Antidepressant-like effects of psychedelics in a chronic despair mouse model: is the 5-HT2A receptor the unique player?

Major depressive disorder (MDD) is one of the most disabling psychiatric disorders in the world. First-line treatments such as selective serotonin reuptake inhibitors (SSRIs) still have many limitations, including a resistance to treatment in 30% of patients and a delayed clinical benefit that is observed only after several weeks of treatment. Increasing clinical evidence indicates that the acute administration of psychedelic agonists of the serotonin 5-HT2A receptor (5-HT2AR), such as psilocybin, to patients with MDD induce fast antidepressant effects, which persist up to five weeks after the treatment. However, the involvement of the 5-HT2AR in these antidepressant effects remains controversial. Furthermore, whether the hallucinogenic properties of 5-HT2AR agonists are mandatory to their antidepressant activity is still an open question. Here, we addressed these issues by investigating the effect of two psychedelics of different chemical families, DOI and psilocybin, and a non-hallucinogenic 5-HT2AR agonist, lisuride, in a chronic despair mouse model exhibiting a robust depressive-like phenotype. We show that a single injection of each drug to wild type mice induces anxiolytic- and antidepressant-like effects in the novelty-suppressed feeding, sucrose preference and forced swim tests, which last up to 15 days. DOI and lisuride administration did not produce antidepressant-like effects in 5-HT2A-/- mice, whereas psilocybin was still effective. Moreover, neither 5-HT1AR blockade nor dopamine D1 or D2 receptor blockade affected the antidepressant-like effects of psilocybin in 5-HT2A-/- mice. Collectively, these findings indicate that 5-HT2AR agonists can produce antidepressant-like effects independently of hallucinogenic properties through mechanisms involving or not involving the receptor.

Designing lisuride intranasal nanocarrier system for reduction of oxidative damage with enhanced dopamine level in brain for Parkinsonism.

In the present study, nanoemulsion (NE) loaded with lisuride were formulated for delivering drug to brain via intranasal route. Dopamine levels, pharmacokinetic, and antioxidant activity were estimated. Antioxidant effect of lisuride NE was assessed in-vivo using oxidative stress models revealing symptoms like those of Parkinson's disease. Intranasally administered lisuride NE-treated group revealed a greater number of antioxidant enzymes, such as superoxide dismutase (SOD) and glutathione (GSH) as compared to the intravenously administered lisuride suspension in haloperidol rat model. Additionally, it was observed that lisuride NE can decrease dopamine loss. When lisuride NE was administered intranasally resulted in considerably higher dopamine concentrations (17.48 ± 0.05 ng/mL) in comparison to rats receiving haloperidol (7.28 ± 0.02 ng/mL). From study, it is suggested that NE is a possible strategy to deliver lisuride intranasally to lower free radical damage and prevent the biochemical alterations associated with Parkinson's disease.

Lisuride reduces involuntary periodic leg movements in spinocerebellar ataxia type 2 patients.

Periodic leg movements (PLMs) are a common sleep disorder in spinocerebellar ataxia type 2 (SCA2) being associated to higher disease severity and altered sleep patterns. To assess the efficacy and safety of lisuride for the treatment of PLMs in SCA2 patients, an open-label clinical trial was conducted in 12 SCA2 patients suffering from PLMs associated to other subjective sleep complaints. All subjects received 0.1 mg of oral lisuride daily for 4 weeks. Primary outcome measure was the change of PLMs index. Changes in the subjective sleep quality, other polysomnographical sleep parameters, Scale for the Assessment and Rating of Ataxia score, and saccadic velocity were assessed as secondary outcome parameters. Safety assessments included hemoglobin, hematocrit, cholesterol, creatinine, and TGP. A significant decrease in both the PLMs index and R stage latency were observed during the treatment, associated to subjective improvement of frequent awakenings, early insomnia, restless leg syndrome, and nocturnal limb paresthesias in most cases. Ataxia score and saccadic pathology were unchanged. No significantly adverse events were observed. Our study suggests the efficacy of dopamine agonist therapy in the treatment of PLMs in SCA2, improving various subjective sleep complaints. These findings serve to promote the adequate management of sleep-related disorders in SCA2, which could improve the life quality of the patients.

