Effects of fluperlapine on dopaminergic systems in rat brain

Abstract

Fluperlapine has been reported to possess antischizophrenic and antidepressant properties, with low incidence of extrapyramidal side-effects. In order to get more information about the interactions of fluperlapine with rat brain dopaminergic systems, its binding to striatal D2 receptors, measured ex vivo, and its effects on DA metabolism in different brain areas were investigated. Clozapine and haloperidol served as reference compounds in these investigations. It was found that all three agents blocked D2 receptors and increased DA metabolism. Clozapine and fluperlapine differed from haloperidol in that their potency was much lower. Although occupation of striatal D2 receptors by the two dibenzo-epines developed rapidly, the duration was considerably shorter than that of haloperidol. There was no indication that the two dibenzo-epines had a stronger or longer-lasting effect on limbic or cortical DA metabolism compared to that on the striatum. Both drugs caused a weak increase in striatal DA, whereas haloperidol decreased it. It was concluded that the low incidence of extrapyramidal side-effects of fluperlapine, and also of clozapine, is probably due to their weak and relatively brief action on brain DA systems and not due to a selective action on A10 neurotransmission. The anticholinergic properties of the dibenzo-epines might even further reduce the consequences of their already weak effects on DA systems.

Central α2-Adrenoceptor-Mediated Inhibition of Gastric Motility in Rats

“…These findings in dicate that the action of SM-9018 in the striatum relative to that in the cerebral cortex is weaker than that of haloperidol. Our findings are consistent with previous reports (13)(14)(15) indicating that atypical neuroleptics (e.g., clozapine) exhibit similar potencies in increasing DA turnover both in the cortex and striatum, whereas typical neuroleptics (e.g., haloperidol) preferentially en hance the striatal DA turnover. Thus SM-9018, like other atypical neuroleptics, appeared to have a propensity to act on the mesocortical (vs. nigrostriatal) dopaminergic system as compared with typical neuroleptics.…”

Antipsychotic Dosing in Preclinical Models Is Often Unrepresentative of the Clinical Condition: A Suggested Solution Based on in Vivo Occupancy

“…Rats that received a subcutaneous injection of haloperidol, olanzapine, or risperidone were sacrificed 2 h after drug administration (Campbell et al, 1980;Schotte et al, 1996). Those rats that received clozapine or quetiapine were sacrificed 1 h after drug administration since these drugs have been shown to have peak effects in the brain earlier than the other antipsychotics (Burki, 1986;Saller and Salama, 1993). It should be pointed out that the "peak" times were chosen based on previous studies relating to pharmacokinetics and functional effects and therefore should be regarded as approximations as opposed to definitive periods of maximal occupancy.…”

Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors

“…Another enduring theory of atypicality is based on the dissociation kinetics of APDs from the D 2 R. This concept originated from the observation that some atypical APDs have lower affinity for the D 2 R than typical APDs 14 – 16 , which was later demonstrated to be due to a faster dissociation rate 17 – 19 . This led Seeman and Kapur to propose the “fast off hypothesis,” whereby rapid dissociation from the D 2 R contributes to the reduced side effect profile of atypical APDs 13 .…”