Several novel
antipsychotics activate
serotonin 5-HT1A receptors as well as antagonising
dopamine D2/3 receptors. Such a pharmacological profile is associated with a lowered liability to produce extrapyramidal side effects and enhanced efficacy in treating negative and
cognitive symptoms of
schizophrenia. However,
5-HT1A receptor agonists increase plasma
corticosterone and many
antipsychotics disturb the regulation of
glucose. Here, we compared the influence on plasma
glucose and
corticosterone of acute treatments with 'new generation'
antipsychotics which target
dopamine D2/3 receptors and 5-HT1A receptors, with that of atypical
antipsychotics, and with
haloperidol.
Olanzapine and
clozapine,
antipsychotics that are known to produce
weight gain and diabetes in humans, both
at 10 mg/kg p.o., substantially increased plasma
glucose (from 0.8 to 1.7 g/l) at 1 h after administration, an effect that returned to control levels after 4 h. In comparison,
F15063 (40 mg/kg p.o.) was without effect at any time point.
Olanzapine and
clozapine dose-dependently increased plasma
glucose concentrations as did
SLV313 and
SSR181507.
Haloperidol and
risperidone had modest effects whereas
aripiprazole,
ziprasidone and
bifeprunox,
antipsychotics that are not associated with metabolic dysfunction in humans, and
F15063 had little or no influence on plasma
glucose. The same general pattern of response was found for plasma
corticosterone levels. The present data provide the first comparative study of conventional, atypical and 'new generation'
antipsychotics on
glucose and
corticosterone levels in rats. A variety of mechanisms likely underlie the
hyperglycemia and
corticosterone release observed with
clozapine and
olanzapine, whilst the balance of
dopamine D2/3/5-HT1A interaction may contribute to the less favourable impact of
SLV313 and
SSR181507 compared with that of
bifeprunox and
F15063.