Terguride ameliorates monocrotaline-induced pulmonary hypertension in rats.

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterised by vasoconstriction and remodelling of the pulmonary vasculature. The serotonin (5-hydroxytryptamine (5-HT)) pathway has been shown to play a major role in the pathogenesis of PAH, but pharmacological modulation of this pathway for treatment of PAH is, to date, at a pre-clinical level. Terguride is a 5-HT receptor (5-HTR) antagonist that is well tolerated and clinically approved for ovulation disorders. Immunohistochemistry against 5-HTR(2A/B) on human lungs revealed their localisation to the vascular smooth muscle layer and quantitative RT-PCR showed 5-HTR(2B) upregulation in pulmonary artery smooth muscle cells (PASMC) isolated from PAH patients. Proliferation and migration of cultured primary human PASMC were dose-dependently blocked by terguride. Therapeutic 5-HT signalling inhibition was 1) demonstrated in isolated, ventilated and perfused rat lungs and 2) by chronic terguride treatment of rats with monocrotaline (MCT)-induced pulmonary hypertension in a preventive or curative approach. Terguride inhibited proliferation of PASMCs and abolished 5-HT-induced pulmonary vasoconstriction. Chronic terguride treatment prevented dose-dependently the development and progression of MCT-induced PAH in rats. Thus, terguride represents a valuable novel therapeutic approach in PAH.

Resistance to Dopamine Agonists in Pituitary Tumors: Molecular Mechanisms.

Pituitary neuroendocrine tumors (PitNET) are commonly benign tumors accounting for 10-25% of intracranial tumors. Prolactin-secreting adenomas represent the most predominant type of all PitNET and for this subtype of tumors, the medical therapy relies on the use of dopamine agonists (DAs). DAs yield an excellent therapeutic response in reducing tumor size and hormonal secretion targeting the dopamine receptor type 2 (D2DR) whose higher expression in prolactin-secreting adenomas compared to other PitNET is now well established. Moreover, although DAs therapy does not represent the first-line therapy for other PitNET, off-label use of DAs is considered in PitNET expressing D2DR. Nevertheless, DAs primary or secondary resistance, occurring in a subset of patients, may involve several molecular mechanisms, presently not fully elucidated. Dopamine receptors (DRs) expression is a prerequisite for a proper DA function in PitNET and several molecular events may negatively modify DR membrane expression, through the DRs down-regulation and intracellular trafficking, and DR signal transduction pathway. The current mini-review will summarise the presently known molecular events that underpin the unsuccessful therapy with DAs.

Increased expression of 5-hydroxytryptamine2A/B receptors in idiopathic pulmonary fibrosis: a rationale for therapeutic intervention.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) has a poor prognosis and limited responsiveness to available treatments. It is characterised by epithelial cell injury, fibroblast activation and proliferation and extracellular matrix deposition. Serotonin (5-hydroxytryptamine; 5-HT) induces fibroblast proliferation via the 5-HTR(2A) and 5-HTR(2B) receptors, but its pathophysiological role in IPF remains unclear. A study was undertaken to determine the expression of 5-HT receptors in IPF and experimental lung fibrosis and to investigate the effects of therapeutic inhibition of 5-HTR(2A/B) signalling on lung fibrosis in vivo and in vitro. METHODS AND RESULTS: Quantitative RT-PCR showed that the expression of 5-HTR(1A/B) and 5-HTR(2B) was significantly increased in the lungs of patients with IPF (n=12) and in those with non-specific interstitial pneumonia (NSIP, n=6) compared with transplant donors (n=12). The expression of 5-HTR(2A) was increased specifically in IPF lungs but not in NSIP lungs. While 5-HTR(2A) protein largely localised to fibroblasts, 5-HTR(2B) localised to the epithelium. To assess the effects of 5HTR(2A/B) inhibition on fibrogenesis in vivo, mice were subjected to bleomycin-induced lung fibrosis and treated with the 5-HTR(2A/B) antagonist terguride (or vehicle) in a therapeutic approach (days 14-28 after bleomycin). Terguride-treated mice had significantly improved lung function and histology and decreased collagen content compared with vehicle-treated mice. Functional in vitro studies showed that terguride is a potent inhibitor of transforming growth factor ß(1)- or WNT3a-induced collagen production. CONCLUSION: The studies revealed an increased expression of 5-HTR(2A) specifically in IPF. Blockade of 5-HTR(2A/B) signalling by terguride reversed lung fibrosis and is thus a promising therapeutic approach for IPF.

