Second-generation
antipsychotics including
olanzapine are associated with
weight gain,
dyslipidemia and other metabolic disorders. Both animal and clinical studies have shown that co-treatment with
betahistine (a
histamine H1 receptor agonist/
H3 receptor antagonist) is effective in controlling
olanzapine-induced
weight gain. In the present study, we investigate whether co-treatment with
betahistine is able to prevent
dyslipidemia induced by chronic
olanzapine treatment and the underlying mechanisms. Female rats were orally administered with
olanzapine (1 mg/kg, t.i.d.) for 3.5 consecutive weeks and then a 2.5-week
drug withdrawal. Then, rats were divided into 4 groups for 5 weeks treatment: (1) vehicle, (2)
olanzapine-only (1 mg/kg, t.i.d.), (3)
betahistine-only (9.6 mg/kg, t.i.d.), and (4)
olanzapine and
betahistine (O+B) co-treatment. After completing treatment, hepatic
mRNA expression was measured by qRT-PCR, while the
protein levels were detected by western blot. In our study,
olanzapine-only treatment significantly increased
triglyceride accumulation and non-
esterified fatty acids (
NEFA), and upregulated
mRNA expression of
sterol regulatory element binding protein 1 (SREBP-1) and its target genes, while these alterations were ameliorated by O+B co-treatment. Hepatic
AMP-activated protein kinase α (AMPKα) was activated in the O+B co-treatment group, with a significant reduction in nuclear SREBP-1
protein expression but an increased expression of
peroxisome proliferator-activated receptor-α (PPARα) and its-responsive molecule(CPT1A), compared with
olanzapine-only treatment. In addition,
olanzapine significantly increased hepatic
histamine H1 receptors, while O+B co-treatment significantly reversed them to normal levels. This study provided the first evidence that
betahistine could act on hepatic
H1 receptors via modulation of AMPKα-SREBP-1 and PPARα-dependent pathways to ameliorate
olanzapine-induced
dyslipidemia in rats.