Kappa opioid receptor activation decreases inhibitory transmission and antagonizes alcohol effects in rat central amygdala.
- Authors
- Gilpin, Nicholas W; Roberto, Marisa; Koob, George F; Schweitzer, Paul
- Year
- 2014
- Journal
- Neuropharmacology
- PMID
- 24157490
- DOI
- 10.1016/j.neuropharm.2013.10.005
- PMCID
- PMC3873141
Activation of the kappa opioid receptor (KOR) system mediates negative emotional states and considerable evidence suggests that KOR and their natural ligand, dynorphin, are involved in ethanol dependence and reward. The central amygdala (CeA) plays a major role in alcohol dependence and reinforcement. Dynorphin peptide and gene expression are activated in the amygdala during acute and chronic administration of alcohol, but the effects of activation or blockade of KOR on inhibitory transmission and ethanol effects have not been studied. We used the slice preparation to investigate the physiological role of KOR and interaction with ethanol on GABA(A) receptor-mediated synaptic transmission. Superfusion of dynorphin or U69593 onto CeA neurons decreased evoked inhibitory postsynaptic potentials (IPSPs) in a concentration-dependent manner, an effect prevented by the KOR antagonist norbinaltorphimine (norBNI). Applied alone, norBNI increased GABAergic transmission, revealing a tonic endogenous activity at KOR. Paired-pulse analysis suggested a presynaptic KOR mechanism. Superfusion of ethanol increased IPSPs and pretreatment with KOR agonists diminished the ethanol effect. Surprisingly, the ethanol-induced augmentation of IPSPs was completely obliterated by KOR blockade. Our results reveal an important role of the dynorphin/KOR system in the regulation of inhibitory transmission and mediation of ethanol effects in the CeA.
Kappa receptor ligands decrease GABAA-mediated synaptic transmissionA. Representative recordings showing IPSPs elicited before (Control) and during superfusion of 1 μM dynorphin (Dyn) in a CeA neuron. Dynorphin diminished the evoked IPSP with recovery to control level after washout. Recordings were performed at RMP, −82 mV for this neuron. Stimulus artifact indicated by arrows; traces identified with numbers are magnified and superimposed on the right for comparison. B. Graph average of dynorphin effect on IPSP amplitudes over time. Dynorphin (1 μM; application indicated with bar) was added at t = 0 and the maximum effect was obtained after 9 min of superfusion. C. In the presence of the KOR antagonist norBNI (0.2 μM), dynorphin did not affect IPSP amplitude. RMP was −79 mV. D. Superfusion of U69 at concentrations of 0.5 μM (open circles) or 1 μM (closed squares) decreased IPSPs to the same extent as dynorphin and with a similar time course.
Dynorphin activates kappa receptors to decrease IPSPs at a presynaptic siteA. Concentration-response curve (logistic fit) of the dynorphin effect. Dynorphin decreased IPSPs by a maximum of 23%, with an apparent EC50 of 0.50 μM (dashed line) and a near maximum effect at 1 μM. U69 also depicted (open squares) for comparison: near-maximum effect was obtained at 0.5 μM. B. Upper panel: IPSP recordings obtained with the PPF paradigm. Dynorphin (1 μM) diminished P1 with little effect on P2, increasing the paired-pulse ratio (P2/P1). RMP was −76. Arrows indicate stimulation artifact. Lower left: recordings from upper panel superimposed and normalized to P1 to magnify the increase of PPF. For equivalent P1 amplitudes, P2 (identified with numbers) was larger in the presence of dynorphin. Lower right: bar graph average depicting the PPF change relative to control condition: dynorphin (1 μM) and U69 (1 μM) increased PPF by 28% and 26% respectively.
Kappa receptor ligands diminish the action of ethanolA. Top: superfusion of ethanol (EtOH) onto this neuron increased the amplitude of the evoked IPSP with recovery to control level upon washout. RMP was −80 mV. Bottom: pooled data showing the time course of the effect of ethanol, which on average increased inhibitory transmission by 48%. B. Dynorphin (1–2 μM; t = 0) decreased IPSPs to 79% of control. Addition of 44 mM ethanol (t = 15) reversed the dynorphin effect, increasing IPSPs by a net 32%. C. We observed a similar pattern with U69: U69 alone (0.5–1 μM) decreased IPSPs to 81% of control and addition of ethanol reversed the U69 effect, increasing IPSPs by a net 29%.
Kappa receptor blockade reveals a tonic endogenous opioidergic activityA. In this representative neuron, norBNI (0.2 μM) applied alone markedly increased IPSP amplitude by 34%. RMP was −77 mV. B. Average time course of the effect of 0.2 μM norBNI. C. Top: in this CeA neuron, a PPF paradigm revealed that norBNI increased the first IPSP but had little effect on the second IPSP. Bottom left: traces superimposed and scaled to the first IPSP, magnifying the PPF decrease elicited by norBNI. Bottom right: on average, norBNI decreased PPF to 77% of control, suggesting a tonic presynaptic effect of an endogenous KOR ligand to decrease GABA release. RMP was −78 mV. D. Applied alone, norBNI increase IPSPs by 36%. In the presence of the mu opioid receptor antagonist CTAP, norBNI still increased inhibitory transmission by a net 29%.
Ethanol and norBNI reciprocally block each others’ effect on GABA transmissionA. Top: in this neuron, superfusion of norBNI increased the IPSP but subsequent addition of ethanol in the continued presence of norBNI had no further effect. RMP was −77 mV. Bottom: graph depicting the complete lack of ethanol effect with KORs blocked. B. Top: reciprocally, ethanol applied first increased the IPSP amplitude but further addition of norBNI was without effect. Bottom: graph average showing the average effect of the sequence ethanol then norBNI. C. Bar graph summarizing the influence of the dynorphin/KOR system on the effect of ethanol in CeA neurons. The effect of ethanol was significantly diminished by activation of KORs but completely obliterated by KOR blockade. D. The ethanol-induced decrease of the paired-pulse ratio was also affected by the KOR ligands and obliterated by the KOR antagonist, consistent with a presynaptic of interaction.
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