Pharmacological and biochemical criteria can be used to separate those dopamine receptors which are linked to the enzyme adenylyl cyclase and those which are not.

Multiple receptors for dopamine.

Missale, Cristina, S. Russel Nash, Susan W. Robinson, Mohamed Jaber, and Marc G. Caron. Dopamine Receptors: From Structure to Function. Physiol. Rev. 78: 189–225, 1998. — The diverse physiological actions of dopamine are mediated by at least five distinct G protein-coupled receptor subtypes. Two D1-like receptor subtypes (D1 and D5) couple to the G protein Gs and activate adenylyl cyclase. The other receptor subtypes belong to the D2-like subfamily (D2 , D3 , and D4) and are prototypic of G protein-coupled receptors that inhibit adenylyl cyclase and activate K+ channels. The genes for the D1 and D5 receptors are intronless, but pseudogenes of the D5 exist. The D2 and D3 receptors vary in certain tissues and species as a result of alternative splicing, and the human D4 receptor gene exhibits extensive polymorphic variation. In the central nervous system, dopamine receptors are widely expressed because they are involved in the control of locomotion, cognition, emotion, and affect as well as neuroendocrine s...

Dopamine Receptors: From Structure to Function

Celsus described four of the five cardinal signs of inflammation 2000 years ago, and Eustachio discovered the adrenal glands almost 500 years ago, but not until 1936 did Selye note that in rats exposed to stressors, the adrenal glands were enlarged, and the thymus and lymph nodes shrunken.1–3 Cortisone, the active principle of the adrenal glands, was isolated by Kendall and Reichstein in the late 1940s and shown to suppress immune organs. These scientists, along with Hench, received the Nobel Prize in Physiology and Medicine, after Hench and colleagues showed that cortisone could ameliorate rheumatoid arthritis.4,5 In recent . . .

The Hypothalamic–Pituitary–Adrenal Axis and Immune-Mediated Inflammation

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

Receptors for most interleukins and cytokines that regulate immune and hematopoietic systems belong to the class I cytokine receptor family. These molecules form multichain receptor complexes in order to exhibit high-affinity binding to, and mediate biological functions of, their respective cytokines. In most cases, these functional receptor complexes share common signal transducing receptor components that are also in the class I cytokine receptor family, i.e. gp130, common beta, and common gamma molecules. Interleukin-6 and related cytokines, interleukin-11, leukemia inhibitory factor, oncostatin M, ciliary neurotrophic factor, and cardiotrophin-1 are all pleiotropic and exhibit overlapping biological functions. Functional receptor complexes for this interleukin-6 family of cytokines share gp130 as a component critical for signal transduction. Unlike cytokines sharing common beta and common gamma chains that mainly function in hematopoietic and lymphoid cell systems, the interleukin-6 family of cytokines function extensively outside these systems as well, e.g. from the cardiovascular to the nervous system, owing to ubiquitously expressed gp130. Stimulation of cells with the interleukin-6 family of cytokines triggers homo- or hetero-dimerization of gp130. Although gp130 and its dimer partners possess no intrinsic tyrosine kinase domain, the dimerization of gp130 leads to activation of associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors. This paper reviews recent progress in the study of the interleukin-6 family of cytokines and gp130.

Gp130 and the interleukin-6 family of cytokines

A study of the in vitro effect of dopamine on the release of newly synthesized prolactin is reported. Pituitary glands of female rats were incubated with 4,5-3H-leucine and the radioactive prolactin present in the pituitary gland and that released into the incubation medium were measured. Incubation with 5 × l 10–7M dopamine caused an 85% decrease in prolactin release. Prior injection of the rats with perphenazine or haloperidol rendered the pituitary gland refractory to the in vitro inhibitory effect of dopamine. Although in vitro perphenazine and haloperidol had little or no effect on release of prolactin, 5 × 10–9M of these drugs directly blocked the in vitro action of dopamine on prolactin release. Phentolamine, an α-blocking agent, was partially able to block the inhibitory effect, of dopamine. Propranolol, however, was not effective. Apomorphine, an agent known to mimic the effects of dopamine, caused a significant decrease in the amount of radioactive and radioimmunoassayable prolactin released int...

