Elevated Plasma Prolactin Research Articles

Low Dose Spironolactone Reverses Experimentally-Induced Pcos-Associated Metabolic Perturbations

Polycystic ovarian syndrome (PCOS), is a multifactorial endocrine disorder in women of reproductive age. It usually associates with metabolic disorders (MDs), which aggravates the risk of infertility, cardiometabolic events and associated comorbidities in women with PCOS. Adiponectin, a circulating protein produced by adipocytes, which has been suggested to inversely correlate with MDs. Spironolactone, a non-selective mineralocorticoid receptor (MR) antagonist, has been in wide clinical use for several decades. Herein, we investigated the effects of low dose spironolactone (LDS) and the role of adiponectin in endocrine-metabolic disturbances in experimentally-induced PCOS rats. Eighteen female Wistar rats (160-180 g) were randomly allotted into 3 groups and treated with vehicle (p.o.), letrozole (LET; 1 mg/kg) and LET + SPL (0.25 mg/kg), once daily for 21 days, respectively. The results showed that LET- treated animals had features of PCOS, characterized by elevated plasma testosterone and prolactin, increased body weight gain and ovarian weight as well as disrupted ovarian cytoarchitecture and degenerated follicles. Additionally, elevated fasting blood glucose, 1hr- postload glucose and plasma insulin, impaired glucose tolerance, insulin resistance, reduced insulin sensitivity, increased plasma and ovarian lipid profile, plasma lipid peroxidation, TNF-α, IL-6 and decreased plasma glutathione peroxidase and glutathione content were observed. These alterations were associated with decreased circulating adiponectin and were reversed when treated with LDS. The present results suggest that LDS ameliorates endocrine-metabolic disturbances and inflammation-related comorbidities associated with LET-induced PCOS by modulating circulating androgen-adiponectin status.

Low dose spironolactone-mediated androgen-adiponectin modulation alleviates endocrine-metabolic disturbances in letrozole-induced PCOS

Polycystic ovarian syndrome (PCOS), is a multifactorial endocrine disorder in women of reproductive age. It usually associates with metabolic disorders (MDs), which aggravates the risk of infertility, cardiometabolic events and associated comorbidities in women with PCOS. Adiponectin, a circulating protein produced by adipocytes, which has been suggested to inversely correlate with MDs. Spironolactone, a non-selective mineralocorticoid receptor (MR) antagonist, has been in wide clinical use for several decades. Herein, we investigated the effects of low dose spironolactone (LDS) and the role of adiponectin in endocrine-metabolic disturbances in experimentally-induced PCOS rats. Eighteen female Wistar rats (160–180 g) were randomly allotted into 3 groups and treated with vehicle (p.o.), letrozole (LET; 1 mg/kg) and LET + LDS (0.25 mg/kg), once daily for 21 days, respectively. The results showed that LET-treated animals had features of PCOS, characterized by elevated plasma testosterone and prolactin, increased body weight gain and ovarian weight as well as disrupted ovarian cytoarchitecture and degenerated follicles. Additionally, elevated fasting blood glucose, 1 h-postload glucose and plasma insulin, impaired glucose tolerance, insulin resistance, reduced insulin sensitivity, increased plasma and ovarian lipid profile, plasma lipid peroxidation, TNF-α, IL-6 and decreased plasma glutathione peroxidase and glutathione content were observed. These alterations were associated with decreased circulating adiponectin and were reversed when treated with LDS. The present results suggest that LDS ameliorates endocrine-metabolic disturbances and inflammation-related comorbidities associated with LET-induced PCOS by modulating circulating androgen-adiponectin status.

