Clozapine, but not olanzapine, disrupts conditioned avoidance response in rats by antagonizing 5-HT 2A/2C receptors

Ming Li, Tao Sun, Alexa Mead

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)497-505
Number of pages9
JournalJournal of Neural Transmission
Volume119
Issue number4
DOIs
StatePublished - Apr 1 2012

Fingerprint

olanzapine
Receptor, Serotonin, 5-HT2C
Receptor, Serotonin, 5-HT2A
Clozapine
Phencyclidine
Therapeutic Uses
Amphetamine
Acoustics
Antipsychotic Agents
Sprague Dawley Rats
Serotonin

Keywords

  • 2,5-Dimethoxy-4-iodo-amphetamine
  • 5-HT2 receptor
  • Clozapine
  • Conditioned avoidance response
  • D receptor
  • Olanzapine
  • Repeated antipsychotic treatment
  • Sensitization
  • Tolerance

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Psychiatry and Mental health
  • Biological Psychiatry

Cite this

Clozapine, but not olanzapine, disrupts conditioned avoidance response in rats by antagonizing 5-HT 2A/2C receptors. / Li, Ming; Sun, Tao; Mead, Alexa.

In: Journal of Neural Transmission, Vol. 119, No. 4, 01.04.2012, p. 497-505.

Research output: Contribution to journalArticle

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abstract = "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.",
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