TY - JOUR
T1 - Clozapine, but not olanzapine, disrupts conditioned avoidance response in rats by antagonizing 5-HT 2A/2C receptors
AU - Li, Ming
AU - Sun, Tao
AU - Mead, Alexa
N1 - Funding Information:
This study was supported in part by the NIMH grant (R01MH085635) to Professor Ming Li. We thank Ms. Natashia Swalve and Heidi Gonzalez for their editorial help.
PY - 2012/4
Y1 - 2012/4
N2 - The present study was designed to assess the role of 5-HT 2A/2C receptors in the acute and repeated effect of clozapine and olanzapine in a rat conditioned avoidance response model, a validated model of antipsychotic activity. Male Sprague-Dawley rats that were previously treated with either phencyclidine (0.5-2.0 mg/kg, sc), amphetamine (1.25-5.0 mg/kg, sc), or saline and tested in a prepulse inhibition of acoustic startle study were used. They were first trained to acquire avoidance response to a white noise (CS1) and a pure tone (CS2) that differed in their ability to predict the occurrence of footshock. Those who acquired avoidance response were administered with clozapine (10.0 mg/kg, sc) or olanzapine (1.0 mg/kg, sc) together with either saline or 1-2,5-dimethoxy-4-iodoamphetamine (DOI:, a selective 5-HT 2A/2C agonist, 1.0 or 2.5 mg/kg, sc), and their conditioned avoidance responses were tested for four consecutive days. After two drug-free retraining days, the long-term repeated effect was assessed in a challenge test during which all rats were injected with a low dose of clozapine (5 mg/kg, sc) or olanzapine (0.5 mg/kg). Results show that pretreatment of DOI: dosedependently reversed the acute disruptive effect of clozapine on both CS1 and CS2 avoidance responses, whereas it had little effect in reversing the acute effect of olanzapine. On the challenge test, pretreatment of DOI: did not alter the clozapine-induced tolerance or the olanzapine-induced sensitization effect. These results confirmed our previous findings and suggest that clozapine, but not olanzapine, acts on through 5-HT 2A/2C receptors to achieve its acute avoidance disruptive effect and likely its therapeutic effects. The long-term clozapine tolerance and olanzapine sensitization effects appear to be mediated by non-5-HT 2A/2C receptors.
AB - The present study was designed to assess the role of 5-HT 2A/2C receptors in the acute and repeated effect of clozapine and olanzapine in a rat conditioned avoidance response model, a validated model of antipsychotic activity. Male Sprague-Dawley rats that were previously treated with either phencyclidine (0.5-2.0 mg/kg, sc), amphetamine (1.25-5.0 mg/kg, sc), or saline and tested in a prepulse inhibition of acoustic startle study were used. They were first trained to acquire avoidance response to a white noise (CS1) and a pure tone (CS2) that differed in their ability to predict the occurrence of footshock. Those who acquired avoidance response were administered with clozapine (10.0 mg/kg, sc) or olanzapine (1.0 mg/kg, sc) together with either saline or 1-2,5-dimethoxy-4-iodoamphetamine (DOI:, a selective 5-HT 2A/2C agonist, 1.0 or 2.5 mg/kg, sc), and their conditioned avoidance responses were tested for four consecutive days. After two drug-free retraining days, the long-term repeated effect was assessed in a challenge test during which all rats were injected with a low dose of clozapine (5 mg/kg, sc) or olanzapine (0.5 mg/kg). Results show that pretreatment of DOI: dosedependently reversed the acute disruptive effect of clozapine on both CS1 and CS2 avoidance responses, whereas it had little effect in reversing the acute effect of olanzapine. On the challenge test, pretreatment of DOI: did not alter the clozapine-induced tolerance or the olanzapine-induced sensitization effect. These results confirmed our previous findings and suggest that clozapine, but not olanzapine, acts on through 5-HT 2A/2C receptors to achieve its acute avoidance disruptive effect and likely its therapeutic effects. The long-term clozapine tolerance and olanzapine sensitization effects appear to be mediated by non-5-HT 2A/2C receptors.
KW - 2,5-Dimethoxy-4-iodo-amphetamine
KW - 5-HT2 receptor
KW - Clozapine
KW - Conditioned avoidance response
KW - D receptor
KW - Olanzapine
KW - Repeated antipsychotic treatment
KW - Sensitization
KW - Tolerance
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U2 - 10.1007/s00702-011-0722-6
DO - 10.1007/s00702-011-0722-6
M3 - Article
C2 - 21986871
AN - SCOPUS:84863455526
VL - 119
SP - 497
EP - 505
JO - Journal of Neural Transmission
JF - Journal of Neural Transmission
SN - 0300-9564
IS - 4
ER -