Physiological concomitants of an autonomous day programme" in geriatric day care"

Sixty-five geriatric patients with a mean age of 74 years (range 61-90) who were referred to the day care unit of a geriatric hospital were randomly allocated to an experimental and a control group in groups of 5-8 patients, respectively. Controls were cared for according to usual routines. Patients in the experimental groups were subject to a new organizational routine. These patient groups constituted a forum for discussion and definition of individual treatment goals. Patients in the experimental and control conditions were observed before as well as 6, 12 and 24 weeks after the start of the treatment, which lasted for twelve weeks. Patients in the intervention programme had significantly lower plasma prolactin levels following the initiation of the programme than patients in the control group. According to literature, an absence of a plasma prolactin elevation during a crisis period may indicate active coping. Such a conclusion was supported by other observations in the study which indicated a progressively more internalized locus of control in the experimental group

Antipsychotic-like effects of a novel phosphodiesterase 10A inhibitor T-251 in rodents

Phosphodiesterase 10A (PDE10A) is a dual-substrate PDE that hydrolyzes both cAMP and cGMP. PDE10A is selectively expressed in medium spiny neurons in the striatum, suggesting the potential of PDE10A inhibitors in the treatment of schizophrenia. This study presents the pharmacological profile of a novel PDE10A inhibitor, 2-[(E)-2-(7-fluoro-3-methylquinoxalin-2-yl)vinyl]-6-pyrrolidin-1-yl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine hydrochloride (T-251) in rodent models of schizophrenia. T-251 showed a potent inhibitory activity against human PDE10A (IC50 = 0.050 nmol/L) and showed high selectivity over other PDE families which have over 10,000-fold IC50 values. Oral administration of T-251 (0.1–1.0 mg/kg) increased cAMP and cGMP in the striatum in a dose-dependent manner. Oral administration of T-251 attenuated MK-801 induced hyperactivity (ED50 = 0.68 mg/kg) and suppressed conditioned avoidance response (ID50 = 0.87 mg/kg) in rats in a dose dependent manner. Furthermore, T-251 significantly attenuated MK-801 induced prepulse inhibition deficits and cognitive deficits in rats. Unlike haloperidol and olanzapine, T-251 (1.0–30 mg/kg) did not cause catalepsy in rats. Moreover, T-251 (0.6 and 6.0 mg/kg) did not increase plasma levels of prolactin at 1 h after administration, whereas haloperidol and olanzapine significantly increased them. The antipsychotic-like effects and cognitive enhancement of T-251 without catalepsy or plasma prolactin elevation observed in rats suggests that T-251 would be a novel antipsychotic with an improved side-effect profile.

1166-P: Bromocriptine-QR (BQR) Therapy Reduces Elevated Sympathetic Nervous System Activity (SNSA) and Oxidative Stress (OS) in Type 2 Diabetes (T2D) Subjects whose Dysglycemia Is Poorly Controlled on GLP-1 Receptor Agonist (GLP-1RA)

Elevated SNSA induces dysglycemia by enhancing adipose lipolysis and stimulating hepatic glucose production. It also promotes cardiovascular disease (CVD) by multiple mechanisms including augmenting systemic and vascular reactive oxygen and nitrogen species (ROS, RNS) generation. Elevated plasma prolactin (subclinical hyperprolactinemia) has also been associated with systemic inflammation, which can potentiate dysglycemia and CVD. BQR, the only dopamine agonist approved for treatment of T2D, improves postprandial dysglycemia and reduces CVD events. To evaluate mechanisms for the glucose lowering and CVD protective effects of BQR, we evaluated BQR’s effect on plasma markers of SNSA and ROS/RNS and plasma prolactin and leptin from a mechanistic study in which BQR added to 15 T2D subjects (HbA1c 8.3%) treated with a GLP-1 RA significantly improved HbA1c (-0.6%), postprandial hyperglycemia (by 22%) and endothelial dysfunction (by 36%). Plasma norepinephrine (NE), normetanephrine (NM), TBAR (a marker of systemic OS), nitrotyrosine (NT, a marker of systemic oxidative/nitrosative stress), prolactin and leptin were measured at baseline and after 4 months of BQR add-on therapy (3.2 mg/day). Plasma NE, NM, TBAR, NT and prolactin levels were elevated at baseline and decreased significantly with BQR [NE by 33% (2.95 to 1.95 ng/mL, p <0.0005); NM by 22% (56.5 to 44.3 pg/ml, p<0.018); TBAR by 10% (10.2 to 9.2 μM, p=0.04); NT by 13% (214 to 187 nM, p<0.02); prolactin by 42% (13.0 to 7.6 ng/ml, p<0.012)]. Plasma leptin, unchanged in the whole group, decreased 23% (35.7 to 27.5 ng/mL, p=0.038) in subjects with elevated leptin (>20 ng/dl, N=7) at baseline. Conclusion: Bromocriptine-QR is the only T2D therapy known to simultaneously reduce elevated plasma NE, NM, prolactin and OS and such actions may be important for the drug’s glucose lowering and CVD protective effects. Disclosure B. Chamarthi: Employee; Self; VeroScience LLC. E. Cersosimo: None. J.M. Adams: None. M. Alatrach: None. C. Agyin: None. C.L. Triplitt: Consultant; Self; Abbott. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc. M. Ezrokhi: Employee; Self; VeroScience LLC. S. Luo: Employee; Self; VeroScience LLC. E. Duvallet: Employee; Self; VeroScience LLC. A.H. Cincotta: Employee; Self; VeroScience LLC. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc.

