Characterization of the head-twitch response induced by hallucinogens in mice: detection of the behavior based on the dynamics of head movement.

RATIONALE: The head-twitch response (HTR) is a rapid side-to-side rotational head movement that occurs in rats and mice after administration of serotonergic hallucinogens and other 5-HT2A agonists. The HTR is widely used as a behavioral assay for 5-HT2A activation and to probe for interactions between the 5-HT2A receptor and other transmitter systems. OBJECTIVE: High-speed video recordings were used to analyze the head movement that occurs during head twitches in C57BL/6J mice. Experiments were also conducted in C57BL/6J mice to determine whether a head-mounted magnet and a magnetometer coil could be used to detect the HTR induced by serotonergic hallucinations based on the dynamics of the response. RESULTS: Head movement during the HTR was highly rhythmic and occurred within a specific frequency range (mean head movement frequency of 90.3 Hz). Head twitches produced wave-like oscillations of magnetometer coil voltage that matched the frequency of head movement during the response. The magnetometer coil detected the HTR induced by the serotonergic hallucinogens 2,5-dimethoxy-4-iodoamphetamine (DOI; 0.25, 0.5, and 1.0 mg/kg, i.p.) and lysergic acid diethylamide (LSD; 0.05, 0.1, 0.2, and 0.4 mg/kg, i.p.) with extremely high sensitivity and specificity. Magnetometer coil recordings demonstrated that the non-hallucinogenic compounds (+)-amphetamine (2.5 and 5.0 mg/kg, i.p.) and lisuride (0.8, 1.6, and 3.2 mg/kg, i.p.) did not induce the HTR. CONCLUSIONS: These studies confirm that a magnetometer coil can be used to detect the HTR induced by hallucinogens. The use of magnetometer-based HTR detection provides a high-throughput, semi-automated assay for this behavior, and offers several advantages over traditional assessment methods.

[Prescription of ergot derivatives for lactation inhibition in France: Current practices]. / Pratiques de prescription des dérivés de l'ergot de seigle dans l'inhibition de la lactation en France.

OBJECTIVES: To provide an overview of ergot derivatives prescription for lactation inhibition in France, either label (bromocriptine 2.5mg and lisuride 0.2mg) or off-label prescription (dihydroergocryptine and cabergoline). PATIENTS AND METHODS: Analysis based on a questionnaire sent to all 618 French maternity wards in 2009, and prescription modalities from social security reimbursement data in the Rhône-Alpes region. RESULTS: The mean response rate to the questionnaire was 43% and main characteristics of respondents in this sample were very close to those found at the national level. The use of bromocriptine (89%) was the most frequently proposed. Dihydroergocryptine and cabergoline were mentioned as first or second alternatives in 39 and 24% of cases, respectively. Lisuride, homeopathy and phytotherapy were very rarely mentioned. The analysis of social security reimbursement data in the Rhône-Alpes region between 2008 and 2009 evidenced an increase in the rate of dihydroergocryptine prescriptions (from 37 to 46%), which were more frequent in women also treated with cardiovascular or psychotropic drugs, while that of bromocriptine decreased. CONCLUSION: This study shows that, in France, the main alternative to bromocriptine for lactation inhibition is the off-label use of dihydroergocryptine followed by cabergoline, which seems to be safer.

Anticonvulsive effects of the dopamine agonist lisuride maleate after experimental traumatic brain injury.

Traumatic brain injury is a heterogeneous disease, encompassing a wide range of pathologies. The dopamine agonist lisuride is well established in the therapy of Parkinson's disease. Additionally to its dopaminergic effects it decreases prolactine release, reducing the amount of inflammatory mediators such as TNF-alpha or Il-6. Lisuride has strong binding affinity to serotonergic and histaminergic receptors on neuronal and glial cells leading to scavenging of highly reactive free radicals. Due to its interaction with dopaminergic D2 and D4 receptors as well as 5-HT-1A receptors, NMDA-receptor signaling and glutamate-mediated excitotoxicity can be modulated beneficially. Despite of these promising neuroprotective effects, experimental data scrutinizing the effects of lisuride after acute brain injury are sparse. We therefore investigated the effect of lisuride after controlled cortical impact injury (CCII) in rats. 70 male Sprague-Dawley rats were randomized to lisuride or to placebo treatment by an initial s.c. loading dose (0.3mg/kg BW) and following continuous application (0.5mg/kg/d) by s.c. implanted osmotic pumps. In three experimental groups we determined (sub)acute neuro-physiological changes after trauma. Mean arterial blood pressure, intracranial pressure, and electrical brain activity were monitored acutely for up to 3h after trauma. Brain edema formation was assessed 24h after CCII. Furthermore, contusion volumes were quantified by magnetic resonance tomography and neurological testing was performed for up to 7 days after injury. Associated with the administration of lisuride there was a significant reduction in duration and number of post-traumatic seizures. Despite of a sustained arterial hypotension following the initial bolus administration in the treatment group, contusion volumes and neurological function tests did not differ significantly in comparison to the control group. Overall, lisuride seems to have significant anticonvulsive effects but seems not to influence secondary brain damage in this experimental model.

