Potential role of 5-HT2 and D2 receptor interaction in the atypical antipsychotic action of the novel succimide derivative, perospirone.
The pharmacological profile of the novel serotonin-dopamine antagonists (SDA)-type antipsychotic, perospirone, was compared with other SDA and typical antipsychotics, and a potential role of 5-HT2 and D2 receptor interaction in the atypical antipsychotic property of SDA was discussed based on the findings with selective 5-HT2 antagonists. Our study revealed that perospirone, like other SDA, differed from the typical antipsychotics by exhibiting 1) putative anxiolytic and/or antidepressant actions in some animal models (e.g., conditioned fear stress-induced freezing model and rat social interaction), 2) reduced extrapyramidal side effects (EPS) liability (catalepsy and bradykinesia induction), 3) weaker blocking actions at striatal D2 receptors as revealed by c-fos expression and dopamine turnover and 4) lower propensity to induce supersensitivity of dopamine receptors after repeated treatments (e.g., dopamine agonist-induced stereotyped behavior and vacuous chewing movement). The 5-HT2 antagonists mimicked the action of SDA antipsychotics in the animal models of mood disorder. In addition, combined treatments of 5-HT2 antagonists with typical antipsychotic could attenuate EPS induction and striatal c-fos expression associated with D2 receptor blockade, and could prevent the sensitization of D1 receptor function after repeated treatments. These findings suggest that the blockage of 5-HT2 receptors contributes to the broad efficacy profile of SDA (i.e., antipsychotic and mood stabilizing actions) and may counteract the D2 (and/or D1) blocking activities of antipsychotics in the striatum to reduce EPS.
Ohno
Y
Y
Discovery Research Laboratories II, Sumitomo Pharmaceuticals Co., Ltd., Osaka, Japan.
Ishida-Tokuda
K
K
Ishibashi
T
T
Sakamoto
H
H
Tagashira
R
R
Horisawa
T
T
Yabuuti
K
K
Matsumoto
K
K
Kawabe
A
A
Nakamura
M
M
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D018492:Dopamine Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007211:Indoles / Q000494:pharmacology* / Q000633:toxicity; D054833:Isoindoles; D019964:Mood Disorders / Q000188:drug therapy; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology* / Q000633:toxicity
D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D007211:Indoles; D054833:Isoindoles; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013844:Thiazoles; C065533:perospirone