Extrahypothalamic brain prolactin: characterization and evidence for independence from pituitary prolactin

Prompted by reports of immunohistochemical localization of a prolactin-like immunoreactivity (PLI) within the rat brain, a study was undertaken to define the immunologic and biologic characteristics of this material in extrahypothalamic regions of the rat brain. Ninety-seven percent recovery of rat prolactin standard, added to homogenates of brain parts, insured that neuronal tissue did not interfere with the radioimmunoassay for rat prolactin. PLI was consistently found in the cerebellum, thalamus, brainstem (pons-medulla), hippocampus, cerebral cortex and caudate. Examination of the elution profile of each of the extrahypothalamic brain parts from Sephadex G-75 columns showed that, although a small amount of brain PLI elutes in the vicinity of the anterior pituitary prolactin marker, the bulk of brain-based PLI migrates with the void volume and as late eluting, low molecular weight material. While increasing amounts of brain extracts progressively displaced more 125I-prolactin from antibody binding, the displacement curve was not parallel to that produced by the addition of increasing amounts of anterior pituitary prolactin standards of rat origin. Extracts of various brain parts from hypophysectomized animals, analyzed for biologic activity in the Nb2 lymphoma cell assay, revealed prolactin-like bioactivity, but the bioactivity/immunoreactivity ratio for some of the brain parts was significantly lower than that for pituitary prolactin. Hypophysectomy, which led to the expected fall in serum prolactin to undetectable levels, and restraint stress, which resulted in a statistically significant 4-fold rise in serum prolactin, caused no change in prolactin concentrations in extrahypothalamic brain parts, indicating that brain PLI is regulated independently of pituitary prolactin and of circulating serum prolactin levels.     

Prolactin response to sodium valproate in schizophrenics with and without tardive dyskinesia

Sodium valproate, a GABAergic agent (800 mg), and placebo were administered orally, as a single dose, to nine chronic schizophrenics with tardive dyskinesia (TD), seven chronic schizophrenics without TD and ten healthy controls, according to a double blind design. Blood samples were collected before and after drug administration, to determine plasma prolactin concentrations. Sodium valproate decreased plasma prolactin levels in healthy subjects (P<0.001) and in schizophrenic patients with TD (P<0.001), but not in chronic schizophrenics without TD. Moreover, in dyskinetic subjects, the maximum per cent decrease of plasma prolactin from basal value was positively correlated to the score of the abnormal involuntary movement scale (r=0.724, P<0.02). Although the neural or biochemical substrate underlying the different responses of plasma prolactin to sodium valproate in schizophrenics with and without TD remains unclear, these results provide the first neuroendocrine evidence able to differentiate dyskinetic subjects from those without TD within a schizophrenic population.     

Assessment of the effects of a synthetic gonadotropin-releasing hormone associated peptide on hormone release from the in situ and ectopic pituitaries in adult male rats

The in vivo effects of synthetic human gonadotropin-releasing hormone associated peptide (GAP) were evaluated in adult male rats. In normal rats, intracerebroventricular (III ventricle) injection of 5 ng GAP significantly increased plasma LH levels after 60 minutes. Intracerebroventricular administration of 5, 25 or 125 ng of GAP elevated circulating LH levels also at 120 minutes of injection but did not alter plasma FSH, prolactin or testosterone concentrations. In hypophysectomized-pituitary-grafted rats injection of 125 ng GAP directly into the ectopic pituitary induced no changes in peripheral hormone levels. However, intrapituitary graft injection of 25 ng of GnRH significantly elevated circulating levels of LH and testosterone. These results indicate that the ectopic pituitary graft can respond to acute exogenous GnRH stimulation and that the commercially available synthetic GAP fails to inhibit prolactin release in adult male rats.     

Prolactin studies in normals: implications for clinical research

Dopaminergic (DA) transmission is a major regulator of pituitary prolactin (PRL) secretion. Strategies to assess abnormalities of DA regulation in mental illness have thus included comparisons of patients' and normals' serum PRL levels before and after the administration of DA agonists and antagonists. These clinical research strategies suffer from a number of shortcomings. There is a wide interindividual variability of normal basal PRL levels, and intraindividual variability has been little studied. Large interindividual variability of PRL responses to DA antagonist challenges has also been observed in normals and reported to be strongly correlated to variation in serum levels of the challenge drug. Assessment of DA agonist challenges is hampered by the fact that low basal levels of serum PRL make suppression difficult to measure; a further problem is the confounding effect of nausea when these drugs are given in high doses. In this study of normals, individual basal serum PRL levels were found to be stable over a mean period of 10 months, with interindividual variance vastly greater than intraindividual variance. Thus, state alterations in mental illness may best be studied using a longitudinal design for measurements of PRL levels in patients, thereby avoiding confounding interindividual variability. Moreover, it appears that alterations of PRL levels between groups or within patients, even though within the normal range, may have individual physiological significance. A study of the PRL responses to haloperidol (hal) and hal + apomorphine (apo) challenges in normals revealed a strong correlation despite a highly significant 51% reduction in PRL response with the addition of apo. Because this correlation is dependent upon a normal or limited range of DA regulation, the study of these two responses in abnormal populations may be more revealing of DA abnormalities than the study of PRL responses to single DA agonist or antagonist challenges.     

