Mechanism of the body weight increase induced by systemic sulpiride

doi:10.1016/0091-3057(89)90427-9

Pharmacology Biochemistry and Behavior

Volume 33, Issue 1, May 1989, Pages 45-50

https://doi.org/10.1016/0091-3057(89)90427-9 Get rights and content

Abstract

Long-term intraperitoneal administration of sulpiride induced body weight increase in female but not in male rats. The hypothesis that systemic sulpiride causes an endocrine unbalance which in turn causes body weight gain and hyperphagia was tested in four experiments. First, it was shown that even when they are on a high-fat diet male rats do not show body weight gain induced by systemic sulpiride. Second, sulpiride suppressed the estrous cycle. Third, gonadectomy prevented the body weight gain induced by systemic sulpiride in female rats. Fourth, estradiol simultaneously administered with sulpiride prevented the expected sulpiride-induced body weight gain. These results are discussed in terms of an hypothetical functional castration produced by systemic sulpiride. The well known hyperprolactinemia, induced by the pituitary D2 dopamine receptor blockade, might bring about an impairment of the steroidogenesis with subsequent decrease in estrogens level, which in turn might be responsible for the hyperphagia and body weight increase induced by systemic injections of sulpiride.

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Pathological hyperprolactinaemia causes effects that mirror the physiological actions of the hormone but are de-correlated from reproductive state. These include gynecomastia and galactorrhea (see Haddad and Wieck, 2004), infertility through oligo- or amenorrhea, (Delvoye et al., 1978; Greer et al., 1980; Smith et al., 2002; see Caufriez, 1985), diminished sexual drive, anorgasmia and ejaculatory dysfunction (Ghadirian et al., 1982; Buvat et al., 1985; Serretti and Chiesa, 2011; see Bolyakov and Paduch, 2011), obesity and metabolic syndrome (Parada et al., 1989; see Ben-Jonathan et al., 2006) as well as osteoporosis due to sex hormone imbalance (Klibanski et al., 1980). For an extensive review on the biology and actions of prolactin, the reader is referred to Freeman et al. (2000).
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Lactational exposure to sulpiride: Assessment of maternal care and reproductive and behavioral parameters of male rat pups
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In our study, SUL did not alter weight and food intake in dams during lactation. Although increased body weight was described in non-pregnant female rats [37,38], we believe that the lack of SUL-induced increase in body weight observed in this study with lactating dams is explained by the tremendous energy investment during lactation [39]. Mesolimbic and striatal dopaminergic pathways are thought to influence motor function such that DA receptor agonists stimulate and antagonists inhibit motor activity [25].
Dopaminergic receptor antagonists may be used as galactagogues because they increase serum prolactin (PRL) by counteracting the inhibitory influence of dopamine on PRL secretion. The antipsychotic drug sulpiride (SUL) is documented to be effective as a galactagogue, but it is transferred through milk to the neonates. The aim of the present study was to evaluate if maternal exposure to SUL during lactation could disrupt maternal care and/or male offspring reproductive development. The dams were treated daily (gavage) with SUL 2.5 mg/kg or 25 mg/kg during lactation. Maternal behavior was analyzed on lactational days 5 and 10. In offspring, reproductive and behavioral parameters were analyzed at different time points. SUL treatment did not impair maternal care, but caused testicular damage in male offspring. At postnatal day 90, a reduction in testis weight, volume of seminiferous tubule and histopathological alterations such as an increased percentage of abnormal seminiferous tubules were observed. Data shows that maternal exposure to SUL during lactation may impact the reproductive development of male rats and the testes seem to be the main target organ at adulthood.
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Antipsychotic treatment during pregnancy is indicated when risk of drug exposure to the fetus is outweighed by the untreated psychosis in the mother. Although increased risk of congenital malformation has not been associated with most available antipsychotic drugs, there is a paucity of knowledge on the subtle neurodevelopmental and behavioral consequences of prenatal receptor blockade by these drugs. In the present study, antipsychotic drugs, sulpiride (SUL, a selective D2 receptor antagonist) and risperidone (RIS, a D2/5HT2 receptor antagonist) were administered to pregnant Sprague–Dawley dams from gestational day 6 to 18. Both RIS and SUL prenatal exposed rats had lower birth body weights compared to controls. RIS exposure had a significant main effect to retard body weight growth in male offspring until postnatal day (PND) 60. Importantly, water maze tests revealed that SUL prenatal exposure impaired visual cue response in visual task performance (stimulus–response, S–R memory), but not place response as reflected in hidden platform task (spatial memory acquisition and retention). In addition, prenatal SUL treatment reduced spontaneous activity as measured in open field. Both behavioral deficits suggest that SUL prenatal exposure may lead to subtle disruption of striatum development and related learning and motor systems. RIS exposure failed to elicit deficits in both water maze tasks and increased rearing in open field test. These results suggest prenatal exposure to SUL and RIS may produce lasting effects on growth, locomotion and memory in rat offspring. And the differences may exist in the effects of antipsychotic drugs which selectively block dopamine D2 receptors (SUL) as compared to second generation drugs (RIS) that potently antagonize serotonin and dopamine receptors.
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Lithium treatment of patients and laboratory animals causes increased body weight but no single organ or system has been found responsible. In the present work, we showed that lithium increased the weight of the female rat's gastrointestinal (GI) tract including its contents. The weight gain of the female rat GI tract was the same order of magnitude as the weight gain of the whole body of the females. All three parts of the GI tract (stomach, small intestine, colon) participated in the weight gain. Lithium treatment of male rats also increased GI tract weight, but lithium did not increase their overall body weight because of loss of weight at other sites.
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Obesity research generally suggests that a complex system of neurotransmitters, neuropeptides, hormones and immune related factors interact in neural circuits involving at least the hypothalamus, the solitary tract and cortical structures to regulate energy homeostasis and body weight. Antipsychotics that have weight gain inducing properties may disrupt associated pathways at any of these levels, although it remains unclear what the mechanisms of action might be. Given the potential deleterious effects of weight gain, individual predictors of weight gain would be extremely helpful at the beginning of pharmacological treatment with atypical antipsychotics, allowing obesity to be avoided or for counteractive steps such as dietary restrictions to be taken in predisposed individuals. So far, only a few predictors to detect individuals at high risk have been reported and these have limited power. It is likely that genetic factors play a major role in determining individual response to antipsychotics as well as their side effect profile. In this article, we have reviewed literature related to antipsychotic-induced weight gain and have discussed the major issues, before updating the reader on current obesity research findings. Finally, we emphasize previous studies relating to the pharmacogenetics of antipsychotic-induced weight gain.

