Effects of Ovariectomy and 17<i>β</i>-Estradiol Replacement on Dopamine D2 Receptors in Female Rats: Consequences on Sucrose, Alcohol, Water Intakes and Body Weight

Abstract

Background: Mechanisms underlying overeating-induced obesity in postmenopausal woman include functional lack of 17β-estradiol dysregulating dopamine D2 receptors, thereby inducing food addiction, glucose craving or alcohol dependence through reward circuitry. This study aimed at further understanding 17β-estradiol and dopamine D2 receptors interferences in the etiology of woman obesity. Method: Seventy-two Wistar female rats weighing 200 -205 g, individually-housed, were divided into non-ovariectomized control (C = 6 groups) and ovariectomized rats (OVX = 6 groups) which were concurrently subjected to the following treatments: Non-drug-treated (DMSO vehicle), 17β-estradiol (E2, 5 µg/kg, s.c.), sulpiride (SUL, 20 mg/kg, i.p.), bromocriptine (BR, 0.1 mg/kg, i.p.), E2 + SUL or E2 + BR, designating the 6 constitutive groups of either control or ovariectomy. Within each experimental group, consumption of different solutions (10% alcohol, 10% sucrose and water) as well as food intake and body weight were daily measured, for 10 consecutive days. Results: This study indicated that D2S was a specific inducer of alcohol and food intakes, but reduced sugar consumption. In addition, 17β-estradiol regulated the body weight set point, modulating D2S functions towards increased food intake at lower weights and decreased food intake at higher weights. D2S met the slow genomic actions induced by 17β-estradiol. Conversely, D2L inhibited alcohol and food intakes, but induced specifically sugar consumption, thereby regulating blood glucose levels and promoting energy expenditure in reducing body weight. Indeed, 17β-estradiol exerted a tonic inhibition on D2L which was released by OVX, exacerbating sugar intake and increasing body weight. D2L mediated the rapid metabolic effects of that activation of the mostly expressed presynaptically D2S-class autoreceptors decreased dopamine release stimulating food intake, whereas activation of the predominantly postsynaptic isoform D2L receptors increased dopamine activity inhibiting food intake. Our studies indicated that 17β-estradiol acted on the two types of D2 receptors showing opposite functions to equilibrate energy intake vs. expenditure for weight set point regulation. Our data also supported biochemical findings reporting that 17β-estradiol induced D2 genes transcriptional regulation, thereby involving both types of D2 receptors in the etiology of obesity. The combined dysregulated effects of D2L and D2S receptors, as 17β-estradiol was lacking, would be causal factors underlying the etiology of obesity.

Effects of 17<i>β</i>-Estradiol on Dopamine D2 Receptors in Thiamine-Deficient Female Rats: Consequences on Sucrose, Alcohol, Water Intakes and Body Weight

“…The use of E2, BR and SUL in the present experiments was related to our previous studies indicating that 17β-estradiol acted on two types of D2 receptors showing opposite functions to equilibrate energy intake vs. expenditure for weight set point regulation [20]. However, thiamine is the rotating wheel for body energy supply [4].…”

“…Conversely, D2L inhibited alcohol and food intakes, but induced specifically sugar consumption, thereby regulating blood glucose levels. D2L mediated the rapid metabolic effects of E2 [20]. Our studies indicated that 17β-estradiol acted on two types of D2 receptors showing opposite functions to equilibrate energy intake vs. expenditure for weight set point regulation [20].…”

“…These experiments were undertaken for further understanding of the role of thiamine (vitamin B1) on the E2-D2 receptors regulatory system whose disorder has been showed to be involved in mechanisms triggering woman obesity [20]. Since E2 is a female hormone, the present experiments are carried out exclusively on female rats.…”

“…Drugs and Chemicals used in these experiments were: 17β-estradiol (estradiol or E2), bromocriptine mesylate, sulpiride and dimethyl sulfoxide (DMSO) manufactured by Sigma-Aldrich Chemie GmbH (Eschenstrasse 582,024 Taufkirchen, S. Silué, A. Bâ Journal of Biosciences and Medicines Germany). DMSO was the solvent used for all drug dilution [20]. Bromocriptine mesylate (BR) and sulpiride (SUL) were used as selective agonist and antagonist respectively, targeting central dopamine-D2 receptors [21] [22].…”

“…After daily drug injection, the remaining content of the vial (one drug for a non-S. Silué, A. Bâ Journal of Biosciences and Medicines interchangeable 5 ml vial), as well as drinking solution contained in a 150 ml bottle were refreshed every day [20].…”