Generalization of serotonin (5-HT)1A agonists and the antipsychotics, clozapine, ziprasidone and S16924, but not haloperidol, to the discriminative stimuli elicited by PD128,907 and 7-OH-DPAT.
Rats were trained to recognize a discriminative stimulus (DS) elicited by the dopamine D(2)/D(3) receptor agonist, PD128,907 (0.16 mg/kg, i.p.), which suppressed frontocortical release of dopamine (DA) but not 5-HT. The selective 5-HT1A receptor agonists, 8-OH-DPAT and flesinoxan, dose-dependently generalized to PD128,907 with effective dose(50)s (ED50s) of 0.08 and 1.5mg/kg, s.c., respectively, and inhibited the release and synthesis of 5-HT but not of DA. The 'atypical' antipsychotic, clozapine, which displays weak partial agonist properties at 5-HT1A receptors, dose-dependently, though partially, generalized to PD128,907 (50%, 2.5mg/kg, s.c.). Further, S16924 and ziprasidone, which in a like manner, display partial agonist activity at 5-HT1A receptors, generalized with ED50s of 0.6 and 2.3mg/kg, s.c., respectively. In contrast, haloperidol, which is devoid of affinity at 5-HT1A sites, was inactive. At doses equivalent to those generalizing to PD128,907, clozapine, S16924 and ziprasidone reduced serotonergic (but not dopaminergic) transmission, whereas haloperidol was inactive. In rats trained to recognize a further D2/D3 agonist, 7-OH-DPAT (0.16 mg/kg, i.p.), generalization was obtained similarly with 8-OH-DPAT (ED50 = 0.07 mg/kg, s.c.), flesinoxan (3.4) and clozapine (0.6), but not with haloperidol. In conclusion, although PD128,907 and 7-OH-DPAT do not directly interact with 5-HT1A receptors or influence serotonergic transmission, their DS properties are mimicked by 5-HT1A receptor agonists at doses activating 5-HT1A but not D2/D3 (auto)receptors. These observations likely account for generalization of clozapine, S16924 and ziprasidone to PD128,907 and 7-OH-DPAT inasmuch as they behave as antagonists at D2/D3 receptors, yet agonists at 5-HT1A (auto)receptors.
Dekeyne
A
A
Department of Psychopharmacology, Centre de Recherches de Croissy, Institut de Recherches Servier, 125 Chemin de Ronde, 78290 - Croissy-sur-Seine, Paris, France.
Rivet
J M
JM
Gobert
A
A
Millan
M J
MJ
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology; D004193:Discrimination Learning / Q000187:drug effects* / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D008297:Male; D010078:Oxazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D050637:Receptors, Dopamine D3; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology
D014150:Antipsychotic Agents; D001578:Benzopyrans; C493593:DRD3 protein, human; D018491:Dopamine Agonists; C493595:Drd3 protein, rat; D010078:Oxazines; D010879:Piperazines; D011759:Pyrrolidines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; C114530:S 16924; D017366:Serotonin Receptor Agonists; D013764:Tetrahydronaphthalenes; D013844:Thiazoles; C062458:3,4,4a,10b-tetrahydro-4-propyl-2H,5H-(1)benzopyrano(4,3-b)-1,4-oxazin-9-ol; D012701:Serotonin; C092292:ziprasidone; D003024:Clozapine; D006220:Haloperidol; C031349:7-hydroxy-2-N,N-dipropylaminotetralin; D004298:Dopamine