“We Cut and Drink Blood When We Have Sex. Do We Have a Problem?”

To the Editor: Paraphilias are a complex and heterogeneous group of disorders in which sexual deviance is regarded as a medical phenomenon.1 We present a case of paraphilia disorder with depressive symptoms and suicidal ideations that was ameliorated with risperidone treatment.

Determinants of physical health parameters in individuals with intellectual disability who use long-term antipsychotics

Individuals with intellectual disability frequently use antipsychotics for many years. This may have detrimental health effects, including neurological symptoms and metabolic and hormonal dysregulation, the latter possibly affecting bone metabolism. There is large variability in the degree in which antipsychotic agents lead to these health problems. In the current study we investigated potential determinants of physical symptoms and biological parameters known to be associated with use of antipsychotics in a convenience sample of 99 individuals with intellectual disability who had used antipsychotics for more than one year for behavioural symptoms. We focused on extrapyramidal symptoms; on overweight and presence of components of the metabolic syndrome; and on elevated plasma prolactin and bone turnover parameters. As predictor variables, we used patient (sex, age, genetic polymorphisms, and severity of intellectual disability) and medication use (type and dosage) characteristics. We found extrapyramidal symptoms to be present in 53%, overweight or obesity in 46%, and the metabolic syndrome in 11% of participants. Hyperprolactineaemia and one or more elevated bone turnover markers were present in 17% and 25%, respectively. Higher age and more severe intellectual disability were associated with dyskinesia and a higher dosage of the antipsychotic drug was associated with parkinsonism. Less severe intellectual disability was related to higher Body Mass Index. Use of atypical antipsychotics was associated with higher diastolic blood pressure and elevated fasting glucose. Clinicians who prescribe antipsychotics in individuals with intellectual disability should carefully balance the potential benefits of prolonged treatment against the risk of health hazards associated with the use of antipsychotics.

Role of salsolinol in the regulation of pituitary prolactin and peripheral dopamine release.

(R)-Salsolinol (SAL), a dopamine (DA)-related tetrahydroisoquinoline, has been found in extracts of the neuro-intermediate lobes (NIL) of pituitary glands and in the median eminence of the hypothalamus obtained from intact male rats and from ovariectomized and lactating female rats. Moreover, analysis of SAL concentrations in NIL revealed parallel increases with plasma prolactin (PRL) in lactating rats exposed to a brief (10 min) suckling stimulus after 4-h separation. SAL is sufficiently potent in vivo to account for the massive discharge of PRL that occurs after physiological stimuli (i.e. suckling). At the same time, it was without effect on the secretion of other pituitary hormones. It has been also shown that another isoquinoline derivative, 1-methyldihydroisoquinoline (1MeDIQ), which is a structural analogue of SAL, can dose-dependently inhibit the in-vivo PRL-releasing effect of SAL. Moreover, 1MeDIQ can inhibit the elevation of plasma PRL induced by physiological stimuli, for example suckling, or in different stressful situations also. 1MeDIQ also has a psycho-stimulant action, which is fairly similar to the effect of amphetamine, i.e. it induces an increase in plasma catecholamine concentrations. It is clear from these data that this newly discovered endogenous compound could be involved in regulation of pituitary PRL secretion. It has also been observed that SAL is present in peripheral, sympathetically innervated organs, for example the atrium, spleen, liver, ovaries, vas deferens, and salivary gland. Furthermore, SAL treatment of rats results in dose-dependent and time-dependent depletion of the DA content of the organs listed above without having any effect on the concentration of norepinephrine. More importantly, this effect of SAL can be completely prevented by amphetamine and by 1MeDIQ pretreatment. It is clear there is a mutual interaction between SAL, 1MeDIQ, and amphetamine or alcohol, not only on PRL release; their interaction with catecholamine "synthesis/metabolism" of sympathetic nerve terminals is also obvious.

