Distinct neural mechanisms underlying acute and repeated administration of antipsychotic drugs in rat avoidance conditioning.
BACKGROUND
Acute antipsychotic treatment disrupts conditioned avoidance responding, and repeated treatment induces a sensitization- or tolerance-like effect. However, the neurochemical mechanisms underlying both acute and repeated antipsychotic effects remain to be determined.


OBJECTIVE
The present study examined the neuroreceptor mechanisms of haloperidol, clozapine, and olanzapine effect in a rat two-way conditioned avoidance model.


METHODS
Well-trained Sprague-Dawley rats were administered with haloperidol (0.05 mg/kg, sc), clozapine (10.0 mg/kg, sc), or olanzapine (1.0 mg/kg, sc) together with either saline, quinpirole (a selective dopamine D(2/3) agonist, 1.0 mg/kg, sc), or 2,5-dimethoxy-4-iodo-amphetamine (DOI; a selective 5-HT(2A/2C) agonist, 2.5 mg/kg, sc), and their conditioned avoidance responses were tested over 3 days. After 2 days of drug-free retraining, the repeated treatment effect was assessed in a challenge test.


RESULTS
Pretreatment of quinpirole, but not DOI, attenuated the acute haloperidol-induced disruption of avoidance responding and to a lesser extent, olanzapine-induced disruption. In contrast, pretreatment of DOI, but not quinpirole, attenuated the acute effect of clozapine. On the repeated effect, pretreatment of DOI, but not quinpirole, attenuated the potentiated disruption of haloperidol, whereas pretreatment of quinpirole attenuated the potentiated disruption of olanzapine but enhanced the tolerance-like effect of clozapine.


CONCLUSIONS
These findings suggest that acute haloperidol and olanzapine disrupt avoidance responding primarily by blocking dopamine D(2) receptors, whereas acute clozapine exerts its disruptive effect primarily by blocking the 5-HT(2A) receptors. The repeated haloperidol effect may be mediated by 5-HT(2A/2C) blockade-initiated neural processes, whereas the repeated clozapine and olanzapine effect may be mediated by D(2/3) blockade-initiated neural processes.
Li
Ming
M
Department of Psychology, University of Nebraska-Lincoln, 68588, USA. mli2@unl.edu
Sun
Tao
T
Zhang
Chen
C
Hu
Gang
G
D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects*; D001569:Benzodiazepines / Q000494:pharmacology*; D003024:Clozapine / Q000008:administration & dosage / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D004334:Drug Administration Schedule; D006220:Haloperidol / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D000077152:Olanzapine; D051381:Rats; D017207:Rats, Sprague-Dawley; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology
D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D001569:Benzodiazepines; D003024:Clozapine; D006220:Haloperidol; D000077152:Olanzapine