Classical as well as novel antipsychotic drugs increase self-stimulation threshold in the rat--similar mechanism of action?
Antipsychotic drugs given acutely increase the threshold for intracranial self-stimulation elicited from the ventral tegmental area. As all the antipsychotic drugs share the dopamine D2-receptor antagonism it is reasonable to believe that this is the cause for suppression of intracranial self-stimulation behaviour. The objective of this investigation was to examine the effect of classical (haloperidol) as well as novel antipsychotic drugs (clozapine, olanzapine and sertindole) on intracranial self-stimulation behaviour. Furthermore, the effects of different specific receptor antagonists on intracranial self-stimulation behaviour were examined. Our results showed that both the classical (haloperidol) and the three novel antipsychotic drugs increase the threshold for intracranial self-stimulation. The results obtained with the receptor specific antagonists showed that dopamine D2, alpha1-adrenoceptor and serotonin 5-HT2A receptor antagonisms inhibit intracranial self-stimulation behaviour and that muscarinic receptor antagonism is without effect. Even though all the tested antipsychotic drugs inhibited intracranial self-stimulation behaviour, there seems to be a difference in their ratio between doses that inhibits intracranial self-stimulation behaviour and those that produce antipsychotic effect in a preclinical model (amphetamine hyperactivity). Sertindole was the only antipsychotic drug able to produce antipsychotic effect without significant inhibition of intracranial self-stimulation behaviour at a narrow dose interval. The remaining antipsychotic drugs all inhibited intracranial self-stimulation behaviour at equal or lower doses than those producing antipsychotic effect.
Flagstad
Peter
P
H. Lundbeck A/S, Ottiliavej 9, DK-2500 Copenhagen-Valby, Denmark. PFLA@Lundbeck.com
Arnt
Jørn
J
Olsen
Christina K
CK
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D009042:Motivation; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D012653:Self Stimulation
D014150:Antipsychotic Agents; D018340:Receptors, Adrenergic, alpha-1; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; C078730:serotonin 5 receptor; D006220:Haloperidol