Effect of dopaminergic substances on sleep/wakefulness in saline- and MPTP-treated mice.

Sleep/wakefulness (S/W) disorders are frequent in Parkinson's disease (PD). The underlying causes have yet to be elucidated but dopaminergic neurodegenerative lesions seem to contribute to appearance of the disorders and anti-Parkinsonian medication is known to accentuate S/W problems. Hence, we reasoned that studying the acute effect of dopaminergic compounds on S/W in an animal model of PD might improve our knowledge of S/W regulation in the context of partial dopaminergic depletion. To this end, we tested the effect of levodopa (l-dopa), pergolide (a mixed D(2)/D(1) agonist) and lisuride (a D(2) agonist) on S/W recordings in MPTP-treated mice, in comparison with controls. Our results showed that dopaminergic compounds modify S/W amounts in both control and MPTP mice. Wakefulness amounts are greater in MPTP mice after l-dopa (50 mg kg(-1)) and lisuride (1 mg kg(-1)) injections compared with control mice. Moreover, the paradoxical sleep latency was significantly longer in MPTP mice after high-dose l-dopa administration. Our observations suggest that the actions of both l-dopa and lisuride on S/W differ slightly in MPTP mice relative to controls. Hence, MPTP-induced partial DA depletion may modulate the effect of dopaminergic compounds on S/W regulation.

The effect of terguride in carbon tetrachloride-induced liver fibrosis in rat.

BACKGROUND: Hepatic stellate cells (HSCs) are considered to be of vital importance in the pathogenesis of liver fibrosis. In vitro studies have demonstrated antiproliferative effects of 5-hydroxytryptamine(2) (5-HT(2), serotonin) receptor antagonists upon HSCs. Terguride, recognized as a partial dopamine agonist, also has potent 5-HT(2) receptor antagonist qualities and has been shown to prevent serotonin-induced organ changes and fibrosis in rats. AIM: In the current study, the carbon tetrachloride (CCL(4)) hepatic fibrosis rat model was used in combination with daily administration of terguride to evaluate potential preventive effects of a 5-HT(2) receptor antagonist upon liver fibrosis. MATERIALS AND METHODS: Forty rats (Sprague-Dawley) were included in the study. Twelve animals received terguride in combination with CCL(4) and 12 animals were given only CCL(4). The remaining 16 animals served as model controls. The extent of fibrosis was evaluated by liver weight, histologic analysis, biochemical analysis, and alpha-smooth muscle actin (alpha-SMA) immunohistochemistry. RESULTS: There were no significant differences in liver weight, hydroxyproline content, serum alanine and aspartate transaminases, serum hyaluronic acid, or alpha-SMA immunostaining between rats treated with terguride in combination with CCL(4) and rats given only CCL(4). All parameters, however, were significantly lower (P < 0.01) in the model controls. CONCLUSION: Terguride, a potent 5-HT(2) antagonist, did not prevent the development of liver fibrosis in rats given CCL(4).

Effects of different serotonin receptor subtype antagonists on the development of cardiac allograft vasculopathy in murine aortic allografts.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is the main obstacle for long-term survival after heart transplantation. Alloimmune mediated chronic vascular rejection results in several mechanisms like platelet activation, immigration of inflammatory cells through the endothelial layer and proliferation and migration of smooth muscle cells (SMCs). Serotonin (5-HT) promotes these processes via activation of 5-HT2 receptors. We hypothesized that inhibiting 5-HT2 receptors ameliorates the development of CAV. METHODS: CBA/JRj mice recieved aortic grafts from C57BL/6 mice. After transplantation until recovery of organs, recipients were treated with serotonin receptor antagonists: sarpogrelate (5-HT2A), SB 204741 (5-HT2B) or terguride (5-HT2A+B). Mice were sacrificed after 14 days for qRT-PCR analysis or after 30 days for histological evaluation. Serum serotonin ELISA was done at both time points. RESULTS: Elevated serum serotonin levels were significantly reduced after 5-HT2A antagonist treatment as was 5-HT2A receptor expression. This went along with reduced inflammation characterized by significantly fewer infiltrating macrophages and pro-inflammatory intragraft cytokines and with reduced tissue remodeling evident as significantly less neointima formation. CONCLUSION: Inhibition of the 5HT/5-HT2A receptor axis leads to significantly reduced neointima proliferation after aortic transplantation associated with reduced transendothelial migration of macrophages and decreased expression of inflammatory cytokines. These findings have translational implications as inhibitors of 5HT2A like sarpogrelate are already approved for clinical use.

