Kappa opioid receptors on dopaminergic neurons are necessary for kappa-mediated place aversion.
Kappa-opioid receptor (KOR) agonists have dysphoric properties in humans and are aversive in rodents. This has been attributed to the activation of KORs within the mesolimbic dopamine (DA) system. However, the role of DA in KOR-mediated aversion and stress remains divisive as recent studies have suggested that activation of KORs on serotonergic neurons may be sufficient to mediate aversive behaviors. To address this question, we used conditional knock-out (KO) mice with KORs deleted on DA neurons (DAT(Cre/wt)/KOR(loxp/loxp), or DATCre-KOR KO). In agreement with previous findings, control mice (DAT(Cre/wt)/KOR(wt/wt) or WT) showed conditioned place aversion (CPA) to the systemically administered KOR agonist U69,593. In contrast, DATCre-KOR KO mice did not exhibit CPA with this same agonist. In addition, in vivo microdialysis showed that systemic U69,593 decreased overflow of DA in the nucleus accumbens (NAc) in WT mice, but had no effect in DATCre-KOR KO mice. Intra- ventral tegmental area (VTA) delivery of KORs using an adeno-associated viral gene construct, resulted in phenotypic rescue of the KOR-mediated NAc DA response and aversive behavior in DATCre-KOR KO animals. These results provide evidence that KORs on VTA DA neurons are necessary to mediate KOR-mediated aversive behavior. Therefore, our data, along with recent findings, suggest that the neuronal mechanisms of KOR-mediated aversive behavior may include both dopaminergic and serotonergic components.
Integrative Neuroscience Section, Integrative Neuroscience Branch, National Institute on Drug Abuse, Baltimore, MD, USA.
Vladimir I
VI
Chefer
Cristina M
CM
Bäckman
Eduardo D
ED
Gigante
Toni S
TS
Shippenberg
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology*; D044482:Benzeneacetamides / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017551:Microdialysis; D008845:Microinjections; D009714:Nucleus Accumbens / Q000166:cytology / Q000378:metabolism; D009830:Olfactory Bulb / Q000166:cytology; D011759:Pyrrolidines / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000172:deficiency / Q000378:metabolism*; D014161:Transduction, Genetic; D017557:Ventral Tegmental Area / Q000166:cytology
D000700:Analgesics; D044482:Benzeneacetamides; D050483:Dopamine Plasma Membrane Transport Proteins; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; C493215:Slc6a3 protein, mouse; D049452:Green Fluorescent Proteins; C045444:U 69593