Elevated plasma prolactin in abstinent methamphetamine-dependent subjects

Background: Methamphetamine (MA) use disorders are pervasive global social problems that produce large medical and public health burdens. Abnormalities in pituitary hormonal regulation have been observed in preclinical models of substance abuse and in human substance abusers. They have, however, not been studied before in MA-dependent human subjects. Objectives: To determine if MA-dependent research volunteers differ from healthy control subjects in plasma levels of adrenocorticotropic hormone (ACTH), cortisol, or prolactin, or in pituitary dopamine D2 receptor availability during early abstinence from MA. Methods: MA-dependent subjects (N = 31), who were not seeking treatment, resided on an inpatient ward for up to 5 weeks. Abstinence was confirmed by daily urine drug screening. Venous blood was sampled for plasma hormone levels, and positron emission tomography with [18F]fallypride was performed to determine dopamine D2 receptor availability during the first week of abstinence. Venous blood was sampled again for hormone levels during the fourth week of abstinence. Matched healthy volunteers (N = 23) participated as a comparison group. Results: MA-dependent and healthy comparison subjects did not differ in plasma ACTH or cortisol levels, but had an elevated plasma prolactin at both the first week and fourth week of abstinence. There was no group difference in pituitary dopamine D2 receptor availability. Conclusion: MA-dependent individuals have abnormalities in prolactin regulation, which is not likely due to alterations in pituitary dopamine D2 receptor availability. Scientific significance: MA dependence is associated with elevated prolactin levels, which may contribute to medical comorbidity in afflicted individuals.

Gender differences in the relationship between the risperidone metabolism and the plasma prolactin levels in psychiatric patients

Background Risperidone (RIS) has the highest propensity to elevate plasma prolactin (PRL) levels. While the active metabolite 9-hydroxy-risperidone (9-OH-RIS) plays a predominant role in the efficacy and side effects of RIS, the mechanistic details are still poorly understood. The present study evaluated the gender differences in the relationship between plasma levels of RIS or 9-OH-RIS and PRL. Methods Twenty-one male and 19 female subjects treated with RIS were enrolled in the present series. All patients had been receiving RIS for at least 4 weeks at an average dosage of 4.7 mg/day. Plasma RIS, 9-OH-RIS and PRL levels were measured. Results In the male patients, there was no correlation between the RIS dosage and plasma PRL levels, between plasma RIS levels and PRL levels, or between the plasma 9-OH-RIS levels and PRL levels. In the female patients, there was a significant positive correlation between the plasma 9-OH-RIS levels and PRL levels (rs = 0.456, p = 0.049). There was a trend toward a significant positive correlation between the RIS dosage and plasma PRL levels. There was no correlation between the plasma RIS levels and PRL levels. Conclusion 9-OH-RIS is considered to play a more important role in PRL elevation than RIS, and a gender difference exists in the effect of 9-OH-RIS on PRL level.

Gender-specific prolactin response to antipsychotic treatments with risperidone and olanzapine and its relationship to drug concentrations in patients with acutely exacerbated schizophrenia

Hyperprolactinemia is a frequent consequence of treatment with antipsychotic agents, partially because the prolactin response to antipsychotics is related to dopamine blockade. Recent studies have suggested that the prolactin response to olanzapine is weaker than that to risperidone. Thus, we studied the effects of various factors on the elevated plasma prolactin levels caused by these medications. The subjects were 94 patients with acutely exacerbated schizophrenia (46 males, 48 females). For four weeks, they received 6 mg of risperidone and 20 mg of olanzapine daily. Plasma samples were collected before the medications were given and 12 h after the bedtime dosing each week. Treatment with either risperidone or olanzapine boosted plasma prolactin levels above baseline in both males and females. Prolactin levels were significantly higher in females than in males at all sampling points in both treatments. Risperidone increased prolactin significantly more than did olanzapine in both males and females. Delta prolactin (prolactin level at four weeks minus the baseline prolactin level) during olanzapine treatment significantly correlated with olanzapine concentration at 4th week ( r = − 0.518, p < 0.01) only in males. Multiple regression analyses showed that delta prolactin during risperidone was significantly correlated with gender ( p < 0.001) and age ( p < 0.05) and that delta prolactin during olanzapine significantly correlated with gender ( p < 0.001) and drug concentration ( p < 0.01). The present study suggests that the predominant factors influencing hyperprolactinemia are young female for risperidone treatment, and being female and lower drug concentration as a predictor for hyperprolactinemia under olanzapine.