[A case of ruptured internal carotid artery aneurysm mimicking pituitary apoplexy].

A 48-year-old female presented with a sudden onset of headache and visual impairment. Nineteen years before, she had undergone a transsphenoidal surgery for a prolactin producing pituitary adenoma at our hospital without intraoperative arterial bleeding. On arrival, she exhibited dilated pupils and loss of bilateral visual acuity, but improved immediately after all examinations. MRI revealed a pituitary tumor with intratumoral hemorrhage, intraventricular hemorrhage and subdural hemorrhage. Cerebral angiography revealed a left intracavernous carotid artery aneurysm. Her medical history and radiological findings suggested the rupture of a de novo aneurysm causing a hemorrhage into a pituitary adenoma mimicking pituitary apoplexy. Endovascular occlusion of the aneurysm was performed by use of platinum coils. Because of rapid improvement of visual acuity, administration of terguride was chosen for shrinking the pituitary adenoma. If a pituitary adenoma is present, the possibility of a coincidental aneurysm should always be considered. This association should be kept in mind when evaluating any case of pituitary apoplexy.

Use of biologics and other novel therapies for the treatment of systemic sclerosis.

INTRODUCTION: Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by vasculopathy, inflammation and fibrosis. These three main disease-determining pathways are the target of the currently available treatments used to possibly modify the progression of disease-related manifestations, although this synergy has not been fully applied on SSc joint, skin or lung involvement yet. Areas covered: we describe the current status of SSc treatment/therapy performing a literature search in MEDLINE/Pubmed and Thomson Reuter's Web of Science for articles published until March 2016. Moreover, ongoing registered clinical trials (RCTs) on SSc were searched through clinicaltrials.gov website. Expert commentary: presently, promising drugs are under evaluation to target the different pathogenic pathways of systemic sclerosis: Tocilizumab and Abatacept for skin and lung fibrosis; Riociguat and Selexipag are approved for pulmonary arterial hypertension but promising anti-fibrotic effects are now being studied. Finally, several anti-fibrotic molecules are currently involved in RCTs, such as Nintedanib, IVA-337, Terguride.

Transdermal lisuride: short-term efficacy and tolerability study in patients with severe restless legs syndrome.

BACKGROUND AND PURPOSE: Restless legs syndrome (RLS) patients suffer from symptoms not only at bedtime but also with variable circadian patterns. Transdermal application forms of dopamine agonists are expected to lead to a stable plasma concentration of the active drug which could ease treatment for RLS patients with daytime symptoms and avoid side effects of oral dopaminergic therapies. PATIENTS AND METHODS: In this controlled pilot study, 10 patients (six females, four males, mean age 58 years) with severe and long-lasting idiopathic RLS were treated during an initial open-label phase for 2 weeks either with one (n=3 patients) or, if required, two patches of lisuride every other day (dose per patch: 3mg lisuride, nominal effective release rate 7.0 microg lisuride/h). Patients were then randomized to double-blind treatment with lisuride (n=5) or placebo (n=4) for 1 week. RESULTS: Severity of RLS clearly improved during open-label and double-blind treatment with lisuride but became worse under placebo according to the International Restless Legs Syndrome Study Group Rating Scale (IRLS), RLS-6, and Clinical Global Impressions (CGIs) scales, and actigraphy assessments (periodic leg movement index) in the 1-week double-blind period. CONCLUSION: The explorative findings of this small controlled study suggest that lisuride patches might be an efficacious treatment for RLS patients without clinically relevant tolerability problems.

