Interacting presynaptic kappa-opioid and GABAA receptors modulate dopamine release from rat striatal synaptosomes.
The presynaptic regulation of stimulated dopamine release from superfused rat striatal synaptosomes by opioids and gamma-aminobutyric acid (GABA) was studied. It was found that in addition to dopamine D2 autoreceptors, calcium-dependent K(+)-stimulated [3H]dopamine release was inhibited through activation of a homogeneous population of kappa-opioid receptors in view of the potent inhibitory effect of the kappa-selective agonist U69,593 (EC50 0.2 nM) and its antagonism by norbinaltorphimine. Neither mu- nor delta-selective receptor agonists affected release of [3H]-dopamine. In addition, GABA potently inhibited the evoked [3H]dopamine release (EC50 0.4 nM) through activation of GABAA receptors in view of the GABA-mimicking effect of muscimol, the sensitivity of its inhibitory effect to picrotoxin and bicuculline, and the absence of an effect of the GABAB receptor agonist baclofen. In the presence of a maximally effective concentration of GABA, U69,593 did not induce an additional release-inhibitory effect, indicating that these receptors and the presynaptic D2 receptor are colocalized on the striatal dopaminergic nerve terminals. The excitatory amino acid agonists N-methyl-D-aspartate and kainate, as well as the cholinergic agonist carbachol, stimulated [3H]dopamine release, which was subject to kappa-opioid receptor-mediated inhibition. In conclusion, striatal dopamine release is under regulatory control of multiple excitatory and inhibitory neurotransmitter by activation of colocalized presynaptic receptors for excitatory amino acids, acetylcholine, dopamine, dynorphins, and GABA within the dopaminergic nerve terminals. Together, these receptors locally control ongoing dopamine neurotransmission.
Ronken
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Department of Pharmacology, Faculty of Medicine, Vrije Universiteit, Amsterdam, The Netherlands.
Mulder
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AH
Schoffelmeer
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AN
D000704:Analysis of Variance; D000818:Animals; D044482:Benzeneacetamides; D001640:Bicuculline / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D017473:Receptors, Opioid, kappa / Q000187:drug effects / Q000502:physiology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D044482:Benzeneacetamides; D001640:Bicuculline; D004298:Dopamine; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins; D009271:Naltrexone; D009294:Narcotics; D009842:Oligopeptides; D010852:Picrotoxin; D011188:Potassium; D011759:Pyrrolidines; D011963:Receptors, GABA-A; D017473:Receptors, Opioid, kappa; D005680:gamma-Aminobutyric Acid; C054868:tyrosyl-seryl(O-tert-butyl)-glycyl-phenylalanyl-leucyl-threonine; C051844:norbinaltorphimine; C045444:U 69593