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Biol Psychiatry. 2011 Feb 1;69(3):228-35. doi: 10.1016/j.biopsych.2010.09.014. Epub 2010 Oct 27.

Exposure to cocaine alters dynorphin-mediated regulation of excitatory synaptic transmission in nucleus accumbens neurons.

Author information

1
Washington State University, Pullman, USA.

Abstract

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.

PMID:
21030009
PMCID:
PMC3790254
DOI:
10.1016/j.biopsych.2010.09.014
[Indexed for MEDLINE]
Free PMC Article

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