Olanzapine differentially affects 5-HT2A and 2C receptor mRNA expression in the rat brain

Neurobiology Research Centre of Metabolic and Psychiatric Disorders, School of Health Science, University of Wollongong, Northfields Avenue, Wollongong, NSW 2522, Australia
Behavioural Brain Research (Impact Factor: 3.03). 09/2006; 171(2):355-362. DOI: 10.1016/j.bbr.2006.03.040


This study examined regional changes in rat brain mRNA levels encoding 5-HT2A and 5-HT2C receptors following chronic olanzapine treatment. The immediate effect (2 h after the last treatment) was a down-regulation of 5-HT2A receptor mRNA expression, predominantly in the hypothalamus, limbic system and striatum, while a rebound effect was observed 48 h later. 5-HT2C receptor mRNA expressions were decreased in the substantia nigra. Correlations between 5-HT2A receptor mRNA expression and total food intake, weight gain and energy efficiency were observed.

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    • "Furthermore, feeding efficiency (grams of weight gained/grams of food consumed ) was significantly increased by olanzapine and was positively correlated with total white fat mass, suggesting that the increase in adiposity was (in part) due to reduced energy expenditure (Pouzet et al., 2003; Arjona et al., 2004; Huang et al., 2006; Wallingford et al., 2008; Weston-Green et al., 2011). However, body weight gain in females was also positively correlated with total food intake (Huang et al., 2006; Han et al., 2008; Weston-Green et al., 2011,) and two studies failed to observe weight gain in pair-fed olanzapine-treated (female) rats (Davoodi et al., 2009; Ferno et al., 2011), suggesting that weight-gain depended solely on hyperphagia . Unfortunately, these studies assessed only body weight in the pair-fed group, and it cannot be excluded that adiposity levels increased in the absence of weight gain, as they did in the study by Chintoh et al. (2008). "
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    • "Other evidence is also conflicting. The mRNA receptor expression for the serotonin2C receptor has been reported to be unaffected by olanzapine treatment, which is a strong antagonist on the 5HT2C (Ki = 14) (Huang et al., 2006). On the other hand, aripiprazole, which has a high affinity for the serotonin2C receptor as a partial agonist, has a low weight gain liability. "
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    ABSTRACT: Antipsychotic-induced weight gain is of major clinical importance since it is associated with severe metabolic complications and increased mortality. The serotonin2A receptor system has been suggested to be implicated in weight gain and obesity. However, no previous in vivo imaging data have related serotonin2A receptor binding to weight gain before and after antipsychotic monotherapy. Fifteen antipsychotic-naive first-episode schizophrenia patients were included and investigated before and after six months of quetiapine treatment. We examined the relationship between serotonin2A receptor binding as measured with positron emission tomography (PET) and [18F]altanserin and change in body mass index (BMI). Quetiapine was chosen because it is characterized by a moderately high affinity for the serotonin2A receptor and a fast dissociation rate from the dopamine D2 receptor. At baseline the mean BMI was 24.2 kg/m2, range 18-36 kg/m2. After six months of quetiapine treatment (mean dose: 383 mg/day) the BMI had, on average, increased by 6.7%, corresponding to an average weight gain of 5.0 kg. We found a significant positive correlation both between neocortical serotonin2A receptor binding prior to treatment and subsequent increase in BMI (rho = 0.59, p = 0.022). At follow-up, the serotonin2A receptor occupancy was positively correlated with BMI increase (rho = 0.54, p = 0.038). To our knowledge, these are the first in vivo receptor imaging data in initially antipsychotic-naive first-episode schizophrenia patients to show that the cerebral serotonin2A receptor is associated with antipsychotic-induced weight gain.
    The International Journal of Neuropsychopharmacology 05/2014; 17(11):1-8. DOI:10.1017/S1461145714000777 · 4.01 Impact Factor
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    • "A rat model that mimics olanzapineinduced weight gain has been established in our laboratory (Zhang et al., 2014). SD rats were randomly divided into three groups and treated with olanzapine for 8, 16 and 36 days to represent early, middle and late stages of olanzapineinduced weight gain (Huang et al., 2006). Olanzapine (1 mg/kg) or vehicle was administered orally three times daily (equivalent to 3 mg/kg/day) at eight-hourly intervals at 0700 h, 1500 h and 2300 h (n = 12/group). "
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    ABSTRACT: Although second-generation antipsychotics induce severe weight gain and obesity, there is a lack of detailed knowledge about the progressive development of antipsychotic-induced obesity. This study examined the hypothalamic histamine H1 receptor and AMP-activated protein kinase (H1R-AMPK) signaling at three distinctive stages of olanzapine-induced weight gain (day 1–12: early acceleration, day 13–28: middle new equilibrium, and day 29–36: late heavy weight maintenance). At the early acceleration stage, the rats were hyperphagic with an underlying mechanism of olanzapine-increased H1R mRNA expression and AMPK phosphorylation (pAMPK), in which pAMPK levels positively correlated with H1R mRNA expression and food intake. At the middle stage, when the rats were no longer hyperphagic, the changes in H1R-AMPK signaling vanished. At the late stage, olanzapine increased H1R mRNA expression but decreased pAMPK which were positively and negatively correlated with weight gain, respectively. These data suggest a time-dependent change of H1R-AMPK signaling, where olanzapine activates AMPK by blocking the H1Rs and causing hyperphagia in the acute phase. The chronic blockade of H1R may contribute to the late stage of olanzapine-induced heavy weight maintenance. However, pAMPK was no longer elevated and actually decreased. This indicates that AMPK acts as an energy sensor and negatively responds to the positive energy balance induced by olanzapine. Furthermore, we showed that an H1R agonist, 2-(3-trifluoromethylphenyl) histamine, can significantly inhibit olanzapine-induced hyperphagia and AMPK activation in the mediobasal hypothalamus in a dose dependent manner. Therefore, lowering H1R-AMPK signaling is an effective treatment for the olanzapine-induced hyperphagia associated with the development of obesity.
    Psychoneuroendocrinology 04/2014; 42:153–164. DOI:10.1016/j.psyneuen.2014.01.018 · 4.94 Impact Factor
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