Drug resistance mechanisms in dopamine agonist-resistant prolactin pituitary neuroendocrine tumors and exploration for new drugs.

BACKGROUND: The treatment of dopamine agonists (DA) resistant prolactinomas remains a formidable challenge, as the mechanism of resistance is still unclear, and there are currently no viable alternative drug therapies available. This study seeks to investigate the mechanism of DA resistance in prolactinomas and identify new potentially effective drugs. METHODS: To explore the mechanism of DA resistance in prolactinomas, this study conducted transcriptome sequencing analysis on 27 cases of DA-resistant prolactinomas and 10 cases of sensitive prolactinomas. In addition, single-cell sequencing analysis was performed on 3 cases of DA-resistant prolactinomas and 3 cases of sensitive prolactinomas. Furthermore, to screen for potential therapeutic drugs, the study successfully established an organoids model for DA-resistant prolactinomas and screened 180 small molecule compounds using 8 organoids. The efficacy of the identified drugs was verified through various assays, including CCK-8, colony formation, CTG, and flow cytometry, and their mechanisms of action were confirmed through WB and IHC. The effectiveness of the identified drugs was evaluated both in vitro and in vivo. RESULTS: The results of transcriptome sequencing and single-cell sequencing analyses showed that DA resistance in prolactinomas is associated with the upregulation of the Focal Adhesion (FA) signaling pathway. Additionally, immunohistochemical validation revealed that FAK and Paxillin were significantly upregulated in DA-resistant prolactinomas. Screening of 180 small molecule compounds using 8 organoids identified Genistein as a potentially effective drug for DA-resistant prolactinomas. Experimental validation demonstrated that Genistein inhibited the proliferation of pituitary tumor cell lines and organoids and promoted apoptosis in pituitary tumor cells. Moreover, both the cell sequencing results and WB validation results of the drug-treated cells indicated that Genistein exerts its anti-tumor effect by inhibiting the FA pathway. In vivo, experiments also showed that Genistein can inhibit subcutaneous tumor formation. CONCLUSION: DA resistance in prolactinomas is associated with upregulation of the Focal Adhesion (FA) signaling pathway, and Genistein can exert its anti-tumor effect by inhibiting the expression of the FA pathway.

Antiangiogenic Effect of Dopamine and Dopaminergic Agonists as an Adjuvant Therapeutic Option in the Treatment of Cancer, Endometriosis, and Osteoarthritis.

Dopamine (DA) and dopamine agonists (DA-Ag) have shown antiangiogenic potential through the vascular endothelial growth factor (VEGF) pathway. They inhibit VEGF and VEGF receptor 2 (VEGFR 2) functions through the dopamine receptor D2 (D2R), preventing important angiogenesis-related processes such as proliferation, migration, and vascular permeability. However, few studies have demonstrated the antiangiogenic mechanism and efficacy of DA and DA-Ag in diseases such as cancer, endometriosis, and osteoarthritis (OA). Therefore, the objective of this review was to describe the mechanisms of the antiangiogenic action of the DA-D2R/VEGF-VEGFR 2 system and to compile related findings from experimental studies and clinical trials on cancer, endometriosis, and OA. Advanced searches were performed in PubMed, Web of Science, SciFinder, ProQuest, EBSCO, Scopus, Science Direct, Google Scholar, PubChem, NCBI Bookshelf, DrugBank, livertox, and Clinical Trials. Articles explaining the antiangiogenic effect of DA and DA-Ag in research articles, meta-analyses, books, reviews, databases, and clinical trials were considered. DA and DA-Ag have an antiangiogenic effect that could reinforce the treatment of diseases that do not yet have a fully curative treatment, such as cancer, endometriosis, and OA. In addition, DA and DA-Ag could present advantages over other angiogenic inhibitors, such as monoclonal antibodies.

Effects of the atypical antipsychotic and D3/D2 dopamine partial agonist cariprazine on effort-based choice behavior: implications for modeling avolition.