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Mechanism of the body weight increase induced by systemic sulpiride

Abstract

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Physiol. Behav.

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Trends Pharmacol. Sci.

Pharmacol. Biochem. Behav.

Life Sci.

Physiol. Behav.

Physiol. Behav.

Mol. Cell Endocrinol.

Bioavailability of [14C] sulpiride in dogs

Arch. Int. Pharmacodyn. Ther.

Localization, distribution, elimination and metabolism of 14C-sulpiride in rats

Eur. J. Drug Metab. Pharmacokinet.

Étude autoradiographique du sulpiride 14C chez la souris et le rat. Localisation spécifique au niveau de l'hypophyse du rat aprés admnistration unique et edmnistrations répétées

J. Pharmacol.

Variations in regulation of energy exchange associated with estrus, diestrus and pseudopregnancy in rats

Endocrinology

Stimulatory effect of ovine prolactin upon cultured porcine granulosa cell secretion of inhibitory activity of oocyte maturation

Endocrinology

Bioavailability of [¹⁴C] sulpiride in dogs

Localization, distribution, elimination and metabolism of ¹⁴C-sulpiride in rats

Étude autoradiographique du sulpiride ¹⁴C chez la souris et le rat. Localisation spécifique au niveau de l'hypophyse du rat aprés admnistration unique et edmnistrations répétées