Prolactin is a protein hormone of the anterior pituitary gland that was originally named for its ability to promote lactation in response to the suckling stimulus of hungry young mammals. We now know that prolactin is not as simple as originally described. Indeed, chemically, prolactin appears in a multiplicity of posttranslational forms ranging from size variants to chemical modifications such as phosphorylation or glycosylation. It is not only synthesized in the pituitary gland, as originally described, but also within the central nervous system, the immune system, the uterus and its associated tissues of conception, and even the mammary gland itself. Moreover, its biological actions are not limited solely to reproduction because it has been shown to control a variety of behaviors and even play a role in homeostasis. Prolactin-releasing stimuli not only include the nursing stimulus, but light, audition, olfaction, and stress can serve a stimulatory role. Finally, although it is well known that dopamine of hypothalamic origin provides inhibitory control over the secretion of prolactin, other factors within the brain, pituitary gland, and peripheral organs have been shown to inhibit or stimulate prolactin secretion as well. It is the purpose of this review to provide a comprehensive survey of our current understanding of prolactin's function and its regulation and to expose some of the controversies still existing.

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Prolactin: Structure, Function, and Regulation of Secretion

Physiological and behavioral responses to corticotropin-releasing factor administration: is CRF a mediator of anxiety or stress responses?

Effects of Corticotropin-Releasing Factor on Brain Serotonergic Activity

We previously reported that a single systemic injection of a high dose of morphine (greater than or equal to 20 mg/kg) transiently suppresses splenic natural killer cell cytotoxicity in rats. The present study examined the possibility that the immune-suppressive effect of morphine is mediated by opiate receptors in the brain. Supporting this hypothesis, we found that morphine (20 or 40 micrograms) injected into the lateral ventricle suppressed natural killer cell activity to the same degree as a systemic dose higher by three orders of magnitude. This effect was blocked by an opiate antagonist, naltrexone. Natural killer cell activity was unaffected by systemic administration of N-methyl morphine, a morphine analogue that does not cross the blood-brain barrier. These data implicate opiate receptors in the brain in morphine-induced suppression of natural killer cell cytotoxicity.

https://www.pnas.org/content/pnas/83/18/7114.full.pdf

Involvement of brain opiate receptors in the immune-suppressive effect of morphine

The cerebral content of the biogenic amines, dopamine (DA), norepinephrine (NE), and serotonin (5-HT) and their catabolites 30 min after CRF or saline injections was determined using HPLC with electrochemical detection. Injection of CRF (1.0 μg) into the lateral ventricles (ICV) of mice produced a behavioral activation in which their motor movements appeared as bursts of activity followed by periods of immobility. CRF administration (ICV or SC) did not alter the concentrations of DA, NE, tryptophan, 5-HT, or 5-hydroxyindoleacetic acid (5-HIAA) in any brain region measured. ICV CRF increased the concentrations of dihydroxyphenylacetic acid (DOPAC), the major catabolite of DA, and of 3-methoxy,4-hydroxyphenylethyleneglycol (MHPG), the major catabolite of NE, in several brain regions. DOPAC:DA ratios were consistently increased in prefrontal cortex, septum, hypothalamus, and brain stem relative to animals injected with saline. MHPG:NE ratios were also increased in the prefrontal cortex and hypothalamus, with a marginal effect (p=0.06) in brain stem. SC CRF significantly increased DOPAC:DA in prefrontal cortex, and MHPG:NE in prefrontal cortex, hypothalamus and brain stem. Pretreatment with naloxone did not prevent any of the neurochemical responses to ICV CRF, but naloxone alone increased DOPAC:DA in medial profrontal cortex, and decreased MHPG:NE in nucleus accumbens in CRF-injected mice. These results suggest that administration of CRF either centrally or peripherally induces an activation of both dopaminergic and noradrenergic systems in several regions of mouse brain. The pattern resembles that we observe in mice following stressful treatments such as footshock or restraint, but the effect of CRF on noradrenergic systems is less pronounced. Also, brain free tryptophan which is consistently increased in all brain regions by footshock or restraint was not altered by CRF. Thus CRF triggers a response in CNS catecholamine systems that resembles, but does not precisely mimic, that observed following commonly used stressors. This activation of CNS catecholamine metabolism may be related to some of the behavioral effects of CRF, but not all of them because naloxone, which prevents the effects of CRF on exploratory behavior, did not alter the catecholamine responses to CRF.

Corticotropin-releasing factor administration elicits a stress-like activation of cerebral catecholaminergic systems

β-Endorphin-induced increases in plasma epinephrine, norepinephrine and dopamine in rats: inhibition of adrenomedullary response by intracerebral somatostatin

Intracisternal administration of synthetic human β-endorphin in rats increased plasma prolactin. This effect of β-endorphin is blocked completely by parenteral administration of the dopamine receptor agonist, apomorphine. Increasing availability of brain dopamine with the monoamine oxidase inhibitor, pargyline, blunted the effect of β-endorphin on plasma prolactin. Although the effect of apomorphine could have been mediated either in the hypothalamus or directly on pituitary, the action of pargyline could not have occurred in pituitary, thus providing support for the hypothesis that β-endorphin-induced prolactin secretion is mediated in brain and furthermore through a dopaminergic mechanism. Additional support for both aspects of this hypothesis is provided by the finding that decreasing availability of dopamine with the dopamine synthesis inhibitor, α-methyltyrosine, potentiated the effect of β-endorphin to increase plasma prolactin concentration.Furthermore, this potentiation by α-methyltyrosine of β-en...

beta-Endorphin-induced prolactin secretion is mediated by suppression of release of newly synthesized hypothalamic dopamine.

Lack of effect of corticotropin releasing factor on hypothalamic dopamine and serotonin synthesis turnover rates in rats.

Publisher Summary The importance of endorphins, the generic term for endogenous opioid peptides, in a wide variety of brain functions appears well established. The administration of endorphins into brain is associated with sedation, catalepsy, analgesia, hypothermia, and alterations in pituitary hormone secretion. The chapter discusses a study to examine the possibility that endorphins alter sympathetic outflow from brain, thus altering peripheral catecholamine release and producing changes in plasma concentrations of catecholamines. Adult male Sprague-Dawley rats were housed individually in an environ­mental room with 12 h light-dark cycles for 7 days prior to use in all experiments. The intracisternal administration of human β-endorphin increased plasma concentrations of dopamine, norepinephrine and epinephrine during the 2 h period of study, whereas intra-cisternal (ic) saline produced only transient and nonsignificant increases in plasma concentrations of these catecholamines at the times studied. These data are consistent with stimulation of central sympathetic outflow by β-endorphin. The relatively greater increase in plasma epinephrine than norepinephrine or dopamine is consistent with greater stimulation by β-endorphin of central sympathetic outflow to adrenal medulla than to peripheral sympathetic nerve endings. The thesis that intracerebral β-endorphin increases plasma epinephrine concentration and to some extent plasma dopamine and norepinephrine concentrations by stimulating sympathetic outflow to the adrenal medulla is supported by the observations that adrenal denervation blocked the plasma epinephrine response to ic β-endorphin.

Doris Ho

Papers

β-Endorphin-induced increases in plasma epinephrine, norepinephrine and dopamine in rats: inhibition of adrenomedullary response by intracerebral somatostatin

beta-Endorphin-induced prolactin secretion is mediated by suppression of release of newly synthesized hypothalamic dopamine.

Lack of effect of corticotropin releasing factor on hypothalamic dopamine and serotonin synthesis turnover rates in rats.

Endorphin-induced stimulation of central sympathetic outflow