Effects of central activation of serotonin 5-HT2A/2C or dopamine D 2/3 receptors on the acute and repeated effects of clozapine in the conditioned avoidance response test.

  • Feng M
  • Gao J
  • Sui N
 et al. 
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Abstract

RATIONALE: Acute administration of clozapine (a gold standard of atypical antipsychotics) disrupts avoidance response in rodents, while repeated administration often causes a tolerance effect.

OBJECTIVE: The present study investigated the neuroanatomical basis and receptor mechanisms of acute and repeated effects of clozapine treatment in the conditioned avoidance response test in male Sprague-Dawley rats.

METHODS: 2,5-dimethoxy-4-iodo-amphetamine (DOI, a preferential 5-HT2A/2C agonist) or quinpirole (a preferential dopamine D2/3 agonist) was microinjected into the medial prefrontal cortex (mPFC) or nucleus accumbens shell (NAs), and their effects on the acute and long-term avoidance disruptive effect of clozapine were tested.

RESULTS: Intra-mPFC microinjection of quinpirole enhanced the acute avoidance disruptive effect of clozapine (10 mg/kg, sc), while DOI microinjections reduced it marginally. Repeated administration of clozapine (10 mg/kg, sc) daily for 5 days caused a progressive decrease in its inhibition of avoidance responding, indicating tolerance development. Intra-mPFC microinjection of DOI at 25.0 (but not 5.0) μg/side during this period completely abolished the expression of clozapine tolerance. This was indicated by the finding that clozapine-treated rats centrally infused with 25.0 μg/side DOI did not show higher levels of avoidance responses than the vehicle-treated rats in the clozapine challenge test. Microinjection of DOI into the mPFC immediately before the challenge test also decreased the expression of clozapine tolerance.

CONCLUSIONS: Acute behavioral effect of clozapine can be enhanced by activation of the D2/3 receptors in the mPFC. Clozapine tolerance expression relies on the neuroplasticity initiated by its antagonist action against 5-HT2A/2C receptors in the mPFC.

Author-supplied keywords

  • 2c receptor
  • 3 receptor
  • 5-ht 2a
  • clozapine
  • conditioned avoidance
  • d 2
  • medial
  • prefrontal cortex
  • response
  • tolerance

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Authors

  • Min Feng

  • Jun Gao

  • Nan Sui

  • Ming Li

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