Dephosphorylation/inactivation of tyrosine hydroxylase at the median eminence of the hypothalamus is required for suckling-induced prolactin and adrenocorticotrop hormone responses

We have recently found that dopamine (DA) released from terminals of the hypothalamic neuroendocrine dopamine (NEDA) neurons plays a role not only in prolactin (PRL), but also in adrenocorticotrop hormone (ACTH) secretion, without having any influence on α-melanocyte-stimulating hormone (α-MSH) release in lactating dams. The aim of our present studies was to further investigate this DAerg regulation of ACTH using consecutively applied physiological stimulation (suckling) and pharmacological inhibition of the rate-limiting enzyme of DA synthesis (tyrosine hydroxylase, TH) by α-methyl-p-tyrosine (α-MpT) that acutely affect secretion of these pituitary hormones during lactation. Following 4 h separation period, two experimental groups were formed. In the first group, lactating rats were assembled with their litters for 60 min prior to α-MpT. In the second group, the α-MpT was injected first and 60 min later suckling stimulus was applied. Plasma samples were taken in every 15 min during the 90 min experimental period. Concentrations of plasma PRL, ACTH and α-MSH were measured by specific RIAs. Both stimuli applied in the first sequence, significantly elevated plasma PRL and ACTH levels in separated lactating dams, without having any effect on α-MSH secretion. Suckling applied in the first sequence was able to block the α-MpT-induced elevation of ACTH secretion, while PRL response was also significantly attenuated. α-MpT pretreatment prevented both PRL and ACTH responses to suckling stimulus. Investigating the dephosphorylation/inactivation of TH in the arcuate nucleus-ME (TIDA) regions, no pTH-immunoreactive perikarya or terminals can be found in continuously suckled dams. In contrast, after 4 h separation of the mothers from their litters, pTH-immunoreactivity can be clearly visualized in the external zone of ME. In α-MpT pretreated mothers following 4 h separation no pTH positive terminals are visible. No changes in the TH immunostaining can be observed in any of these experimental groups. In conclusion, dephosphorylation/inactivation of TH (the rate-limiting enzyme of the DA biosynthesis) in NEDA neurons is required for suckling-induced PRL and ACTH responses.

Pregnancy and lactation after breast cancer elevate plasma prolactin, do not shorten and may prolong survival

The affliction of breast cancer is doubled for young patients wishing to have a child. Because estrogens can cause breast cancer and its elevation during pregnancy, clinical advice historically restricted pregnancy to at least 5 years post-diagnosis. Opposing evidence gradually relaxed this. Furthermore, in the last decade it was clarified that overall, post-treatment pregnancy and breast-feeding do not shorten survival. Despite this evidence and patients such as S.B. (deceased) and remarkable L.H. (five children, starting immediately after treatment for node-positive breast cancer), much opposition and restrictive advice remain: additional therapy preferred over pregnancy. In healthy women, pregnancy reduces (cause unknown) the risk of breast cancer and lactation may reduce it. These are accompanied by highly elevated plasma prolactin (PRL) over many months (pregnancy, 15-25 x daily mean 10 ng/ml; lactation, up to 30 x daily mean). PRL concentration too increases in other natural and non-biological conditions, also apparently without increasing breast cancer incidence. Nevertheless, firm and implied support for early pregnancy (and lactation) post-diagnosis and treatment may face a new issue. Over a decade, some studies have claimed epidemiological evidence that a relatively minute PRL elevation (from zero to 0.6-0.8 ng/ml) over mean level increases the risk of breast cancer (i.e. it is a carcinogen) and that this supports (and is supported by) a similar view from some laboratory research. This two-pronged mutuality could create further anxiety and unjustified advice dashing the wish for a child. Is this justified? Epidemiology on PRL and breast cancer risk in the eighties/nineties was contradictory and inconclusive; in the last decade, it was also biologically implausible. 'Positive' laboratory results targeting a 'tamoxifen for PRL' have over-shadowed confounding, negative (often called 'inconsistent') laboratory evidence. Increasingly evident complexity of conflicting biochemical, hormonal, cellular and tissue interactions, confused further by failure of molecular genetics to confirm PRL as a carcinogen, make this target more a mirage than an oasis. While recognizing the value of laboratory research primarily for facts, future progress will be most sound and rapid from observation starting with the human entity, not with its parts. Molecular genetics makes this possible and will be the epicentre of breast cancer research. Meanwhile, young breast cancer patients after initial treatment and eager for a child can today reasonably benefit from advice based on phenomena evolved over eons: pregnancy, lactation and accompanying highly-elevated PRL will not increase risk of recurrence and will in some cases prolong survival.