Morphometrical variations of prolactin cells in response to prolonged and systemic administration of Met-enkephalin in female rats

Summary A stimulatory effect on prolactin secretion had been describe after acute and systemic administration of met-enkephalin, but the effects of this opioid after chronic administration has not been reported, and the response of mammotroph cells is not clear. As a complement to previous studies, a morphometric analysis (light and electron microscopy) was carried out on prolactin cells from female rats treated chronically with met-enkephalin. Clear features of cellular hyperactivity appeared after chronic and systemic administration of the opioid, and these persisted for two weeks. The changes consisted in increases of cellular, cytoplasmic and nuclear areas, volume and surface densities of the Golgi complex and rough endoplasmic reticulum, as well as the numbers of exocytotic figures. These morphological alterations were paralleled by an increase in serum prolactin levels as detected by RIA. It is concluded that the increase in the synthesis and secretory activity of prolactin cells following chronic and systemic administration of met-enkephalin is very similar to those observed after acute and intraventricular administration.     

The psychopharmacologic and prolactin response after large doses of naloxone in man

Large doses of naloxone (150–300 mg), placebo, and morphine (15–30 mg) were given intramuscularly to human volunteers and compared using measures of subjective feeling states, physiological measures and discriminative features. Plasma prolactin responses after naloxone 210 mg and placebo were compared. The subjective measures and discriminative features of naloxone revealed that the drug is subtly psychoactive but the stimulus is vague and cannot be identified clearly as an opioid agonist or antagonist in nondependent opioid-using volunteers. The physiologic and prolactin responses closely resembled opiate agonist activity. We conclude that naloxone in this dose range may act as an opiate agonist in man.     

Tobacco use is associated with reduced central serotonergic neurotransmission in type 1 alcohol-dependent individuals

BACKGROUND: Reduced central serotonergic neurotransmission in alcohol dependence may be attributed to the effects of cigarette smoking (and possibly more specifically to nicotine) rather than to alcoholism or its subtypes. The aim of the present study was therefore to compare central serotonergic neurotransmission in tobacco-using (cigarette smokers and users of smokeless tobacco, i.e., snuffers) alcohol-dependent individuals to that of tobacco-nonusing alcohol-dependent individuals. METHODS: The central serotonergic neurotransmission was assessed by the prolactin (PRL) response to the serotonin-releasing agent D-fenfluramine (30 mg orally). Male subjects (n = 37) aged 20-65 years were recruited for this purpose. They were all type 1 alcohol-dependent individuals and had ended their alcohol intake the day before the D-fenfluramine challenge test. RESULTS: There was no difference in baseline PRL concentrations between tobacco-using (n = 18) and tobacco-nonusing (n = 19) alcohol-dependent individuals. On the other hand, the maximum PRL response after D-fenfluramine was significantly lower in the tobacco-using group as compared to the tobacco-nonusing individuals. CONCLUSION: Whether the reduction in central serotonergic neurotransmission in tobacco-using alcohol-dependent individuals is pre-existing or a result of tobacco use remains to be elucidated.     

Elevated prolactin responses to <Emphasis Type="SmallCaps">l</Emphasis>-tryptophan infusion in medication-free depressed patients

Rationale Several previous neuroendocrine studies have demonstrated reduced 5-HT_1A receptor function in major depressive disorder (MDD). However, hypercortisolaemia or previous drug treatment may have been significant confounds. Objectives To replicate previous studies in subjects with MDD who had been drug free for at least 8 weeks and to relate the findings to measures of HPA axis function. Methods Hormonal responses to l-tryptophan infusion were measured in patients with MDD (n=20) and healthy controls (n=20). Basal salivary cortisol and DHEA were also profiled. Results No attenuation of 5-HT_1A receptor-dependent neuroendocrine responses (growth hormone, prolactin) was observed in patients with MDD. The prolactin response to l-tryptophan was significantly greater in MDD patients than in healthy controls (P=0.008). There was a significant negative correlation between prolactin response and basal salivary cortisol secretion over the 3 days prior to the test. Conclusions These data do not support previous findings of reduced 5-HT_1A function in MDD and suggest that hypercortisolaemia or psychotropic medication may have accounted for the attenuation. Basal cortisol, DHEA and the cortisol-DHEA ratio did not differ between patients and controls, and all patients were psychotropic medication-free. The greater prolactin response to l-tryptophan infusion in depressed subjects may be the result of an increase in dopamine receptor sensitivity, secondary to reduced dopamine levels.     

Baseline prolactin and <Emphasis Type="SmallCaps">L</Emphasis>-tryptophan availability predict response to antidepressant treatment in major depression

Abstract Rationale. Depression may be associated with a hypofunction of central serotonin (5HT) systems. The prolactin response to fenfluramine (PRF) is an indicator of 5HT activity. It has been suggested that the PRF may predict response to different forms of treatment. Baseline cortisol, prolactin, and L-tryptophan (L-TRP) availability may affect PRF and may also influence response to treatment. Method. In this study, 46 males and 58 females with a DSM-III-R diagnosis of major depression underwent a detailed clinical evaluation and prior to treatment had baseline measures of prolactin, cortisol, L-TRP, and other large neutral amino acids (LNAAs) taken and underwent a fenfluramine challenge. The subjects with major depression entered a 6-week double-blind treatment trial comparing clomipramine and desipramine. Results. There was no effect on the 6-week outcome of treatment (clomipramine versus desipramine), PRF or baseline cortisol and no interactions between these factors. However, there was a significant effect of baseline prolactin (BLP) and a significant interaction between TRP/LNAA ratio and BLP. Post-hoc analysis revealed that at low TRP/LNAA values, outcome improved as prolactin levels increased while at high TRP/LNAA values the opposite was the case. Conclusion. The PRF did not predict 6-week outcome. BLP and TRP/LNAA ratio measurement is easy and may be useful clinically. We hypothesise that failure to upregulate post-synaptic 5HT receptors in response to low 5HT availability predicts a poor response to antidepressant treatment. Electronic Publication