Are There Connections between the Neuroendocrine and Dopamine Systems in Bipolar Disorder?

Abstract

Background: Bipolar disorder (BPD) represents a frequent and disabling disease, characterized by the occurrence of extreme mood swings leading to episodes of depression or mania. Although dysfunctions in dopamine (DA) neurotransmission are increasingly recognized as key determinants of BPD, little attention has been given to the biological factors which may shape such a cyclicity of mania and depression.

Summary: We propose that BPD may result, at least in part, from skewed connections between the neuroendocrine system, the DA system, and the hypothalamic clock center. First, we provide a brief description of the hypothalamic-pituitary complex, i.e., the core anatomical structure of the neuroendocrine system. We then review clinical data demonstrating the frequent onset of BPD at menopause, during postpartum or in peri-pubertal periods, suggesting that hormonal changes, under neuroendocrine regulation, may favor the clinical expression of BPD. Finally, we revisit the DA hypothesis of BPD and propose that both the hypothalamic clock center and the hypothalamic-pituitary axis exert rheostat effects on the regulation of mood by DA. Thus, in individuals with a genetically determined predisposition to BPD, an alteration of such rheostat functions may translate into a hyper- or hypo-activity of the DA system. Potential therapeutic implications and future research directions are discussed.

Key messages: BPD may be related to altered connections between the DA system, the neuroendocrine system and the hypothalamic clock center. We hope this article will provide a basis for future interactions between endocrinologists, neurobiologists, and psychiatrists.

Keywords: Bipolar disorder; Dopamine system; Hypothalamic clock center; Hypothalamus-pituitary complex; Neuroendocrinology.

Fig. 1.

Hypothalamus-pituitary complex in humans: anatomical structure of the neuroendocrine system. a Hypothalamo-pituitary connections (modified from [21]). Hypothalamo-posterior pituitary connections: hypothalamic neuroendocrine cells of supraoptic nucleus (SON) secreting antidiuretic hormone (ADH) and oxytocin (OX); endings of the hypothalamo-hypophysial tracts within the arterio-venous capillary network of the posterior pituitary. Hypothalamo-anterior pituitary connections, via the arterial portal system: neuroendocrine cells secreting dopamine (DA) and 3′ gonadotrophin-releasing hormone (GnRH) in the ARN. Axon terminals in contact with the capillaries of the first capillary network. Long and short capillaries. Portal vessels between the first capillary network in the stalk and the second capillary network in the anterior pituitary. Red arrow indicates the direction of the blood flow in the arterial portal system. The intermediate and the tuberal parts are not shown. b Hypothalamic nuclei involved in BPD pathophysiology. PON, preoptical nucleus (GnRH secretion); SON, supraoptic nucleus (ADH/OX secretions); SCN, suprachiasmatic nucleus (clock center); PVN, paraventricular nucleus (CRH/TRH/SS secretions) in anterior hypothalamus; ARN, arcuate nucleus (DA/GHRH/GnRH secretions); DMN, dorsomedial nucleus (GnRH/TRH secretions); VMN, ventro medial nucleus in medial hypothalamus; MM, mammillary nucleus, PMN, premammillary nucleus in posterior hypothalamus; SM, sulcus monroe; HLP, hypothalamolimbic pathways (connections between hypothalamic nuclei and brain structures belonging to the limbic system); TRH, thyrotrophin-releasing hormone.

Fig. 2.

DA synapse. Main abnormalities suggested in BPD: abnormal expression or mutation of DAT, abnormal density of DRs, abnormalities of the release or recapture of DA. VMAT, vesicle monoamine transporter; DAT, dopamine transporter; DR, dopamine receptor.