Nicotinic-receptor potentiator drugs, huprine X and galantamine, increase ACh release by blocking AChE activity but not acting on nicotinic receptors.
The main goal of the present study was to analyse the effects of (+/-)-huprine X ((+/-)-HX) and galantamine (GAL), with potentiating action on nicotinic receptors, and huperzine A (HPA), devoid of nicotinic activity, on [3H]-acetylcholine ([3H]-ACh) release in striatal slices of rat brain. All compounds are non-covalent and reversible inhibitors of AChE. Addition of (+/-)-HX (0.01 microM), GAL (10 microM) and HPA (0.1 microM) to the superfusion medium decreased the release of the ACh neurotransmitter to a similar extent: 36%, 30% and 34%, respectively (P<0.01). This effect was reverted in the presence of atropine (ATR; 0.1 microM), which blocks the pre-synaptic muscarinic M2 receptor. After that, a wide range of concentrations of drugs, concomitantly with ATR (0.1 microM), was studied in the presence of haloperidol (HAL; 0.01 microM), a dopamine D2 antagonist. In these conditions, a dose-dependent increase of [3H]-ACh release was observed in the presence of (+/-)-HX, GAL and HPA. To test the role of nicotinic receptors in the drugs' effects on [3H]-ACh release, mecamylamine (MEC) 100 microM was used to block such receptors. MEC alone significantly decreased neurotransmitter release by 18% (P<0.05), but no change was obtained in the presence of both ATR and MEC. Under these conditions, (+/-)-HX, GAL and HPA increased the release of [3H]-ACh by 37%, 25% and 38%, respectively (P<0.01). Taking into account all of these data, the present results suggest that the effects induced by (+/-)-HX and GAL nicotinic-receptor potentiators seem to be mainly due to their ability in inhibiting acetylcholinesterase activity, but not by interaction on the nicotinic receptors.
Roman
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Departament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de Barcelona, Institut de Neurociències Universitat Autònoma de Barcelona, 08193-Bellaterra, Barcelona, Spain.
Badia
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Camps
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Muñoz-Torrero
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Clos
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D000109:Acetylcholine / Q000378:metabolism*; D000470:Alkaloids; D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002800:Cholinesterase Inhibitors; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005702:Galantamine / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D066298:In Vitro Techniques; D008464:Mecamylamine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010276:Parasympatholytics / Q000494:pharmacology; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects*; D012717:Sesquiterpenes / Q000494:pharmacology
D000470:Alkaloids; D000634:Aminoquinolines; D002800:Cholinesterase Inhibitors; D018492:Dopamine Antagonists; D006576:Heterocyclic Compounds, 4 or More Rings; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D010276:Parasympatholytics; D011978:Receptors, Nicotinic; D012717:Sesquiterpenes; C404518:huprine X; C050426:huperzine A; D005702:Galantamine; D008464:Mecamylamine; D001285:Atropine; D006220:Haloperidol; D000109:Acetylcholine