Receptors, Opioid, kappa; D014316:Tritium; D003042:Cocaine; D004298:Dopamine