Kappa opioid inhibition of somatodendritic dopamine inhibitory postsynaptic currents - PubMed (original) (raw)

Kappa opioid inhibition of somatodendritic dopamine inhibitory postsynaptic currents

Christopher P Ford et al. J Neurophysiol. 2007 Jan.

Abstract

In the midbrain, dopamine neurons can release dopamine somatodendritically. This results in an inhibitory postsynaptic current (IPSC) within adjacent dopamine cells that occurs by the activation of inhibitory D(2) autoreceptors. Kappa, but not mu/delta, opioid receptors inhibit this IPSC. The aim of the present study was to determine the mechanism by which kappa-opioid receptors inhibit the dopamine IPSC. In both the ventral tegmental area (VTA) and substantia nigra compacta (SNc) the kappa-receptor agonist U69593 inhibited the IPSC, but not the current induced by the exogenous iontophoretic application of dopamine. The endogenous peptide dynorphin A (1-13) also inhibited IPSCs in the VTA and SNc, but also the dopamine iontophoretic current in the VTA. Although both kappa agonists induced a postsynaptic outward current in the VTA, the current induced by dynorphin was dramatically larger. This suggests that the decrease in iontophoretic dopamine current was the result of occlusion. Occlusion alone, however, could not completely account for suppression of the IPSC. The kappa opioid inhibition of the IPSC was not affected by global increases or decreases in dopamine cell activity within the slice. These findings suggest that, although kappa opioid receptors can hyperpolarize dopamine neurons, they also suppress dopamine release by direct actions at the release site. The results thus demonstrate both pre- and postsynaptic actions of kappa receptor agonists. The actions of dynorphin indicate that VTA dopamine cells are selectively regulated by kappa receptors.

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Figures

FIG. 1

Actions of κ_-opioids on ventral tegmental area (VTA) dopamine neurons. A: (5_α,7_α_,8_α_)-(+)-_N_-methyl-_N_-[7-(pyrrolidinly)-1-oxaspiro[4,5]dec-8-yl]-benzeneacatamide (U69593, 200 nM) inhibited D2 inhibitory postsynaptic currents (IPSCs) but had no effect on currents generated by the iontophoretic application of dopamine. B: dynorphin (Dyn, 200 nM) inhibited both the IPSC and the dopamine iontophoretic current. C and D: summary of the effects of U69593 and Dyn on VTA dopamine cells. Effects of U69593 and dynorphin were reversed by the opioid antagonist naloxone (NLX, 1 _μ_M). E and F: Dyn produces a greater whole cell current than U69593 in VTA dopamine cells. Top traces: examples of the effects of U69593 and dynorphin on single cells. Bottom graphs: summarized data.

FIG. 2

U69593 and dynorphin inhibit the D2 IPSC in substantia nigra compacta (SNc) cells by a presynaptic mechanism. A: U69593 (200 nM) inhibited D2 IPSCs but had no effect on currents generated by the iontophoretic application of dopamine in SNc cells. B: Dyn (200 nM) inhibited both IPSCs but caused a small potentiation of the iontophoretic current in SNc cells. C and D: summary of the effects of U69593 and dynorphin on SNc dopamine cells. E and F: Dyn produces a greater whole cell current than U69593 in SNc dopamine cells.

FIG. 3

Effects of dynorphin arise from activation of _κ_-opioid receptors. A: in the presence of the _μ_-opioid antagonist _N_-

-phe-cys-tyr-

-trp-agr-thr-pen-thr-nh2 (CTAP, 500 nM), dynorphin still suppressed the IPSC and produced outward currents. B: application of the _κ_-opioid antagonist norBNI (100 nM) completely prevented dynorphin (200 nM) from either activating an outward current or suppressing the IPSC.

FIG. 4

Summary of effects of dynorphin and U69593 in the VTA and SNc. A: summary of the inhibition produced by U69593 and dynorphin on the D2 IPSC. Note that dynorphin and U69593 caused a similar degree of inhibition of the IPSC and both induced a greater suppression in VTA dopamine cells. B: summary of amplitudes of whole cell outward currents generated by dynorphin and U69593. Note the range of currents produced by either agonist does not match the range of IPSC suppression observed in A. C: correlation between the whole cell current produced by dynorphin vs. the degree of IPSC suppression and the whole cell current produced by dynorphin vs. the degree of suppression of the iontophoretic response. A stronger correlation existed for the iontophoretic response than for the IPSC. D: effect of U69593 on the current produced by iontophoretically applied dopamine or on the IPSC failed to correlate with the outward current induced. Only inhibitory responses to U69593 or dynorphin are plotted in C and D.

FIG. 5

Effects of U69593 are not dependent on alterations in membrane potential of adjacent neurons. A and B: current-clamp recordings from representative midbrain dopamine cells illustrating the hyperpolarizing effect of cocaine (1 _μ_M) (A) and the depolarizing effect of 10 mM KCl (B). Note the suppression of spontaneous action potentials (APs) on application of cocaine and the increase in frequency of APs on application of KCl. C: summary of change in membrane potential of dopamine cells resulting from cocaine (1 _μ_M) and KCl (10 mM). D and E: effect of cocaine (1 _μ_M) (D) or KCl (10 mM) (E) on dopamine D2 IPSCs. Application of cocaine or KCl failed to alter the U69593-induced inhibition of the IPSC (E, note: _V_h = −70 mV for E only). Application of 10 mM KCl shifts equilibrium potential for K+ (_E_K) to −56 mV, causing D2 IPSCs to become inward currents. F: summary of U69593-induced inhibition for control cells, cells in the presence of cocaine (1 _μ_M), or cells in the presence of KCl (10 mM).

FIG. 6

Mechanism of suppression of the D2 IPSC by U69593. A: Ca2+ entry by voltage-gated Ca2+ channel blockers is necessary to evoke D2 IPSCs, but does not prevent the U69593-mediated suppression. N-type channel blocker _ω_-Conotoxin GVIA (_ω_-CTX, 1 _μ_M) and the R/T-type channel blocker mibefradil (10 _μ_M) both caused an inhibition of the IPSC, illustrating the involvement of these channels in mediating the IPSC. Neither blocker nor the P/Q-type channel blocker _ω_-Agatoxin IVA (100 nM) prevented the U69593-mediated suppression of the IPSC. B: summary of results showing the effects of N-, P/Q-, R/T-, and L-type Ca2+ channel blockers (_ω_-Conotoxin GVIA, 1 _μ_M, _ω_-Agatoxin IVA, 100 nM, mibefradil 10 _μ_M, nimodipine 10 _μ_M), K+ channel blocker [4-aminopyridine (4-AP), 10 _μ_M], 12-lipoxygenase inhibitor (baicalein, 5 _μ_M), kinase inhibitor (staurosporine, 1 _μ_M), and the protein kinase A (PKA) inhibitor (H-89, 10 _μ_M) on the U69593-induced IPSC suppression.

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Kappa opioid inhibition of somatodendritic dopamine inhibitory postsynaptic currents - PubMed (original) (raw)