RATIONALE: Cariprazine is an atypical antipsychotic that acts as a D3/D2 receptor partial agonist. In addition to treating positive symptoms of schizophrenia, cariprazine may have utility for treating negative symptoms. Rodent studies have focused on the effects of cariprazine on cognitive functions and behaviors thought to be related to anhedonia. Avolition, which is characterized by reduced initiation and persistence of goal-directed behavior, is another important negative symptom. OBJECTIVES: Effort-related choice tasks have been used as animal models of avolition. In these studies, cariprazine was assessed for its effects on effort-based choice in both rats and mice. Previous work has shown that D2 antagonists such as haloperidol and eticlopride produce a low-effort bias in rodents tested on effort-based choice tasks. RESULTS: Low doses of cariprazine produced a low-effort bias in rats tested on the fixed ratio 5/chow feeding choice task, decreasing lever pressing for high carbohydrate pellets but increasing chow intake. Cariprazine did not alter preference or intake of these foods in free-feeding tests. The effort-related effects of cariprazine were reversed by co-administration of the adenosine A2A antagonist istradefylline, and cariprazine failed to reverse the effort-related effects of the dopamine-depleting agent tetrabenazine. In mouse touchscreen choice tests, low doses of cariprazine also produced a low-effort bias, shifting behavior away from panel pressing. CONCLUSIONS: These results demonstrate that with these rodent models of avolition, cariprazine appears to act like a D2-family antagonist even at very low doses. Furthermore, the pharmacological regulation of avolition may differ from that of other negative symptoms.

Dopamine agonists for the treatment of pituitary tumours: From ergot extracts to next generation therapies.

Dopamine agonists are a key tool in the therapeutic arsenal of endocrinologists worldwide. They exert their effects by binding to dopamine-2 (D2) receptors expressed by pituitary tumour cells to modulate hormonal secretion and tumour size. They are the established first-line treatment for prolactinomas which express high levels of D2 receptors. Growing data support their use as an adjuvant treatment option for other pituitary tumours including growth hormone, adrenocorticotrophic hormones, thyroid hormone secreting adenomas and nonfunctional pituitary tumours, all of which have been shown to express D2 receptors as well, albeit to varying extents. For those pituitary tumours inadequately treated by dopamine agonist alone, combined agonism of D2 and somatostatin receptors represent a new frontier in clinical development. Here we review the development and role of dopamine agonist for the treatment of prolactinomas, the literature supporting their adjuvant use for the treatment of all other pituitary tumours, and recent progress in the development of the next generation of chimeric compounds that target D2 and other receptor subtypes highly expressed on pituitary tumour cells.

SKF83959 Attenuates Memory Impairment and Depressive-like Behavior during the Latent Period of Epilepsy via Allosteric Activation of the Sigma-1 Receptor.

Memory impairment and emotional disorder are two common clinical comorbidities in patients with epilepsy. It is imperative to develop a novel therapeutic agent or a strategy. 6-Chloro-7,8-dihydroxy-3-methyl-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959) is a dopamine-1 receptor agonist and sigma-1 receptor allosteric modulator, which displays the neuron-protective and anti-neuroinflammation activity. We examined the effect of SKF83959 on the memory impairment and emotional disorder in the latent period of epilepsy using the mice post-status epilepticus model. We found that SKF83959 ameliorated memory impairment and depressive-like mood, alleviated the neuron damage and the formation of gliosis in hippocampus, suppressed the rise of pro-inflammatory cytokines, including tumor necrosis factor-α and interleukin-1ß, and induced nitric oxide synthase in the latent period of epilepsy. Additionally, SKF83959 significantly inhibited the activity of calcineurin and glycogen synthase kinase-3ß. All of these protective actions were reversed by BD1047 (a sigma-1 receptor antagonist). In addition, the intra-hippocampus injection of ketoconazole (a dehydroepiandrosterone synthesis inhibitor) also reversed the protective activity of SKF83959. Thus, we concluded that SKF83959 ameliorated the memory impairment and depressive-like mood in epilepsy via allosterically activating the sigma-1 receptor and subsequently inhibiting the calcineurin/glycogen synthase kinase-3ß pathway.

Metabolic effects of prolactin and the role of dopamine agonists: A review.

Prolactin is a polypeptide hormone that is well known for its role in reproductive physiology. Recent studies highlight its role in neurohormonal appetite regulation and metabolism. Elevated prolactin levels are widely associated with worsening metabolic disease, but it appears that low prolactin levels could also be metabolically unfavorable. This review discusses the pathophysiology of prolactin related metabolic changes, and the less commonly recognized effects of prolactin on adipose tissue, pancreas, liver, and small bowel. Furthermore, the effect of dopamine agonists on the metabolic profiles of patients with hyperprolactinemia are discussed as well.

