Inhibition of calcium channels by opioid- and adenosine-receptor agonists in neurons of the nucleus accumbens.
The pharmacological effects of opioid- and adenosine-receptor agonists on neural signalling were investigated by measuring drug actions on barium current flowing through calcium channels in acutely-dissociated neurons of the rat nucleus accumbens (NAc). Under whole-cell voltage clamp, opioids acted via mu, but not delta or kappa, receptors to partially inhibit barium current. Mean inhibition was 35+/-2% (+/-s.e.mean, n = 33) for methionine-enkephalin and 37+/-1% (n = 65) for the selective mu receptor agonist DAMGO, both measured at saturating agonist concentrations in neurons with diameter > or = 20 microm. EC(50) for DAMGO was 100 nM. Perfusion of naloxone reversed the current inhibition by DAMGO. Adenosine also partially inhibited barium current in these neurons. Mean inhibition was 28+/-2% (n = 29) for adenosine and 33+/-3% (n = 27) for the selective A1 receptor agonist N(6)CPA, both at saturating concentrations in neurons with diameter > or = 20 microm. EC(50) for N(6)CPA was 34 nM. Adenosine inhibition was reversed by perfusion of an A1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine, while the selective A2A receptor agonist, CGS 21680, had no effect. Inhibition by opioids and adenosine was mutually occlusive, suggesting a converging pathway onto calcium channels. These actions involved a G-protein-coupled mechanism, as demonstrated by the partial relief of inhibition by strong depolarization and by the application of N-ethylmaleimide or GTP-gamma-S. Inhibition of barium current by opioids had their greatest effect in large neurons, that is, in presumed interneurons. In contrast, opioid inhibition in neurons with diameter < or = 15 microm was 11+/-2% (n = 26) for methionine-enkephalin and 11+/-4% (n = 17) for DAMGO, both measured at saturating agonist concentrations. Adenosine inhibition in neurons with diameter < or = 15 microm was 22+/-5% (n = 9). These results implicate the interneurons as a locus for the modulation of the excitability of projection neurons in the NAc during the processes of addiction and withdrawal.
Chieng
B
B
Division of Neuroscience, John Curtin School of Medical Research, Australian National University, Canberra ACT 0200, Australia. bchieng@med.usyd.edu.au
Bekkers
J M
JM
D000241:Adenosine / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001464:Barium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism*; D048429:Cell Size; D004594:Electrophysiology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000494:pharmacology; D005033:Ethylmaleimide / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000819:agonists* / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D000701:Analgesics, Opioid; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D009292:Narcotic Antagonists; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D011957:Receptors, Opioid; D018047:Receptors, Purinergic P1; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D001464:Barium; D009270:Naloxone; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D020881:Enkephalin, D-Penicillamine (2,5)-; D020962:Heterotrimeric GTP-Binding Proteins; D000241:Adenosine; D005033:Ethylmaleimide