Alpha 2-adrenoceptor agonist-mediated inhibition of [3H]noradrenaline release from rat hippocampus is reduced by 4-aminopyridine, but that caused by an adenosine analogue or omega-conotoxin is not.
The inhibitory effect of an adenosine analogue, R-PIA, and an alpha 2-adrenoceptor agonist, UK 14,304, on [3H]NA efflux from field-stimulated rat hippocampal slices was examined. The effect of 0.1 microM UK 14,304 was mimicked by 30 nM omega-conotoxin and by 10 microM cadmium chloride, inhibitors of N- and L-type Ca2+ channels. R-PIA (1 microM) had no effect per se, but caused a clear-cut inhibition after blockade of the pre-synaptic alpha 2-receptor by yohimbine. 4-Aminopyridine (4-AP) caused a dose-dependent increase in evoked transmitter release. At 30 microM 4-AP did not affect the actions of omega-conotoxin or cadmium chloride. The pre-synaptic effect of R-PIA was similarly unaffected by 30 microM 4-AP. The pre-synaptic effect of UK 14,304 was virtually abolished by 4-AP (30 microM). The effect of UK 14,304 (0.1 microM) could be partly restored by reducing the Ca2+ concentration during treatment with 4-AP (22% inhibition compared to 42% with normal Ca2+). The magnitude of increase in evoked [3H]NA efflux by yohimbine (1 microM) was decreased by 4-AP in a concentration-dependent manner from 142% increase in controls to 21% at 100 microM 4-AP. The present results indicate that NA release is reduced by somewhat different mechanisms by pre-synaptic alpha 2- and adenosine A1-receptors. Furthermore, the results indicate that pre-synaptic A1-receptors on hippocampal NA neurons do not primarily regulate 4-AP-dependent potassium channels, but they might act directly on a Ca2+ conductance.
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Department of Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Fredholm
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D015761:4-Aminopyridine; D000241:Adenosine / Q000031:analogs & derivatives*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D000068438:Brimonidine Tartrate; D002104:Cadmium / Q000494:pharmacology; D019256:Cadmium Chloride; D020916:Conotoxins; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D008978:Mollusk Venoms / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism*; D010660:Phenylisopropyladenosine / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D015016:Yohimbine / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D000631:Aminopyridines; D020916:Conotoxins; D008978:Mollusk Venoms; D011810:Quinoxalines; D002104:Cadmium; D010660:Phenylisopropyladenosine; D015016:Yohimbine; D000068438:Brimonidine Tartrate; C029960:conotoxin GI; D015761:4-Aminopyridine; D019256:Cadmium Chloride; D000241:Adenosine; D009638:Norepinephrine