ß-Arrestin2-biased Drd2 agonist UNC9995 alleviates astrocyte inflammatory injury via interaction between ß-arrestin2 and STAT3 in mouse model of depression.

BACKGROUND: Major depressive disorder (MDD) is a prevalent and devastating psychiatric illness. Unfortunately, the current therapeutic practice, generally depending on the serotonergic system for drug treatment is unsatisfactory and shows intractable side effects. Multiple evidence suggests that dopamine (DA) and dopaminergic signals associated with neuroinflammation are highly involved in the pathophysiology of depression as well as in the mechanism of antidepressant drugs, which is still in the early stage of study and well worthy of investigation. METHODS: We established two chronic stress models, including chronic unpredictable mild stress (CUMS), and chronic social defeat stress (CSDS), to complementarily recapitulate depression-like behaviors. Then, hippocampal tissues were used to detect inflammation-related molecules and signaling pathways. Pathological changes in depressive mouse hippocampal astrocytes were examined by RNA sequencing. After confirming the dopamine receptor 2 (Drd2)/ß-arrestin2 signaling changes in the depressive mice brain, we then established the depressive mouse model using the ß-arrestin2 knockout mice or administrating the ß-arrestin2-biased Drd2 agonist to investigate the roles. Label-free mass spectrometry was used to identify the ß-arrestin2-binding proteins as the underlying mechanisms. We modeled neuroinflammation with interleukin-6 (IL-6) and corticosterone treatment and characterized astrocytes using multiple methods including cell viability assay, flow cytometry, and confocal immunofluorescence. RESULTS: Drd2-biased ß-arrestin2 pathway is significantly changed in the progression of depression, and genetic deletion of ß-arrestin2 aggravates neuroinflammation and depressive-like phenotypes. Mechanistically, astrocytic ß-arrestin2 retains STAT3 in the cytoplasm by structural combination with STAT3, therefore, inhibiting the JAK-STAT3 pathway-mediated inflammatory activation. Furtherly, pharmacological activation of Drd2/ß-arrestin2 pathway by UNC9995 abolishes the inflammation-induced loss of astrocytes and ameliorates depressive-like behaviors in mouse model for depression. CONCLUSIONS: Drd2/ß-arrestin2 pathway is a potential therapeutic target for depression and ß-arrestin2-biased Drd2 agonist UNC9995 is identified as a potential anti-depressant strategy for preventing astrocytic dysfunctions and relieving neuropathological manifestations in mouse model for depression, which provides insights for the therapy of depression.

Dopamine D1-like receptor blockade and stimulation decreases operant responding for nicotine and food in male and female rats.

Dopamine has been implicated in the reinforcing effects of smoking. However, there remains a need for a better understanding of the effects of dopamine D1-like receptor agonists on nicotine intake and the role of sex differences in the effects of dopaminergic drugs on behavior. This work studied the effects of D1-like receptor stimulation and blockade on operant responding for nicotine and food and locomotor activity in male and female rats. The effects of the D1-like receptor antagonist SCH 23390 (0.003, 0.01, 0.03 mg/kg) and the D1-like receptor agonist A77636 (0.1, 0.3, 1 mg/kg) on responding for nicotine and food, and locomotor activity were investigated. The effects of SCH 23390 were investigated 15 min and 24 h after treatment, and the effects of the long-acting drug A77636 were investigated 15 min, 24 h, and 48 h after treatment. Operant responding for nicotine and food and locomotor activity were decreased immediately after treatment with SCH 23390. Treatment with SCH 23390 did not have any long-term effects. Operant responding for nicotine was still decreased 48 h after treatment with A77636, and food responding was decreased up to 24 h after treatment. Treatment with A77636 only decreased locomotor activity at the 48 h time point. There were no sex differences in the effects of SCH 23390 or A77636. In conclusion, the D1-like receptor antagonist SCH 23390 reduces nicotine intake and causes sedation in rats. Stimulation of D1-like receptors with A77636 decreases nicotine intake at time points that the drug does not cause sedation.

Dopamine regulates astrocytic IL-6 expression and process formation via dopamine receptors and adrenoceptors.

