Aripiprazole and haloperidol suppress excessive dopamine release in the amygdala in response to conditioned fear stress, but show contrasting effects on basal dopamine release in methamphetamine-sensitized rats

Although emotional dysfunction in patients with schizophrenia is thought to be associated with poorer outcomes in terms of overall quality of well-being, only a few basic studies have examined the biochemical effect of antipsychotics on emotional function. In this investigation, we examined differences in the effects of aripiprazole and haloperidol on the conditioned fear response in methamphetamine-sensitized and fear-conditioned rats in an in vivo microdialysis study. Aripiprazole is the first antipsychotic drug with an action involving partial dopamine D2 receptor agonism, thus differing from haloperidol, a typical antipsychotic that shows selective dopamine D2 receptor full antagonism. After exposure to a conditioned stimulus, methamphetamine-sensitized rats exhibited significantly higher dopamine release in the amygdala than unsensitized rats. We considered this hypersensitivity of dopamine release to be a biochemical marker of hypersensitivity and vulnerability to stress in psychosis. In the present study, we found that aripiprazole and haloperidol equally suppressed the marked increase in extracellular dopamine levels in fear-conditioned rats, whereas haloperidol increased and aripiprazole decreased tonic dopamine levels. In conclusion, the effect of an antipsychotic drug is likely to be involved in attenuation of the phasic increase in dopamine associated with the fear response, at least in the amygdala. In addition, the contrasting effects of haloperidol and aripiprazole on tonic dopamine levels in the amygdala are likely due to the difference in their actions (selective dopamine D2 receptor full antagonist vs. partial agonist, respectively).