Interrelationship between prolactin and progesterone in normal mammary gland growth in SHN virgin mice.

In order to clarify the interrelationship between prolactin and progesterone on normal mammary gland growth, SHN strain of virgin mice were given the pituitary grafting under the kidney capsule, the subcutaneous implantation of progesterone pellet or the bilateral ovariectomy singly or in combination at 40 days of age. All mice were killed 60 days after treatments and mammary end-bud formation, mammary DNA content and plasma prolactin level were examined. The single pituitary grafting elevated plasma prolactin levels in both the intact and the ovariectomized animals, however, mammary gland growth was enhanced only in the former. Progesterone pellet implantation also stimulated mammary gland growth in the intact mice, while prolactin changed little. Progesterone effect was nullified by ovariectomy associated with the decline in plasma prolactin level. The simultaneous single pituitary grafting and progesterone pellet implantation in combination or the grafting with three pituitaries restored mammary gland regression by ovariectomy. All findings have demonstrated that the manifestation of progesterone effect on mammary glands is dependent upon prolactin and that the role of prolactin is both direct on the glands and indirect through its luteotropic effect - through its stimulation of ovarian progesterone secretion.

Subnanomolar dopamine D3 receptor antagonism coupled to moderate D2 affinity results in favourable antipsychotic-like activity in rodent models: I. neurochemical characterisation of RG-15

RG-15 (trans-N-[4-[2-[4-(3-cyano-5-trifluoromethyl-phenyl)-piperazine-1-yl]-ethyl]-cyclohexyl]-3-pyridinesulfonic amide dihydrochloride) displayed subnanomolar affinity to human and rat dopamine D3 receptors (pKi 10.49 and 9.42, respectively) and nanomolar affinity to human and rat D2 receptors (pKi 8.23 and 7.62, respectively). No apparent interactions were found with the other 44 receptors and four channel sites tested in this study. RG-15 inhibited dopamine-stimulated [35S]GTPgammaS binding in membranes from rat striatum, in murine A9 cells expressing human D2L receptors and in CHO cells expressing human D3 receptors (IC50 values were 21.2, 36.7 and 7.2 nM, respectively). In these tests RG-15 showed the highest affinity toward D3 receptors when compared to amisulpride, haloperidol and SB-277011. RG-15, similar to haloperidol and amisulpride, dose-dependently inhibited in vivo [3H]raclopride binding in mouse striatum, enhanced dopamine turnover and synthesis rate in mouse and rat striatum and olfactory tubercle. SB-277011 did not change [3H]raclopride binding in mouse striatum nor biosynthesis or turnover rates in either region in mice or rats. RG-15 and haloperidol, but not SB-277011, antagonised dopamine synthesis inhibition induced by the D3/D2 full agonist 7-OH-DPAT in GBL-treated mice. RG-15, but not SB-277011, elevated plasma prolactin levels. In vitro receptor binding and functional experiments demonstrated that RG-15 had an antagonist profile on both D3 and D2 receptors. with high selectivity for dopamine D3 receptors over D2 receptors. However, in vivo, its neurochemical actions were similar to those of D2 receptor antagonists. Neurochemical comparison of RG-15 with antagonists having a different affinity and selectivity toward D3 and D2 receptors indicate that D3 receptors have little, if any, role in the control of presynaptic dopamine biosynthesis/release in dopaminergic terminal regions.