Dopamine levels in the central nervous system change under pathological conditions such as Parkinson's disease, Huntington's disease, and addiction. Under those pathological conditions, astrocytes become reactive astrocytes characterized by morphological changes and the release of inflammatory cytokines involved in pathogenesis. However, it remains unclear whether dopamine regulates astrocytic morphology and functions. Elucidating these issues will help us to understand the pathogenesis of neurodegenerative diseases caused by abnormal dopamine signaling. In this study, we investigated the effects of dopamine on IL-6 expression and process formation in rat primary cultured astrocytes and acute hippocampal slices. Dopamine increased IL-6 expression in a concentration-dependent manner, and this was accompanied by CREB phosphorylation. The effects of a low dopamine concentration (1 µM) were inhibited by a D1-like receptor antagonist, whereas the effects of a high dopamine concentration (100 µM) were inhibited by a ß-antagonist and enhanced by a D2-like receptor antagonist. Furthermore, dopamine (100 µM) promoted process formation, which was inhibited by a ß-antagonist and enhanced by both an α-antagonist and a D2-like receptor antagonist. In acute hippocampal slices, both a D1-like receptor agonist and ß-agonist changed astrocytic morphology. Together, these results indicate that dopamine promotes IL-6 expression and process formation via D1-like receptors and ß-adrenoceptors. Furthermore, bidirectional regulation exists; namely, the effects of D1-like receptors and ß-adrenoceptors were negatively regulated by D2-like receptors and α2-adrenoceptors.

Dopamine receptor signaling regulates fibrotic activation of retinal pigmented epithelial cells.

Retinal pigmented epithelial (RPE) cells play an important role in retinal fibrotic diseases such as proliferative vitreoretinopathy (PVR). The purpose of this study was to elucidate the involvement of dopamine receptor signaling in regulating the fibrotic activation of RPE cells. Dopamine receptor expression, the effect of dopamine on fibrotic activity, and dopamine production were measured in the human RPE cell line ARPE-19. The fibrotic activation of RPE cells was evaluated in response to treatments with selective dopamine receptor agonists and antagonists by measuring gene expression, migration, proliferation, and fibronectin deposition. DRD2 and DRD5 are the dominant dopaminergic receptors expressed in ARPE-19 cells and TGF-ß stimulation enhances the autocrine release of dopamine, which we show further exasperates fibrotic activation. Finally, treatment with D2 dopamine receptor antagonists or D5 dopamine receptor agonists inhibits profibrotic gene expression, migration, proliferation, and fibronectin deposition and thus may serve as effective mechanisms for treating retinal fibrosis including PVR.

Signaling via dopamine and adenosine receptors modulate viral peptide-specific and T-cell IL-8 response in COVID-19.

B-cell but not T-cell responses have been extensively studied using peripheral blood mononuclear cells (PBMCs) obtained from patients with coronavirus disease 2019 (COVID-19). Our recent study showed that not only T-helper (Th) 17 but also Th1 cells directly produce interleukin (IL)-8, a major source of neutrophilic inflammation, which is also known to induce disseminated intravascular coagulation (DIC) in COVID-19 patients. Neutrophilic inflammation caused by IL-17A or IL-8 can be fatal; thus, therapeutic intervention is highly expected. The present study aimed to investigate the T-cell responses in the Japanese patients. We synthesized spike protein-derived 15-mer peptides that are expected to bind to HLA class II allelic products frequently observed in the Japanese population, and checked the T-cell responses in Japanese patients with COVID-19. We have found that (i) patients show marked IL-8 but not IL-17A responses; (ii) these responses are restricted by HLA-DR; and (iii) IL-8 responses are abrogated by a dopamine D2 like receptor (D2R) agonist, ropinirole, and an adenosine A2a receptor (A2aR) antagonist, istradefylline. Compounds used for the treatment of Parkinson's disease may ease DIC in COVID-19. (183 words).

The Inhibitory Effect of Selected D2 Dopaminergic Receptor Agonists on VEGF-Dependent Neovascularization in Zebrafish Larvae: Potential New Therapy in Ophthalmic Diseases.

