Clozapine attenuates N-methyl-D-aspartate receptor complex-mediated responses in vivo: tentative evidence for a functional modulation by a noradrenergic mechanism.
Recent studies revealed a role for dopamine and noradrenaline in the etiology of ischemia-induced neuronal cell death. In the present investigation, the modulation by clozapine, an atypical antipsychotic agent that interacts with adrenergic receptors, of N-methyl-D-aspartate (NMDA) receptor complex-mediated events were studied by examining its effects on levels of cGMP in the cerebellum. Clozapine decreased basal levels of cGMP in the cerebellum and antagonized harmaline-, methamphetamine-, pentylenetetrazol- and D-serine-induced increases in levels of cGMP with ED50 values of 3.9, 2.36, 2.13 and 2.1 mg/kg (i.p.). However, clozapine (1.25-25 mg/kg) did not attenuate the quisqualate-induced increases in levels of cGMP, indicating a specific modulation of events modulated by the NMDA receptor complex. Antagonists of dopamine (D2), serotonin (5-HT)-5-HT1, 5-HT2 and 5-HT3 [haloperidol, propranolol, ritanserin, ICS 205-930 [(3-tropanyl-indole-3-carboxylate methiodide)] respectively], did not reverse the response to harmaline. However, WB-4101 [(2,6-dimethoxy-phenoxyethyl)aminomethyl-1,4-benzodioxane HCl], and alpha 1-adrenergic antagonist, reversed harmaline-, D-serine-, PTZ- and MA-induced increases in levels of cGMP, indicating an adrenergic modulation of the events mediated by the NMDA receptor complex. Intracerebellar and intracerebroventricular administration of clozapine and intracerebellar administration of WB-4101 reversed the D-serine-induced response, indicating a central locus of action. These results indicated that clozapine modulates levels of cGMP predominantly through its interactions with central adrenergic receptors.
Rao
T S
TS
CNS Diseases Research, G. D. Searle & Co., St. Louis, MI 63198.
Contreras
P C
PC
Cler
J A
JA
Emmett
M R
MR
Mick
S J
SJ
Iyengar
S
S
Wood
P L
PL
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D003024:Clozapine / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism; D004146:Dioxanes / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D006246:Harmaline / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D009638:Norepinephrine / Q000502:physiology*; D010433:Pentylenetetrazole / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D016713:Ritanserin / Q000494:pharmacology; D012694:Serine / Q000494:pharmacology; D000077526:Tropisetron
D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D006635:Histamine H2 Antagonists; D007211:Indoles; D016194:Receptors, N-Methyl-D-Aspartate; D016713:Ritanserin; D008694:Methamphetamine; D012694:Serine; D000077526:Tropisetron; D006246:Harmaline; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane; D006152:Cyclic GMP; D003024:Clozapine; D006220:Haloperidol; D010433:Pentylenetetrazole; D009638:Norepinephrine