Antipsychotics and hyperprolactinaemia: Clinical recommendations

A group of international experts in psychiatry, medicine, toxicology and pharmacy assembled to undertake a critical examination of the currently available clinical guidance on hyperprolactinaemia. This paper summarises the group's collective views and provides a summary of the recommendations agreed by the consensus group to assist clinicians in the recognition, clinical assessment, investigation and management of elevated plasma prolactin levels in patients being treated for severe mental illness. It also deals with the special problems of particular populations, gives advice about information that should be provided to patients, and suggests a strategy for routine monitoring of prolactin. The recommendations are based upon the evidence contained in the supplement 'Hyperprolactinaemia in schizophrenia and bipolar disorder: Clinical Implications' (2008). The guidance contained in this article is not intended to replace national guidance (such as that of the National Institute of Clinical Excellence), however, it does provide additional detail that is unlikely to be covered in existing guidelines, and focuses on areas of uncertainty and disagreement. We hope it will add to the debate about this topic.

Plasma progesterone and prolactin concentrations in overtly pseudopregnant bitches: A clinical study

Plasma concentrations of progesterone (P 4) and prolactin (PRL) were measured in 35 bitches presented at veterinary clinics for symptoms of overt pseudopregnancy (PSP) between 50 and 95 days after the onset of proestrus. Results were compared to those from samples collected from 35 control bitches at comparable stages of the ovarian cycle (expressed as days after the onset of observed signs of proestrus). In the PSP bitches at 71.4 ± 1.6 (mean ± S.E.M.) days of the cycle, P 4 (1.5 ± 0.2 ng/mL) was lower ( P < 0.01) and PRL (16.0 ± 1.9 ng/mL) was higher ( P < 0.01), compared to P 4 (2.7 ± 0.4 ng/mL) and PRL (2.9 ± 0.6 ng/mL) in control bitches at 70.6 ± 1.5 days of the cycle. Low P 4 was not a prerequisite for elevated PRL. Although elevated (≥10 ng/mL) PRL (20.9 ± 2.0 ng/mL) occurred more often with low (<2 ng/mL) P 4 (20 of 24 cases) it also occurred with P 4 above 3 ng/mL in two affected bitches and in two control bitches. Whether the occurrence of relatively low PRL concentrations (<4 ng/mL) in samples obtained from 4 of the 35 pseudopregnant bitches reflected variable and often elevated PRL secretion or increased sensitivity to PRL in the absence of elevated prolactin in those animals was not determined. We inferred that elevated plasma PRL was often involved in the etiology of overt PSP; furthermore, a premature decline in circulating P 4 concentrations may be a factor in some instances.

The Impact on Clinical Practice of Routine Screening for Macroprolactin

Prolactin (PRL) normally circulates in part as a high-molecular-weight form termed big-big PRL, which is a complex of PRL with an anti-PRL IgG autoantibody known as macroprolactin. Many patients with hyperprolactinemia resulting from macroprolactin lack classic hyperprolactinemic symptoms. Macroprolactin has reduced bioactivity in vivo. The investigators, working over 5 years at a single center, routinely screened for macroprolactin using the method of polyethylene glycol precipitation. The study population were individuals whose serum PRL exceeded the upper limit of the normal reference range (500 mU/L for females, 290 mU/L for males). Elevated plasma PRL levels were found in 2089 individuals, representing 21% of all samples analyzed. A majority of these samples contained more than 700 mU/L of total PRL. More than one fifth (22%) of hyperprolactinemic samples were accounted for by macroprolactin. This was the case more often for females than for males. Those with mild hyperprolactinemia (total PRL of 700 mU/L or less) more often had macroprolactinemia, but the proportion of clinically significant hyperprolactinemic samples accounted for by macroprolactin was comparable at all levels of total PRL. There were no differences in frequency of headache or infertility between patients with true hyperprolactinemia and those with macroprolactinemia, but galactorrhea and oligomenorrhea were more frequent in the former group. Although scans were done in similar proportions of patients, abnormalities were found mainly in the hyperprolactinemic group. Treatment with a dopamine agonist decreased serum prolactin levels in both groups; 15 of 19 treated women having true hyperprolactinemia and galactorrhea improved symptomatically. Macroprolactinemic patients had significantly higher plasma levels of estradiol than did those with true hyperprolactinemia, although there was overlap between the groups. Levels of luteinizing hormone (LH) and the LH/follicle-stimulating hormone (FSH) ratio were significantly greater in macroprolactinemic patients. Macroprolactinemia is a common cause of elevated serum PRL. Routine screening of hyperprolactinemic individuals for macroprolactin may alter treatment in as many as one fifth of patients with hyperprolactinemia. Imaging is needed less often, as is dopamine agonist treatment, offsetting the added cost of screening and making the procedure cost-effective.