Pathological angiogenesis is correlated with many ophthalmic diseases. The most common are exudative age-related macular degeneration and proliferative diabetic retinopathy. The current treatment for these diseases is based on regularly administered anti-VEGF antibodies injections. In the study, we investigated selected D2 dopaminergic receptor agonists, namely bromocriptine, cabergoline and pergolide, on hypoxia-induced neovascularization. We used the zebrafish laboratory model, specifically three-day post fertilization (dpf) Tg(fli-1: EGFP) zebrafish larvae. To induce abnormal angiogenesis of hyaloid-retinal vessels (HRVs) and intersegmental vessels (ISVs), the larvae were treated with cobalt chloride (II) (CoCl2) (a hypoxia-inducing agent) from 24 h post fertilization. The inhibitory role of D2 dopaminergic receptor agonists was investigated using confocal microscopy and qPCR. Additionally, the results were compared to those obtained in the group treated with CoCl2 followed by bevacizumab, the well-known antiangiogenic agent. Confocal microscopy analyses revealed severe deformation of vessels in the CoCl2 treated group, while co-incubation with bromocriptine, cabergoline, pergolide and bevacizumab, respectively, significantly inhibited abnormalities of angiogenesis. The qPCR analyses supported the protective role of the chosen dopaminergic agonists by demonstrating their influence on CoCl2-derived upregulation of vegfaa expression. The present results suggest that the D2 receptor agonists can be considered as a new direction in research for antiangiogenic therapy.

Parasitoid wasp venom manipulates host innate behavior via subtype-specific dopamine receptor activation.

The subjugation strategy employed by the jewel wasp is unique in that it manipulates the behavior of its host, the American cockroach, rather than inducing outright paralysis. Upon envenomation directly into the central complex (CX), a command center in the brain for motor behavior, the stung cockroach initially engages in intense grooming behavior, then falls into a lethargic sleep-like state referred to as hypokinesia. Behavioral changes evoked by the sting are due at least in part to the presence of the neurotransmitter dopamine in the venom. In insects, dopamine receptors are classified as two families, the D1-like and the D2-like receptors. However, specific roles played by dopamine receptor subtypes in venom-induced behavioral manipulation by the jewel wasp remain largely unknown. In the present study, we used a pharmacological approach to investigate roles of D1-like and D2-like receptors in behaviors exhibited by stung cockroaches, focusing on grooming. Specifically, we assessed behavioral outcomes of focal CX injections of dopamine receptor agonists and antagonists. Both specific and non-specific compounds were used. Our results strongly implicate D1-like dopamine receptors in venom-induced grooming. Regarding induction of hypokinesia, our findings demonstrate that dopamine signaling is necessary for induction of long-lasting hypokinesia caused by brain envenomation.

Atractylon, a novel dopamine 2 receptor agonist, ameliorates Parkinsonian like motor dysfunctions in MPTP-induced mice.

BACKGROUND: Motor symptoms of Parkinson's disease (PD) are characterized by bradykinesia, resting tremor, rigidity, slow movement, impaired gait and postural instability, resulting from progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Atractylon is a natural furan compound in Atractylodes rhizomes, exhibiting anticancer, anti-inflammation, antiviral and gastroprotective activities, and so on. However, it is still unknown whether atractylon is beneficial to motor dysfunctions of PD. METHODS: GPCR-targeted piggyBac-TANGO compound screening system, cAMP assay, and immunostaining of p-CREB and BDNF were used to identify dopamine 2 receptor (DRD2) activation. The effects of atractylon on motor deficits and gait disturbances, as well as tyrosine hydroxylase (TH) in the SNpc were investigated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. RESULTS: Atractylon treatment increased the eGFP expression in dose-dependent manner in piggyBac-TANGO assay, decreased cAMP production, and enhanced the levels of p-CREB and BDNF in DRD2 highly expresseding SY-SY5Y cells. In MPTP-induced mice, atractylon improved the slow movement, diminished voluntary locomotion, and abnormal gait parameters, such as duration, cadence, average speed, step cycle, stride length, and so on. Moreover, atractylon rescued the TH positive cells in SNpc and TH positive nerve fibers in striatum. CONCLUSIONS: Atractylon could effectively activate DRD2, attenuate motor deficits and gait disorders, and protect dopaminergic neurons in MPTP-induced PD mice. Our findings stretch out the therapeutic potential of atractylon for motor symptoms of PD.

Quinagolide Treatment Reduces Invasive and Angiogenic Properties of Endometrial Mesenchymal Stromal Cells.

