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Published on: June 22, 2015
Distinct neural mechanisms underlying acute and repeated administration of antipsychotic drugs in rat avoidance
1Department of Psychology, University of Nebraska-Lincoln, 68588, USA. mli2@unl.edu
Rationale:
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.
Insights
Antipsychotics like haloperidol and olanzapine disrupt avoidance by blocking dopamine D(2) receptors, while clozapine uses 5-HT(2A) receptors. Repeated effects involve complex interactions between dopamine and serotonin pathways.
Area of Science:
- Neuroscience
- Pharmacology
- Behavioral Science
Background:
- Antipsychotic medications disrupt conditioned avoidance behavior.
- Understanding the neurochemical basis of acute and repeated antipsychotic effects is crucial.
- Sensitization or tolerance can occur with repeated antipsychotic treatment.
Purpose of the Study:
- To investigate the neuroreceptor mechanisms of haloperidol, clozapine, and olanzapine.
- To examine their effects on conditioned avoidance responding in rats.
- To elucidate the roles of dopamine D(2/3) and serotonin 5-HT(2A/2C) receptors.
Main Methods:
- Rats were trained on a two-way conditioned avoidance task.
- Administered haloperidol, clozapine, or olanzapine with dopamine D(2/3) agonist (quinpirole) or 5-HT(2A/2C) agonist (DOI).
- Assessed acute and repeated treatment effects on avoidance responses.
Main Results:
- Quinpirole attenuated acute haloperidol and olanzapine disruption; DOI attenuated acute clozapine disruption.
- DOI attenuated repeated haloperidol disruption; quinpirole attenuated repeated olanzapine disruption.
- Quinpirole enhanced the tolerance-like effect of clozapine with repeated treatment.
Conclusions:
- Acute haloperidol and olanzapine primarily block dopamine D(2) receptors.
- Acute clozapine primarily blocks 5-HT(2A) receptors.
- Repeated effects involve complex dopamine and serotonin receptor interactions, with differing mechanisms for each drug.
