Dopamine prolactin inhibiting effects

Koenig JI, Mayfield MA, McCann SM, Krulich L (1982) On the prolactin-inhibiting effect of neurotensin. The role of dopamine. Neuroendocrinology 35 277-281. 

Prolactin-inhibiting hormone (PIH), also known as dopamine, is not a peptide (Chapter 17). It functions as a neurotransmitter in the CNS and as a precursor of norepinephrine and epinephrine in the adrenal medulla. In the hypothalamus, it originates in the TIDA and is released at the median eminence. Dopamine is a potent inhibitor of PRL release by the lactotropes (and mammosomatotropes) of the anterior pituitary, and this effect is mediated by D2 receptors that are coupled to Gj inhibition of adenylate cyclase. The lactotropes are unique in that they do not require stimulation by the hypothalamus to secrete PRL in fact, blockage of the blood flow from the hypothalamus to the anterior pituitary results in elevated serum levels of PRL, due to withdrawal of dopamine. Thus, unlike somatostatin, the effectiveness of dopamine does not depend on the presence of a stimulating hormone (Chapter 34). 

Bromocriptine was the first D2-receptor agonist to be used in the treatment of hyperprolactinemia and has been the mainstay of therapy for over 20 years. It inhibits the release of prolactin by directly stimulating postsynaptic dopamine receptors in the hypothalamus. Hypothalamic release of dopamine (prolactin-inhibitory hormone) inhibits the release of prolactin. Decreases in serum prolactin concentrations occur within 2 hours of oral administration with maximal suppression occurring after 8 hours, and suppressive effects persisting for up to 24 hours. Medical therapy with bromocriptine normalizes prolactin serum concentrations, restores gonadotropin production, and shrinks tumor size in approximately 90% of patients with prolactinomas. ... 

F. Prolactin-Inhibiting Hormone (PIH, Dopamine) Dopamine is the physiologic inhibitor of prolactin release. Because of its peripheral effects and the need for parenteral administration, dopamine is not useful in the control of hyperprolactinemia, but bromocriptine and other orally active ergot derivatives (eg, cabergoline. pergolide) are effective in reducing prolactin secretion from the normal gland as well as from pituitary tumors. 

In (he pituitary gland, dopamine acting on D,-dopamine receptors inhibits prolactin release. This effect is blocked by neuroleptics and the resulting increase in prolactin release often causes endocrine side-effects (boitoni right). 

Prolactin is peptide hormone secreted by the pituitary gland. It acts on prolactin receptors in breast tissue where it stimulates production of casein and lactalbu-min. It also acts on the testes and ovaries to inhibit the effects of gonadotrophins. Since the secretion of prolactin is under tonic dopaminergic inhibition by the hypothalamus, dopamine D2-receptor antagonists... 

Dopamine A few studies have examined the dopaminergic effects of LSD. The affinity of LSD for D2 receptors is similar to its affinity for 5-HT2 sites, and it has a slightly lower affininty for D1 receptors (Watts et al. 1995). LSD has partial agonist effects at D2 receptors as seen in the inhibition of prolactin release (Giacomelli et al. 1998). Neuroleptic drugs are also used clinically to terminate an LSD experience. Thus, the effects of LSD on dopaminergic function may contribute to its hallucinogeinc effects. 

Mechanism of Action A dopamine agonist that directly stimulates dopamine receptors in the corpus striatum and inhibits prolactin secretion. Also suppresses secretion of growth hormone. Therapeutic Effect Improves symptoms of parkinsonism, suppresses galactorrhea, and reduces serum growth hormone concentrations in acromegaly. 

Amoxapine has been found to be effective in several double-blind studies (Table 7-4 and Table 7-6). It is a dibenzoxazepine derivative that has both NE and serotonin uptake inhibiting properties. Amoxapine is converted into 8-hydroxyamoxapine, which has considerable dopamine receptor binding properties (i.e., radioreceptor bioassays on patients given amoxapine have found activity levels similar to those of patients on typical antipsychotics), a chemical structure similar to loxapine, and effects similar to antipsychotics (1Q3). As a result of this metabolite, amoxapine theoretically may have unique beneficial effects in psychotically depressed patients. However, this possibility has never been adequately tested. Nevertheless, this metabolite is likely responsible for some of the antidopamine effects reported in patients taking amoxapine, including acute and chronic extrapyramidal side effects and elevated prolactin levels ( 104). Like TCAs, amoxapine can be lethal in... 

Receptor Class Mu (pi) Primary Therapeutic Effect(s) Spinal and supraspinal analgesia Other Effects Sedation respiratory depression constipation inhibits neurotransmitter release (acetylcholine, dopamine) increases hormonal release (prolactin growth hormone)... 

The G protein-GTP complexes related to receptors for these hormones activate adenylyl cyclase, which synthesizes the second messenger cAMP. Cyclic AMP activates protein kinases, which phosphorylate certain intracellular proteins (eg, enzymes), thus producing the hormonal effect. Conversely, dopamine binding to lactotroph receptors causes conformational changes in its G protein that reduce the activity of adenylyl cyclase and inhibit the secretion of prolactin. 