Salsolinol induces a decrease in cyclic AMP at the median eminence and an increase at the adenohypophysis in lactating rats

Investigating the cellular events in the pituitary gland, the intracellular cyclic AMP (cAMP) of the median eminence (ME), neuro-intermediate lobe (NIL) and the anterior lobe (AL) have been measured following 15-min of intravenous injection of salsolinol (SAL). Parallel to the elevation of plasma prolactin (PRL), SAL induced a significant decrease of cAMP concentration in the ME. In contrast, SAL injection resulted in a significant increase of cAMP at the level of the AL. Changes in cAMP of the NIL as well as in the plasma level of vasopressin (VP) could not be detected. The observed changes in the level of cAMP following the acute treatment of SAL in the ME and the AL seems to be related to interacting neuroendocrine signals delivered from the ME to the AL through the long portal vessels to release PRL.

Quetiapine

Quetiapine (Seroquel), a dibenzothiazepine derivative, is an atypical antipsychotic with demonstrated efficacy in acute schizophrenia. In short-term, randomised, double-blind trials, it was usually more effective than placebo, and was generally effective against both positive and negative symptoms. Overall, quetiapine (up to 750 mg/day) was at least as effective as chlorpromazine (up to 750 mg/day) and had similar efficacy to haloperidol (up to 16 mg/day) in patients with acute schizophrenia in randomised, double-blind trials; it was at least as effective as haloperidol 20 mg/day in patients with schizophrenia unresponsive or partially responsive to previous antipsychotic treatment. Improvements in overall psychopathology and positive and negative symptoms with quetiapine (up to 800 mg/day) were similar to those with risperidone (up to 8 mg/day) or olanzapine (15 mg/day) [interim analysis]. Efficacy was maintained for at least 52 weeks in open-label follow-up studies in adult and elderly patients. Quetiapine improved cognitive function versus haloperidol, and depressive symptoms and hostility/aggression versus placebo. Quetiapine is well tolerated. It is associated with placebo-level incidence of extrapyramidal symptoms (EPS) across its entire dose range, appears to have a low risk for EPS in vulnerable patient groups (e.g. the elderly, adolescents or patients with organic brain disorders) and has a more favourable EPS profile than risperidone. Irrespective of dose, quetiapine, unlike risperidone and amisulpride, does not elevate plasma prolactin levels compared with placebo, and previously elevated levels may even normalise. Quetiapine appears to have minimal short-term effects on bodyweight and a favourable long-term bodyweight profile. Preliminary studies indicate that there is a high level of patient acceptability and satisfaction with quetiapine. In conclusion, quetiapine has shown efficacy against both positive and negative symptoms of schizophrenia, and has benefits in improving cognitive deficits, affective symptoms and aggression/hostility. The beneficial effects of quetiapine have been maintained for at least 52 weeks. Quetiapine was effective and well tolerated in hard-to-treat patients, and may be of particular use in these individuals. It is at least as effective as standard antipsychotics and appears to have similar efficacy to risperidone and olanzapine. The relative risk/benefit profile of quetiapine compared with other atypical antipsychotics requires further research in head-to-head trials, although quetiapine's relatively benign tolerability profile distinguishes it from other commonly used atypical agents, particularly with respect to bodyweight, EPS and plasma prolactin levels. Overall, quetiapine has an excellent risk/benefit profile and is a suitable first-line option for the treatment of schizophrenia.