BACKGROUND: Dysregulation of excitatory synaptic input to nucleus accumbens (NAc) medium spiny neurons (MSNs) underlies a key pathophysiology of drug addiction and addiction-associated emotional and motivational alterations. Dynorphin peptides, which exhibit higher affinity to κ type opioid receptors, are upregulated within the NAc upon exposure to cocaine administration, and the increased dynorphin-signaling in the NAc has been critically implicated in negative mood observed in cocaine- or stress-exposed animals. Despite such apparent behavioral significance of the NAc dynorphins, the understanding of how dynorphins regulate excitatory synaptic transmission in the NAc remains incomplete. METHODS: We used electrophysiological recording in brain slices to examine the effects of dynorphins on excitatory synaptic transmission in the NAc. RESULTS: We focused on two key dynorphins, dynorphin A and B. Our current results show that dynorphin A and B differentially regulated excitatory postsynaptic currents (EPSCs) in NAc MSNs. Whereas perfusions of both dynorphin A and B to NAc slices decreased EPSCs in MSNs, the effect of dynorphin A but not dynorphin B was completely reversed by the κ receptor-selective antagonist nor-binaltorphimine. These results implicate κ receptor-independent mechanisms in dynorphin B-mediated synaptic effects in the NAc. Furthermore, repeated exposure to cocaine (15 mg/kg/day via intraperitoneal injection for 5 days, with 1, 2, or 14 days withdrawal) completely abolished dynorphin A-mediated modulation of EPSCs in NAc MSNs, whereas the effect of dynorphin B remained largely unchanged. CONCLUSIONS: Given the quantitatively higher abundance of dynorphin B in the NAc, our present results suggest that the dynorphin B-mediated, κ receptor-independent pathways predominate in the overall effect of dynorphins in cocaine-pretreated animals and potentially in cocaine-induced alterations in mood. Copyright Â
BACKGROUND: Dysregulation of excitatory synaptic input to nucleus accumbens (NAc) medium spiny neurons (MSNs) underlies a key pathophysiology of drug addiction and addiction-associated emotional and motivational alterations. Dynorphin peptides, which exhibit higher affinity to κ type opioid receptors, are upregulated within the NAc upon exposure to cocaine administration, and the increased dynorphin-signaling in the NAc has been critically implicated in negative mood observed in cocaine- or stress-exposed animals. Despite such apparent behavioral significance of the NAc dynorphins, the understanding of how dynorphins regulate excitatory synaptic transmission in the NAc remains incomplete. METHODS: We used electrophysiological recording in brain slices to examine the effects of dynorphins on excitatory synaptic transmission in the NAc. RESULTS: We focused on two key dynorphins, dynorphin A and B. Our current results show that dynorphin A and B differentially regulated excitatory postsynaptic currents (EPSCs) in NAc MSNs. Whereas perfusions of both dynorphin A and B to NAc slices decreased EPSCs in MSNs, the effect of dynorphin A but not dynorphin B was completely reversed by the κ receptor-selective antagonist nor-binaltorphimine. These results implicate κ receptor-independent mechanisms in dynorphin B-mediated synaptic effects in the NAc. Furthermore, repeated exposure to cocaine (15 mg/kg/day via intraperitoneal injection for 5 days, with 1, 2, or 14 days withdrawal) completely abolished dynorphin A-mediated modulation of EPSCs in NAc MSNs, whereas the effect of dynorphin B remained largely unchanged. CONCLUSIONS: Given the quantitatively higher abundance of dynorphin B in the NAc, our present results suggest that the dynorphin B-mediated, κ receptor-independent pathways predominate in the overall effect of dynorphins in cocaine-pretreated animals and potentially in cocaine-induced alterations in mood. Copyright Â
Authors: B N Dhawan; F Cesselin; R Raghubir; T Reisine; P B Bradley; P S Portoghese; M Hamon Journal: Pharmacol Rev Date: 1996-12 Impact factor: 25.468
Authors: Yan Dong; Thomas Green; Daniel Saal; Helene Marie; Rachael Neve; Eric J Nestler; Robert C Malenka Journal: Nat Neurosci Date: 2006-03-05 Impact factor: 24.884
Authors: Yanhua H Huang; Ying Lin; Travis E Brown; Ming-Hu Han; Daniel B Saal; Rachael L Neve; R Suzanne Zukin; Barbara A Sorg; Eric J Nestler; Robert C Malenka; Yan Dong Journal: J Biol Chem Date: 2007-11-30 Impact factor: 5.157
Authors: Hugo A Tejeda; Danielle S Counotte; Eric Oh; Sammanda Ramamoorthy; Kristin N Schultz-Kuszak; Cristina M Bäckman; Vladmir Chefer; Patricio O'Donnell; Toni S Shippenberg Journal: Neuropsychopharmacology Date: 2013-03-29 Impact factor: 7.853
Authors: Brandon D Turner; Daniel T Kashima; Kevin M Manz; Carrie A Grueter; Brad A Grueter Journal: ACS Chem Neurosci Date: 2018-01-24 Impact factor: 4.418
Authors: M D Scofield; J A Heinsbroek; C D Gipson; Y M Kupchik; S Spencer; A C W Smith; D Roberts-Wolfe; P W Kalivas Journal: Pharmacol Rev Date: 2016-07 Impact factor: 25.468