Studies on the mechanism of the dopamine-mediated inhibition of prolactin secretion.

Interleukin-6 (IL-6), a cytokine produced by inflammatory reactions, was found to stimulate PRL, GH and LH release from anterior pituitary cells at concentrations similar to those which affected lymphocyte mitogenesis. Perifused pituitary cells responded to IL-6 with prompt increases in hormone release that declined rapidly following cessation of exposure. Dopamine (DA) attenuated IL6-induced PRL release. In addition, IL-6 potentiated both GHRF- and TRH-induced hormone release without an affect on intracellular cAMP. These data demonstrate a new biological activity for IL-6 and provide evidence for immune system regulation of anterior pituitary hormone release.

Interleukin-6 stimulates anterior pituitary hormone release in vitro.

herapy for large prolactinomas remains controversial. Surgery is often unsuccessful in restoring endocrine function to normal. However, medical therapy with bromocriptine, a dopamine agonist, not only suppresses PRL levels, but may also lead to a reduction in tumor size. Previous reports have demonstrated radiographic evidence of tumor regression only after 3 or more months of bromocriptine therapy. We have now documented, for the first time, objective evidence of extremely rapid reduction in tumor size in two patients harboring large PRL-secreting pituitary tumors (mean pretreatment serum PRL levels, 2350 and 3900 ng/ml) who were prospectively treated with bromocriptine (7.5 mg/day) in preference to surgical intervention despite marked visual impairment in one of the patients. After 2 and 6 weeks of therapy, respectively, marked reduction in tumor size was demonstrated radiographically in both patients. Headache, visual acuity, and visual fields had improved after only 3 days. Although the mechanism of b...

Rapid regression of pituitary prolactinomas during bromocriptine treatment.

We recently reported that the cytokine interleukin-6 (IL-6) is a potent stimulator of anterior pituitary hormone release in vitro. Since IL-6 is not normally detectable in the blood, we hypothesized that IL-6 may be produced by the anterior pituitary in situ and thereby affect hormone secretion through paracrine or autocrine mechanisms. The present study demonstrates that cultured anterior pituitary cells spontaneously secrete large quantities of IL-6 in vitro. IL-6 was detectable in the incubation medium within 2 h, and by 8 h of culture had attained concentrations of 2000–4000 U/ml-4 × 105 cells. IL-6 production was stimulated by phorbol myristate acetate (10–100 nM) approximately 2-fold and by lipopolysaccharide (0.001–10.0 μg/ml) 4-fold during 4-h incubations. In contrast, the cytokine recombinant human IL-la had no effect on IL-6 release by cultured pituitary cells. Freshly dissected hemipituitary tissue also secreted more than 3000 U/ml IL-6 during a 4-h incubation. This secretion was enhanced 3-fol...

Production of interleukin-6 by anterior pituitary cells in vitro.

Medical therapy of prolactinomas with bromo-criptine has been demonstrated to reduce serum PRL levels to normal and also to reduce the size of such tumors. This size reduction may occur very rapidly. It is widely recognized that PRL levels rise again after withdrawal of bromocriptine therapy. We now describe the effects of drug withdrawal and reinstitution on tumor size in two young men harboring large prolactinomas. Bromocriptine had been extremely successful in lowering serum PRL levels by more than 80%, as well as reducing tumor size. After 12 months of therapy bromocriptine was withdrawn. Within 48 h PRL levels had started to rise, reaching 2580 ng/ml at 13 days off therapy and 1040 ng/ml at 4 weeks off therapy in patients 1 and 2, respectively. At 13 days bitemporal hemianopsia recurred in patient 1, and this was associated with radiographic demonstration of expansion in the pituitary mass from a partially empty pituitary fossa to a large 12-mm suprasellar extension. The second patient remained asymp...

Robert M. MacLeod

Papers

Studies on the mechanism of the dopamine-mediated inhibition of prolactin secretion.

Interleukin-6 stimulates anterior pituitary hormone release in vitro.

Rapid regression of pituitary prolactinomas during bromocriptine treatment.

Production of interleukin-6 by anterior pituitary cells in vitro.

Rapid changes of prolactinoma volume after withdrawal and reinstitution of bromocriptine.