The role of cyclic AMP as modulator of prolactin secretion was first suggested by the finding of a stimulatory effect of cyclic AMP derivatives (17-22) and inhibitors of cyclic nucleotide phosphodiesterase activity such as theophylline and IBMX (22-26) on the secretion of this hormone. More convincing evidence supporting a role of cyclic AMP in the action of dopamine on prolactin secretion had to be obtained, however, by measurement of adenohypophysial adenylate cyclase activity or cyclic AMP accumulation under the influence of the catecholamine. As illustrated in Fig. 1, addition of 100 nM dopamine to male rat hemipituitaries led to a rapid inhibition of cyclic AMP accumulation, a maximal effect (30% inhibition) being already obtained 5 min after addition of the catecholamine. Thus, while dopamine is well known to stimulate adenylate cyclase activity in the striatum (27, 28), its effect at the adenohypophysial level in intact cells is inhibitory. Dopamine has also been found to exert parallel inhibitory effects on cyclic AMP levels and prolactin release in ovine adenohypophysial cells in culture (29) and purified rat mammotrophs (30). Using paired hemipituitaries obtained from female rats, Ray and Wallis (22) have found a rapid inhibitory effect of dopamine on cyclic AMP accumulation to approximately 75% of control. 

In this volume a good deal of emphasis is placed on studies of dopamine receptors in pituitary. This emphasis seems well justified. The clear-cut effects of dopamine in suppressing prolactin secretion from anterior lobe mammotrophs, and the inhibitory effects on secretion of a-MSH and related secretory products from intermediate lobe are important models for dopamine receptor studies. In both cases new evidence was put forward to support the hypothesis that the actions of dopamine on the secretory cells are mediated by inhibition of adenylate cyclase. This is far easier to demonstrate in the intermediate lobe, where all cells appear to respond to dopamine, than in the anterior lobe, where the dopamine-sensitive cells probably represent only a small minority. 

Prolactin has been shown to increase LH receptor numbers in dwarf mice, seasonally repressed hamsters and hypophysectomized rats (see Ref. 6 for other references). In the hypophysectomized rats the combined effects of prolactin, growth hormone and LH were necessary to maintain the LH receptors [46]. The induction of hyperprolactinemia leads to increased LH receptors. Decreases in serum prolactin levels caused by treatment with compounds that inhibit the release of prolactin (dopamine analogues) decrease LH receptors (see Ref. 6 for other references). 

It was later found that some effects of dopamine did not involve stimulation of adenylyl cyclase. Particularly, in the pituitary gland, dopamine was found to inhibit prolactin release without stimulating adenylyl cyclase activity and even by inhibiting it (Spano et al., 1978 De Camilli et al., 1979). Moreover, the antipsychotic drug sulpiride blocked the dopamine-induced release of prolactin in the pituitary gland but was unable to antagonize the dopamine response on adenylyl cyclase activity in the striatum (Trabucchi et al., 1975). These observations led to the hypothesis that the dopamine receptors exist as two... 

In pituitary adenoma cells, dopamine was found to activate K+ currents through D2 type receptor, leading to cell hyperpolarization (Israel et al., 1985). Similar effects have been described in lactotroph and melanotroph cells in the anterior pituitary as well as in the mesencephalic neurons in the CNS (Israel et al., 1985 Lacey et al., 1988 Greif et al., 1995). The K+ current-induced hyperpolarization appears to underlie the inhibition of DA release mediated by D2 autoreceptors in dopamine neurons and of prolactin release in lactotroph cells. In particular, the blockade of K+ channel by 4-aminopyridine or tetramethylammonium abolished the inhibitory effect of D2 agonists on DA release (Bowyer and Weiner, 1989 Cass and Zahniser, 1991 Tang et al., 1994a). 

Thioxanthenes, such as flupenthixol and clopenthixol, are similar in structure to the phenothiazines. The therapeutic effects are similar to those of the piperazine group. Antipsychotic thioxanthenes are thought to benefit psychotic conditions by blocking postsynaptic dopamine receptors in the brain. They also produce an alpha-adrenergic blocking effect and depress the release of most hypothalamic and hypophyseal hormones. However, the concentration of prolactin is increased due to blockade of prolactin inhibitory factor (PIF), which inhibits the release of prolactin from the pituitary gland. 

Some of the effects of antipsychotic drugs on sexual function have been attributed by Aizenberg et al. to increased prolactin secretion by the anterior pituitary (74, 76), other effects may result from their specific autonomic actions (75). Prolactin secretion by the anterior pituitary is tonically inhibited by the hypothalamus, with dopamine acting as the prolactin release-inhibiting factor (PIF). Thus, conventional neuroleptics cause dose-related increases in serum prolactin levels (hy-... 

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