Chronic clozapine, but not haloperidol, alters the response of mesoprefrontal dopamine neurons to stress and clozapine challenges in rats

Abstract

Previously, we demonstrated that serotonin-lesioned rats had an enhanced mesoprefrontal dopaminergic response to restraint stress. This study attempted to extend our knowledge regarding this serotonin/dopamine interaction by seeing if suppression of serotonin metabolism by chronic administration of the atypical antipsychotic, clozapine, would have similar effects. Both typical and atypical neuroleptics require chronic administration in humans before antipsychotic activity is seen. Rats treated for 21 days with clozapine or haloperidol, a typical antipsychotic without significant binding affinity for serotonergic receptors, showed lowered basal dopamine metabolism in the medial prefrontal cortex, the nucleus accumbens, and the striatum, as expected. Basal serotonin metabolism in the prefrontal cortex was also lowered by clozapine treatment, but not haloperidol. One of two challenges were given to chronically treated rats: 30 min of restraint stress or an acute challenge of clozapine. When corrected for baseline differences, both challenges significantly elevated dopamine metabolism in the prefrontal cortex of the clozapine group more than the saline or haloperidol groups. No hyperresponsiveness was seen with serotonin metabolism in the prefrontal cortex or either dopamine or serotonin metabolism in the nucleus accumbens in clozapine-treated, challenged rats. Additionally, this augmentation of the dopaminergic stress response was not seen with a single, acute administration of clozapine. The significance of the clozapine-induced hyperresponsiveness of the mesoprefrontal dopamine system is discussed with regard to clinical efficacy of clozapine.

Clozapine impact on c‐Fos expression in mild stress preconditioned male rats exposed to a novelty stressor

“…increases the extracellular dopamine in the mPFC and NAc shell (Abercrombie, Keefe, DiFrischia, & Zigmond, ; Holly & Miczek, ; Imperato, Puglisi‐Allegra, Casolini, & Angelucci, ) and elevated dopamine level induced by footshock was reduced/abolished by chronic CLZ administration (Dazzi, Seu, Cherchi, & Biggio, ). Previously it has been shown that rats chronically treated with CLZ for 21 days and then exposed to 30 min of restraint stress or an acute challenge of CLZ had significantly elevated dopamine metabolism (DOPAC/dopamine) in the prefrontal cortex (Morrow, Rosenberg, & Roth, ). Chronic CLZ administration has also been shown to reduce the number of 5‐HT2 receptors and lower the basal serotonin metabolism in the prefrontal cortex.…”

“…Chronic CLZ administration has also been shown to reduce the number of 5‐HT2 receptors and lower the basal serotonin metabolism in the prefrontal cortex. However, no change has been seen after exposure to acute restraint stress (Morrow et al, ). Other study has shown up‐regulated GAD67 mRNA in the NAc induced by chronic CLZ treatment (Lipska, Lerman, Khaing, Weickert, & Weinberger, ).…”