Endometrial mesenchymal stromal cells (E-MSCs) extensively contribute to the establishment and progression of endometrial ectopic lesions through formation of the stromal vascular tissue, and support to its growth and vascularization. As E-MSCs lack oestrogen receptors, endometriosis eradication cannot be achieved by hormone-based pharmacological approaches. Quinagolide is a non-ergot-derived dopamine receptor 2 agonist reported to display therapeutic effects in in vivo models of endometriosis. In the present study, we isolated E-MSCs from eutopic endometrial tissue and from ovarian and peritoneal endometriotic lesions, and we tested the effect of quinagolide on their proliferation and matrix invasion ability. Moreover, the effect of quinagolide on E-MSC endothelial differentiation was assessed in an endothelial co-culture model of angiogenesis. E-MSC lines expressed dopamine receptor 2, with higher expression in ectopic than eutopic ones. Quinagolide inhibited the invasive properties of E-MSCs, but not their proliferation, and limited their endothelial differentiation. The abrogation of the observed effects by spiperone, a dopamine receptor antagonist, confirmed specific dopamine receptor activation. At variance, no involvement of VEGFR2 inhibition was observed. Moreover, dopamine receptor 2 activation led to downregulation of AKT and its phosphorylation. Of interest, several effects were more prominent on ectopic E-MSCs with respect to eutopic lines. Together with the reported effects on endometrial and endothelial cells, the observed inhibition of E-MSCs may increase the rationale for quinagolide in endometriosis treatment.

Dopaminergic neurons project to the nucleus accumbens regulates anxiety-like behaviors through dopamine D1 signaling.

Dopamine (DA) transmission is important in the regulation of mood and anxiety behaviors. However, how specific dopaminergic signaling pathways respond to anxiogenic stimuli as well as regulate behaviors remains unknown. To understand how DA regulates the animal behaviors under anxiety we performed retrograde labeling and c-Fos staining of midbrain DA neurons. Our c-Fos labeling results showed that DA neurons projected to nucleus accumbens (NAc) are activated in animals treated with the elevated plus-maze (EPM). Real-time measurement of DA release using fast scanning cyclic voltammetry (FSCV) in NAc of freely behaving mice showed that increased DA release and more DA transients in the close arms than the open arms in the EPM. Meanwhile, we also observed a reduction of DA level from the close arms to the open arms. Local infusion of DA D1 receptor antagonist, SCH23390 in the core of NAc, leads to an anxiolytic-like effect in the open-field and EPM. These anxiolytic effects were not observed in animals received D2 receptor antagonist sulpiride infusion in the core of NAc. Taken together, our results reveal a novel function of the mesolimbic DA pathway through the D1 receptor in the regulation of anxiety-like behaviors.

MicroRNAs in Dopamine Agonist-Resistant Prolactinoma.

Dopamine agonists (DAs) are preferred for the treatment of prolactinomas and are usually very effective. Nonetheless, 20-30% of bromocriptine- and approximately 10% of cabergoline-treated individuals exhibit resistance to DAs. In addition, the mechanism underlying this phenomenon remains elusive. In this study, we summarize the major findings regarding the role of microRNAs (miRNAs) in the pathogenesis of DA-resistant prolactinoma (DARP). Currently available evidence suggests that miRNAs are usually dysregulated in DARP and that, although controversial, the dysregulated miRNAs target the transforming growth factor (TGF)-ß, dopamine 2 receptor (D2R), or estradiol (E2)/estrogen receptor (ER) signaling pathways to mediate the therapeutic effect of DAs. These findings provide new incentives for research on innovative strategies for predicting patients' responsiveness to dopamine therapies and for developing treatment approaches. Unfortunately, recent studies tended to focus exclusively on the differential miRNA expression profiles between DARP and dopamine-sensitive prolactinoma, and no definitive consensus has been reached regarding the role of these miRNAs in the modulation mechanism. Therefore, current and future efforts should be directed toward the exploration of the mechanism underlying the dysregulation of miRNAs as well as of the target proteins that are affected by the dysregulated miRNAs. Furthermore, the modulation of the expression of dysregulated miRNAs, which target the D2R, TGF-ß, or E2/ER signaling pathways, might be a promising alternative to treat patients with DARP and improve their prognosis.

Prolactin Response to Metformin in Cabergoline-Resistant Prolactinomas: A Pilot Study.