Dopamine receptor agonists, partial agonists and psychostimulant addiction.

Despite the epidemic growth of psychostimulant addiction over the past years, few pharmacological means of intervention are available to date for clinical treatment. This is of importance since the withdrawal syndrome that follows abstinence from drugs such as cocaine and the amphetamines is characterized, among other symptoms, by intense craving for the abused drug, and this is considered a critical factor leading into relapse of drug use. In this article, Luigi Pulvirenti and George Koob focus on the modulatory role shown by drugs acting at the dopamine receptor on the various phases of psychostimulant dependence in preclinical models and in human studies, and suggest that a class of compounds with partial agonist properties at the dopamine receptor may have therapeutic potential.

Lisuride hydrogen maleate: evidence for a long lasting dopaminergic activity in humans.

In 12 acromegalics a single oral dose of 0.2 mg lisuride, an ergoline derivative, significantly reduced plasma PRL but not GH concentrations. Three-tenths milligram of the drug significantly reduced plasma levels of the two hormones. Four-tenths milligram of lisuride did not augment this inhibitory effect. Plasma PRL levels were suppressed in all patients, whereas GH levels were reduced by more than 50% of the base-line values in only seven patients who also responded to the administration of 2.5 mg bromocriptine (CB154). In the patients unresponsive to lisuride, CB154 also failed to change GH levels. The suppressive effect of lisuride started at 60 min (at 150 min for CB154) and plasma GH and PRL levels were still markedly suppressed at 300 min. Plasma GH and PRL concentrations were consistently reduced in two acromegalic patients during 2 weeks of chronic treatment with 0.3 mg lisuride four times a day. In six normal subjects, TRH-induced PRL release was significantly inhibited by pretreatment with 0.3 mg of the drug. The similarity in the effects of lisuride and CB154 suggests that the observed effects of lisuride on GH and PRL are attributable to the known dopaminergic activity of the drug. This conclusion is supported by the data showing that pimozide effectively counteracted the inhibitory action of lisuride on GH and PRL release. We suggest that lisuride may be of value in the medical treatment of acromegaly and hyperprolactinemic states.

Chronic treatment of pathological hyperprolactinemia and acromegaly with the new ergot derivative terguride.

The long term effectiveness and tolerance of terguride, a new ergot derivative, as initial therapy were evaluated in 20 patients with pathological hyperprolactinemia (PHP; group A) and 7 patients with acromegaly. We also studied 10 patients with PHP whose treatment was changed from bromocriptine or lisuride to terguride (group B). Terguride, given for at least 6 months in divided doses ranging from 0.25-1.50 mg/day to group A patients, resulted in normal (11 patients) or markedly reduced plasma PRL levels. Gonadal function was restored in all but 2 patients in this group, and the tumors shrank in 3 of 5 patients with a macroprolactinoma and in 1 of 3 patients with a microprolactinoma. In group B patients, positive effects of the previous treatment on PRL levels, gonadal function, and tumor growth were maintained by terguride. Terguride suppressed plasma GH levels below 50% of baseline in 4 of the 7 acromegalic patients. Two of the 27 patients initially treated with terguride complained of mild nausea and postural hypotension only after the first dose (0.25 mg) of the drug. No patient in group B had any side-effects during terguride, with the exception of 1 patient who was also intolerant to bromocriptine. We conclude that terguride is an effective well tolerated dopaminergic agent in PHP.

Size reduction of macroprolactinomas by bromocriptine or lisuride treatment.

We have administered to 29 patients with macroprolactinoma the dopamine agonists bromocriptine and lisuride for 1-50 months (mean +/- SE, 12.7 +/- 1.8) in order to assess the effects of these drugs on tumor size. Fourteen patients were treated with bromocriptine (dose range, 7.5-20 mg/day), 12 patients were treated with lisuride (0.6-2 mg/day), and 3 patients were given both drugs. Computed tomography performed before and during treatment showed the occurrence of tumor shrinkage in 18 patients (62%), but in no case was a complete disappearance of the tumor observed. In 5 of these patients, it was even possible to document tumor shrinkage within the first month of treatment with low doses of the dopamine agonists, whereas in other patients, tumors shrank only after prolonged treatment with higher doses. Visual field and acuity improved or normalized in 8 of the 13 patients with visual defects; in some cases, the improvement was reported as early as 2 days after the treatment was started. Plasma PRL levels fell in all patients who showed a reduction in tumor size; in 2 other patients, PRL levels were only poorly suppressed, and tumor size remained unchanged. In the remaining patients, PRL levels were lowered without convincing evidence of tumor shrinkage. In considering the high percentage of patients showing tumor shrinkage under medical treatment, we propose a course with dopamine agonists as the first step in the management of patients with macroprolactinomas regardless of the presence of visual impairments.

