Mechanistic role of histaminergic H1 receptors in the regulation of appetite and atypical antipsychotic induced weight gain

F. Batool¹, A. Shah². ¹Biochemistry, University of Karachi Pakistan, Karachi, Pakistan, ²Biotechnology, University of Management Sciences and IT, Kotli, Pakistan.

Introduction: Atypical antipsychotic drugs, as a result of superior efficacy and overall tolerability, have become the treatment of choice for schizophrenia and related disorders, despite their side effects. Weight gain is a common and potentially serious complication of some antipsychotic drug therapy, and may be accompanied by hyperlipidemia, hypertension and hyperglycemia and type II diabetes (1). We proposed that a mechanism for atypical antipsychotic induced weight gain may be partly through the H1 receptors as clozapine has a high affinity for H1 receptors in brain.

Method: Rats (Albino Wistar) (n=48) weighing 180+10gm were purchased from Dow University of Health Sciences, Pakistan. Housing conditions were same as described elsewhere (2). Experiments were conducted in accordance with NIH guidelines and approved by the Institutional Ethical Committee, University of Karachi, Pakistan. Rats were randomized into three groups (n=16). Controls received equal volume of Saline (0.9% NaCl; 1mg.ml^-1.kg^-1) and vehicle. Tests groups received single i.p. injections of Clozapine (2.5mg.kg^-1) and Risperidone (2.5mg.kg^-1) daily for three weeks. Groups were further subdivided into six (n=8) and each group received successive administrations of H1 antagonist Promethazine (5.0mg.kg^-1) for two weeks. Food Intake, body weight and growth rate data were monitored weekly. Catalepsy bar test, elevated plus maze (EPM) test and Motor coordination test were used to evaluate hypolocomotive and extrapyramidal symptoms in rats. Post mortem samples were used to assess serum levels of glucose, cholesterol, insulin and leptin. Statistical analysis was determined by one-way ANOVA and 2-factor ANOVA with repeated measures using Prism v6.0; GraphPad Software San Diego, USA. Data are presented as the mean±SEM (n=48). A probability of less than 0.05 was considered statistically significant.

Results: Administration of Promethazine (5.0mg.kg^-1) significantly (P<0.01) increased food intake and exacerbate the 3-week developed clozapine (2.5mg.kg^-1) induced obesity in rats. Clozapine (2.5mg.kg^-1) treated rats exhibited 60% more catalepsy (P<0.01) and motor incoordination when treated with Promethazine. Significant increases (P<0.01) were observed in serum levels of cholesterol (F=172.3 P<0.01), glucose (F=146.5 P<0.01), Insulin (F=29.6 P<0.01) and leptin (F=142.6 P<0.01).

Conclusions: The findings suggest that histaminergic H1 receptors are crucial for the regulation of feeding and antipsychotic-induced weight gain and Metabolic Syndrome. In addition, antipsychotics with high affinity for H1 receptors are associated with significant weight gain, In future, centrally acting H1 receptors may be a novel therapeutic target for the treatment of obesity and related metabolic disorders.

References:

1. Batool F et al. (2010) Acta Pharm 60: 129–140.