TY - JOUR
T1 - Effects of 5-HT 2A and 5-HT 2C receptor antagonists on acute and chronic dyskinetic effects induced by haloperidol in rats
AU - Creed-Carson, Meaghan
AU - Oraha, Alhan
AU - Nobrega, José N.
N1 - Funding Information:
Supported in part by funds from the Ontario Mental Health Foundation and the Canadian Institutes of Health Research. M.C.-C. was the recipient of an NSERC Graduate Fellowship. The authors thank Dr. P.J. Fletcher for making M100,907 available and Roger Raymond and Mustansir Diwan for excellent technical help.
PY - 2011/6/1
Y1 - 2011/6/1
N2 - An important limitation of classical antipsychotic drugs such as haloperidol (HAL) is their liability to induce extrapyramidal motor symptoms acutely and tardive dyskinetic syndromes when given chronically. These effects are less likely to occur with newer antipsychotic drugs, an attribute that is often thought to result from their serotonin-2 (5-HT 2) receptor antagonistic properties. In the present study, we used selected doses of the 5-HT 2A antagonist M100,907, the 5-HT 2C antagonist SB242,084 and the mixed 5-HT 2A/C antagonist ketanserin to re-examine the respective roles of 2A vs. 2C 5-HT 2 receptor subtypes in both acute and chronic motor effects induced by HAL. Acutely, SB242,084 (0.5mg/kg) reduced HAL-induced catalepsy, while M100,907 (0.5mg/kg) and ketanserin (1mg/kg) were without effect. None of the drugs reduced HAL-induced Fos expression in the striatum or frontal cortex, and M100,907 actually potentiated HAL-induced Fos expression in the n. accumbens. In rats chronically treated with HAL, both ketanserin and SB242,084 attenuated vacuous chewing movements, while M100,907 had no effect. In addition, 5-HT 2C but not 5-HT 2A mRNA levels were altered in several brain regions after chronic HAL. These results highlight the importance of 5-HT2 2C receptors in both acute and chronic motoric side effects of HAL, and suggest that 5-HT 2C antagonism could be targeted as a key property in the development of new antipsychotic medications.
AB - An important limitation of classical antipsychotic drugs such as haloperidol (HAL) is their liability to induce extrapyramidal motor symptoms acutely and tardive dyskinetic syndromes when given chronically. These effects are less likely to occur with newer antipsychotic drugs, an attribute that is often thought to result from their serotonin-2 (5-HT 2) receptor antagonistic properties. In the present study, we used selected doses of the 5-HT 2A antagonist M100,907, the 5-HT 2C antagonist SB242,084 and the mixed 5-HT 2A/C antagonist ketanserin to re-examine the respective roles of 2A vs. 2C 5-HT 2 receptor subtypes in both acute and chronic motor effects induced by HAL. Acutely, SB242,084 (0.5mg/kg) reduced HAL-induced catalepsy, while M100,907 (0.5mg/kg) and ketanserin (1mg/kg) were without effect. None of the drugs reduced HAL-induced Fos expression in the striatum or frontal cortex, and M100,907 actually potentiated HAL-induced Fos expression in the n. accumbens. In rats chronically treated with HAL, both ketanserin and SB242,084 attenuated vacuous chewing movements, while M100,907 had no effect. In addition, 5-HT 2C but not 5-HT 2A mRNA levels were altered in several brain regions after chronic HAL. These results highlight the importance of 5-HT2 2C receptors in both acute and chronic motoric side effects of HAL, and suggest that 5-HT 2C antagonism could be targeted as a key property in the development of new antipsychotic medications.
KW - 5-HT receptors
KW - Catalepsy
KW - Haloperidol
KW - Ketanserin
KW - M100,907
KW - SB242,084
KW - Tardive dyskinesia
KW - Vacuous chewing movements
UR - http://www.scopus.com/inward/record.url?scp=79952702074&partnerID=8YFLogxK
U2 - 10.1016/j.bbr.2011.01.025
DO - 10.1016/j.bbr.2011.01.025
M3 - Article
C2 - 21262266
AN - SCOPUS:79952702074
SN - 0166-4328
VL - 219
SP - 273
EP - 279
JO - Behavioural Brain Research
JF - Behavioural Brain Research
IS - 2
ER -