Dopaminergic treatment of acromegaly: different effects on hormone secretion and tumor size.

We studied the effects of long term treatment with bromocriptine (Br) or lisuride (L) on GH secretion and tumor size in 19 acromegalic patients with large pituitary adenomas. In 22 additional patients with smaller adenomas, only plasma GH levels were monitored during treatment. All patients underwent an acute test with 2.5 mg Br or 0.3 mg L and, on the basis of GH changes, were classified as responders, i.e. reduction in circulating GH concentrations by at least 50% below baseline, or as nonresponders. The chronic treatment was 5-20 mg/day Br in 26 patients or 0.3-2.0 mg/day L in 15 patients. Treatment was given for 4-26 months (mean +/- SE, 13.3 +/- 2.8 months). Plasma GH levels (baseline, 46.3 +/- 8.3 ng/ml) were significantly lower in the group as a whole (22.7 +/- 3.6 ng/ml; P less than 0.01) after the first month of treatment with dopamine agonist agents. GH levels decreased significantly in those acromegalic patients who responded to the acute test (P less than 0.001), but were unchanged in the nonresponders. In addition, there was a significant correlation between the maximal percent GH decrease in the acute test and the response during chronic treatment (r = 0.73; P less than 0.01). Computed tomography failed to show any tumor size changes in any of the GH nonresponders who had a macroadenoma . However, in two patients in the acute responder group with macroadenomas, chronic dopamine agonist therapy resulted in reduction of the extrasellar portion of the tumor (-30% and -40% of tumor area, respectively). These data show that although dopaminergic drugs lower GH levels and reverse signs and symptoms of active disease in those acromegalic patients who are responsive to an acute challenge, tumor size reduction occurred in a minority of such patients.

Combination of a dopamine agonist, MAO-B inhibitor and levodopa--a new strategy in the treatment of early Parkinson's disease.

During 3 years' treatment of de novo parkinsonian patients with lisuride in combination with selegiline and levodopa the optimal therapeutic dose of levodopa was significantly lower than that when given alone or together with lisuride. The improvement in parkinsonian disability was equal in all these patient groups, but treatment with an early combination of lisuride and levodopa without or with selegiline resulted in significantly and equally reduced end-of-dose disturbances and dyskinesias than treatment with levodopa alone. This finding, together with the possible retardation of the progression of the disease with selegiline suggests that dopaminergic treatment in early Parkinson's disease should be initiated using a dopamine agonist such as lisuride in combination with selegiline and levodopa.

Disposition of oral lisuride in Parkinson's disease.

The single and multiple oral dose plasma kinetics of lisuride were followed by a recently developed radioimmunoassay method in 11 patients with Parkinson's disease. A very wide range of plasma drug concentrations resulted from a single dose of 300 micrograms, as reflected in large interindividual differences in peak concentration (0.27 to 3.30 ng/ml) and AUC after the initial dose (43.1 to 617 ng X min/ml). Absorption was rapid, with a mean time to peak of 39 min. Only 0.05% of the dose was excreted unchanged in urine in 24 hr. There was a 110% increase in apparent oral clearance after 2 to 4 wk of treatment.

Neuroendocrinologic findings in patients with untreated Huntington's chorea.

Huntington's chorea (HC) was studied in 14 untreated patients, in six patients receiving long-term neuroleptic treatment, and in four patients after drug withdrawal. Our results showed that patients with HC may be divided into three groups, otherwise clinically indistinguishable, on the basis of growth hormone responsiveness to dopaminergic stimuli. The existence of subpopulations of patients with HC must be considered in further studies on these subjects.