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

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.

Figure 1

Inhibition of EPSCs in NAc MSNs by DynA and DynB. A Examples showing that the amplitude of EPSCs in NAc MSNs was decreased by perfusion of DynA. EPSCs were elicited in a paired-pulse manner. B Summarized results showing that perfusion of DynA inhibited the amplitude of EPSCs in NAc MSNs, and the effect could not be washed. C Summarized results showing that accompanying the DynA-mediated inhibition of EPSC amplitude, the PPR was increased. D Examples showing that the amplitude of EPSCs in NAc MSNs was decreased by perfusion of DynB. E Summarized results showing that perfusion of DynB inhibited the amplitude of EPSCs in NAc MSNs, and the effect could not be washed. F Summarized results showing that accompanying the DynA-mediated inhibition of EPSC amplitude, the PPR was increased.

Figure 2

Differential involvements of kappa receptors in DynA- and DynB-mediated regulation of EPSCs in NAc MSNs. A Examples showing that the amplitude of EPSCs in NAc MSNs was decreased by perfusion of U69593. EPSCs were elicited in a paired-pulse manner. B Summarized results showing that perfusion of U69593 inhibited the amplitude of EPSCs in NAc MSNs, and the effect could not be washed. C Summarized results showing that accompanying the U69593-mediated inhibition of EPSC amplitude, the PPR was increased. D Examples showing that the amplitude of EPSCs in NAc MSNs was not affected by perfusion of nor-BNI. E Summarized results showing that perfusion of nor-BNI did not significantly affect the amplitude of EPSCs in NAc MSNs. F Summarized results showing that the PPR of EPSCs was not significantly affected by perfusion of nor-BNI. G Examples showing that the amplitude of EPSCs in NAc MSNs was decreased by perfusion of U69593, and this effect was reversed by application of nor-BIN. H Summarized results showing that U69593-induced inhibition of EPSC amplitude in NAc MSNs could be reversed by application of nor-BNI. I Summarized results showing that U69593-induced increase in PPR could be reversed by application of nor-BNI. J Examples showing that the amplitude of EPSCs in NAc MSNs was decreased by perfusion of DynA, and this effect was reversed by application of nor-BIN. K Summarized results showing that DynA-induced inhibition of EPSC amplitude in NAc MSNs could be reversed by application of nor-BNI. L Summarized results showing that DynA-induced increase in PPR could be reversed by application of nor-BNI. M Examples showing that the amplitude of EPSCs in NAc MSNs was decreased by perfusion of DynB, and this effect was not completely reversed by application of nor-BIN. N Summarized results showing that DynB-induced inhibition of EPSC amplitude in NAc MSNs could be partially reversed by application of nor-BNI. O Summarized results showing that U69593-induced increase in PPR could be partially reversed by application of nor-BNI.

Figure 3

DynA-, but not DynB-, mediated regulations of EPSCs in NAc MSNs was disrupted by exposure to cocaine. A Examples showing that the amplitude of EPSCs in NAc MSNs was not affected by perfusion of DynA in cocaine-pretreated rats. EPSCs were elicited in a paired-pulse manner. B Summarized results showing that DynA-induced inhibition of EPSC amplitude in NAc MSNs was not present in cocaine-pretreated rats. C Summarized results showing that DynA-induced increase in PPR was not present in cocaine-pretreated rats. D Examples showing that the amplitude of EPSCs in NAc MSNs was decreased by perfusion of DynB in cocaine-pretreated rats. E Summarized results showing that DynB-induced inhibition of EPSC amplitude in NAc MSNs was still present in cocaine-pretreated rats. F Summarized results showing that DynB-induced increase in PPR was still present in cocaine-pretreated rats. G Examples showing that the amplitude of EPSCs in NAc MSNs was not affected by perfusion of U69593. H Summarized results showing that U69593-induced inhibition of EPSC amplitude in NAc MSNs was not present in cocaine-pretreated rats.