Clozapine inhibits serotoninergic transmission by an action at alpha 1-adrenoceptors not at 5-HT1A receptors.
This study examined the mechanism underlying the influence of clozapine upon serotoninergic transmission in the rat. In vitro, clozapine manifested weak affinity at 5-HT1A receptors (pKi = 6.5) as compared to the agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (9.0), but high affinity at alpha 1-adrenoceptors (8.2) as compared to the alpha 1-adrenoceptor antagonist, prazosin (9.7). Ex vivo, clozapine (inhibitory dose (ID)50 = 0.7 mg/kg s.c.) mimicked prazosin (0.5) in potently occupying central alpha 1-adrenoceptors whereas, as compared to 8-OH-DPAT (0.2), it failed to occupy 5-HT1A receptors (> 10.0). The firing of serotoninergic neurones in the dorsal raphe nucleus was abolished by 8-OH-DPAT, clozapine and prazosin with ID50 values of 0.006, 0.09 and 0.07 mg/kg i.v., respectively. At comparable doses, they reduced striatal turnover of 5-HT. While the 5-HT1A receptors antagonists, (-)-tertatolol (2.0 mg/kg i.v.) and spiperone (0.63 mg/kg i.v.), blocked the action of 8-OH-DPAT upon dorsal raphe nucleus firing, they failed to modify the effect of clozapine and prazosin. In contrast, the alpha 1-adrenoceptor agonist, cirazoline (0.005 mg/kg i.v.) prevented the actions of clozapine and prazosin, but not that of 8-OH-DPAT. It is concluded that clozapine only weakly interacts with 5-HT1A receptors and that its potent alpha 1-adrenoceptor antagonist properties underlie inhibition of serotoninergic transmission.
Institut de Recherches Servier, (Paris), France.
F
F
Lejeune
V
V
Audinot
A
A
Gobert
J M
JM
Rivet
M
M
Spedding
M J
MJ
Millan
D006916:5-Hydroxytryptophan / Q000378:metabolism; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D003024:Clozapine / Q000494:pharmacology*; D004594:Electrophysiology; D008297:Male; D009474:Neurons / Q000187:drug effects; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects*; D018047:Receptors, Purinergic P1 / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects*
D018340:Receptors, Adrenergic, alpha-1; D018047:Receptors, Purinergic P1; D011985:Receptors, Serotonin; D012701:Serotonin; D006916:5-Hydroxytryptophan; D003024:Clozapine