Prolactin and dopamine: What is the connection? A Review Article Peter Fitzgerald Department of Psychiatry and Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland. Timothy G Dinan Department of Psychiatry and Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland. Abstract Dopamine (DA) holds a predominant role in the regulation of prolactin (PRL) secretion. Through a direct effect on anterior pituitary lactotrophs, DA inhibits the basally high-secretory tone of the cell. It accomplishes this by binding to D2 receptors expressed on the cell membrane of the lactotroph, activation of which results in a reduction of PRL exocytosis and gene expression by a variety of intracellular signalling mechanisms. The hypothalamic dopaminergic neurons, which provide DA to the anterior pituitary gland, are themselves regulated by feedback from PRL through a ‘short-loop feedback mechanism’. A variety of other modulators of prolactin secretion act at the hypothalamic level by either disinhibition of the dopaminergic tone (e.g. serotonin, GABA, oestrogens and opioids) or by reinforcing it (e.g. substance P). All typical antipsychotic medications are associated with sustained hyperprolactinaemia due to their high affinity for the D2 receptor and their slow dissociation from the receptor once bound, but atypicals differ quite dramatically in their propensity to cause prolonged high prolactin levels. Of those atypicals that are associated with prolactin elevation, the main causative factor appears to be a higher peripheral-to-central dopamine receptor potency of either the parent drug or its active metabolite (e.g. risperidone, 9-hydroxy-risperidone and amisulpride). Antipsychotics that easily cross the blood–brain barrier and exhibit fast dissociation from the dopamine receptor once bound do not result in sustained hyperprolactinaemia. Keywords prolactin; dopamine; regulation; antipsychotics Introduction Prolactin (PRL) is a polypeptide hormone that is predomi- nantly synthesized in and secreted from lactotroph cells of the anterior pituitary gland. Although it is best known as the hor- mone that elicits lactation in mammals and takes its name from this function (Riddle et al., 1933), it is present in all vertebrates and is thus, in evolutionary terms, a very ancient hormone. It has also been found to be extremely versatile, being involved in a broad spectrum of functions beyond reproduction and lacta- tion, including roles in metabolism, behaviour, immunoregula- tion and osmoregulation. Prolactin has more physiological functions than the other pituitary hormones all combined (Free- man et al., 2000), with the current estimation standing at approximately 300 different biological actions in vertebrates (Bole-Feysot et al., 1998). Such diversity of function has led some in the past to call for a name change of the hormone to ‘versatilin’ or ‘omnipotin’ (Bern and Nicoll, 1968; Nicoll, 1974). The predominant control of prolactin secretion is via upstream hypothalamic inhibition of lactotroph activity. This is a unique characteristic of prolactin compared with other pituitary hormones, and can largely be explained by two fac- tors. Firstly, the diversity of its actions on multiple different target cells results in a lack of a classical negative feedback mechanism in regulating its secretion and, secondly, lacto- trophs are unique among endocrine cells in having high basal secretory activity. This review outlines the key role that dopamine, the pre- dominant hypothalamic prolactin inhibiting factor (PIF), plays in prolactin synthesis and regulation of secretion. In addi- tion, factors that influence dopaminergic tone on the lacto- troph are also discussed to illuminate the complex connection between prolactin and dopamine. Finally, the differential effect of alternative antipsychotic medications on prolactin release is outlined, and consideration is given to the cause of such differences. Original Papers Journal of Psychopharmacology 22(2) Supplement (2008) 12–19 © 2008 British Association for Psychopharmacology ISSN 0269-8811 SAGE Publications Ltd, Los Angeles, London, New Delhi and Singapore 10.1177/0269216307087148 Corresponding author: Ted Dinan, Department of Psychiatry and Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland. Email: T.Dinan@ucc.ie at UNIV VERACRUZANA on March 1, 2016 jop.sagepub.com Downloaded from