INTRODUCTION: Cabergoline is the treatment of choice for prolactinomas. However, 10-20% of prolactinomas are resistant to cabergoline. Metformin, a biguanide widely used in the treatment of diabetes mellitus, has been shown to reduce prolactin secretion in various pituitary tumor-cell lineages both in vitro and in vivo and in human pituitary adenomas in vitro. The aim of this study is to test the effects of metformin addition to cabergoline treatment on prolactin levels in patients with resistant prolactinomas. SUBJECTS AND METHODS: This is a prospective study performed in an outpatient clinic in a reference center. Ten adult patients (26-61 years) with prolactinomas (7 M), persistent hyperprolactinemia (38-386 ng/mL) under cabergoline treatment (2-7 mg/week) for at least 6 months (6-108 months), features of metabolic syndrome, and not taking metformin were included. Metformin (1.0-2.5 g v.o./day) was given according to patients' tolerance. Cabergoline doses were kept unchanged. Serum prolactin levels were measured before and after short- (30-60 days) and long-term (120-180 days) metformin treatment. RESULTS: Mean prolactin levels did not show any significant changes (148 ± 39 vs. 138 ± 42 vs. 133 ± 39 ng/mL, before, at 30-60 days, and at 120-180 days, respectively, p = 0.196) after metformin (mean dose: 1.25 g/day; range: 1.0-2.0 g/day). No patient reached a normal prolactin level during metformin treatment. Two patients were considered partial responders for exhibiting prolactin decreases ≥50% at a single time point during metformin. CONCLUSION: Metformin addition to ongoing high-dose cabergoline treatment in patients with cabergoline-resistant prolactinomas failed to show a consistent inhibitory effect in serum prolactin levels.

Speed of response to dopaminergic agents in prolactinomas.

PURPOSE: Hyperprolactinemia in the presence of a sellar lesion can be caused by prolactin secretion from the lesion, or by increased intrasellar pressure/compression of the pituitary stalk ("stalk effect"). The objective of this work was to determine the response to dopamine agonists (DAs) in bona fide prolactinomas presenting with a prolactin range similar to what can be seen in nonhormonal secreting pituitary tumors. METHODS: A descriptive study on 68 prolactinomas presenting with prolactin levels between 50 and 200 ng/mL in a tertiary center in the U.S.A. over 22 years. The main outcome was prolactin decrease from diagnosis to follow-up by 2 months from initiation of DA therapy. RESULTS: With a median time to follow-up from starting DA therapy of 5 weeks [IQR:4, 6], the median prolactin check showed normality at 11.85 ng/mL [IQR: 5.1, 29]. The median prolactin percent change was at 87% [IQR:67, 94] by 2 months. The majority (75%) of patients presenting had a 2/3 (67%) prolactin drop by 2 months, with more than 1/4 (25%) having a percent drop >95%. CONCLUSIONS: A rapid decline in prolactin level can be seen in prolactinomas upon initiation of DA therapy. This significant prolactin drop restricts the ability to establish a threshold beyond which the diagnosis of prolactinoma could be excluded.

Characterization of the discriminative stimulus effect of quinpirole: Further evidence for functional interaction between central dopamine D1/D2-receptors.

Dysfunction of the central dopamine D2-receptor-related network has been proposed to play a critical role in dopamine-related diseases, such as schizophrenia and drug dependence. Generally, the stimulation of dopamine D2-receptors on medium spiny neurons (MSN) induces several behavioral effects, such as sedation, hallucination, aversion and motivation. Furthermore, such physiological responses through dopamine D2-receptor-containing MSN (D2-MSN) may be synchronized with the activity of dopamine D1-receptor-containing MSN (D1-MSN), or both may exhibit dual agonistic/antagonistic innervation. In the present study, we characterized the discriminative stimulus effect of the selective dopamine D2-receptor agonist quinpirole to further investigate the "D1/D2-MSN" interaction using dopamine-related agents, hallucinogens and sedatives in rats. Among dopamine receptor agonists, only selective dopamine D2-receptor agonists substituted for the discriminative stimulus effects of quinpirole. Neither the δ-opioid receptor agonist SNC80 nor the adenosine A2A-receptor antagonist istradefylline, both of which may act on D2-MSNs, substituted for the discriminative stimulus effects of quinpirole. Interestingly, the dopamine D1-receptor antagonist SCH23390 and the GABAB-receptor agonist baclofen, but not hallucinogens or sedatives, substituted for the discriminative stimulus effects of quinpirole. These results suggest that stimulation of central dopamine D2-receptors exerts a distinct discriminative stimulus effect, and blockade of dopamine D1-receptors and agonistic modulation of GABAB-receptors may share the discriminative stimulus effect via the activation of central dopamine D2-receptors.