Co-administration of the partial dopamine D2 agonist terguride with L-dopa attenuates L-dopa-induced locomotor sensitization in hemiparkinsonian mice.

While dopamine replacement remains the standard pharmacotherapy for Parkinson's disease, chronic L-dopa treatment is associated with development of debilitating motor fluctuations such as L-dopa-induced dyskinesia (LID). In this study we evaluated the effects of the partial dopamine D(2) agonist terguride on the development of LID in hemiparkinsonian mice (unilaterally lesioned with 6-hydroxydopamine). First, consistent with the partial agonist property, terguride had 1000-fold higher potency than dopamine, yet producing one-third level of maximal activation of dopamine, as assayed by [(35)S]GTPgammaS binding. Furthermore, in the absence and presence of dopamine in vitro, terguride increased and decreased striatal [(35)S]GTPgammaS binding, respectively. Next, we found that co-administration of terguride (at 0.1 and 0.5mg/kg, i.p.) with L-dopa (1.8 mg/kg) daily for 14 days, significantly attenuated the development and expression of L-dopa-induced rotational sensitization. Furthermore, the cross-challenge paradigm revealed that chronic L-dopa treatment (but not terguride) sensitized locomotor response to the dopamine D(1) agonist SKF 81297 while chronic treatment with terguride (but not L-dopa) produced sensitized locomotor responses to the adenosine A(2A) antagonist 8-(3-chlorostyryl)caffeine (CSC). Importantly, the co-administration of terguride with L-dopa did not show locomotor sensitization to either SFK 81297 or CSC upon challenge. Together, these results suggest that co-administration of partial dopamine D(2) agonists with L-dopa may prophylactically attenuate L-dopa-induced abnormal behavioral responses such as LID.

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.

Long-term serotonin effects in the rat are prevented by terguride.

Long-term hyperserotoninemia induces heart valve disease in rats, and cases of cardiac valvulopathies have been reported in patients using ergolines, possibly through activation of the 5-hydroxytryptamine(2B) (5HT(2B)) receptor. The ergoline terguride (transdihydrolisuride) is a 5HT(2B/2C) receptor antagonist. Using a rat model, we have investigated whether terguride could prevent serotonin-induced changes in general and heart disease specifically. During 4 months, twelve Sprague-Dawley rats were given daily subcutaneous serotonin injections; twelve rats received a combination of serotonin injections and terguride by gavage, whereas ten rats were untreated controls. Using echocardiography, rats with aortic insufficiency were found in all 3 groups, while pulmonary insufficiency was only found in two rats injected with serotonin alone. Animals given serotonin alone had significantly higher heart weights compared to the controls (p=0.029) and rats given terguride (p=0.034). Rats injected with serotonin alone developed macroscopic skin changes at the injection sites, histologically identified as orthokeratosis and acanthosis. Terguride completely prevented these changes (p=0.0001, p=0.0003). Liver weights were higher in the animals given serotonin alone compared to controls (p=0.014) and terguride treated animals (p=0.009). Stomach weights were higher in animals given serotonin alone compared to rats given terguride (p=0.012). In the mesenchymal cell-line MC3T3-E1, terguride almost completely inhibited serotonin-induced proliferation (p<0.01). Serotonin increases heart, liver and stomach weights, possibly through enhanced proliferation. Terguride inhibits these effects. We propose that terguride may have beneficial effects in the treatment of diseases such as carcinoid syndrome, where serotonin plays an important pathogenic role.

Dopamine stimulation via infusion in the lateral ventricle.

Continuous dopamine (DA) stimulation is a therapeutic approach that applies to the treatment of motor fluctuations due to pulsatile DA stimulation in Parkinson's disease (PD), to cure the abuse of drugs, such as cocaine or amphetamine (which produce short-lasting peaks of extracellular DA), and as a safe therapeutic approach to avoid hedonistic homeostatic dysregulation (which sometime develops as an abuse pattern in PD patients receiving a pulsatile DA replacement therapy). However, systemic continuous delivery of DA agonists leads to a variety of side effects. In search for an alterative approach, in the present study we evaluated the possibility of delivering intracerebroventricularly (i.c.v.), a DA agonist: lisuride that was already shown to be effective when administered continuously subcutaneously (s.c.). In particular, we were interested in examining whether lisuride infused within the lateral ventricle was still able to stimulate DA receptor by inducing contralateral turning behavior in hemiparkinsonian rats. We found that lisuride, when infused in the lateral ventricle was effective in reducing the threshold for stimulating DA receptors. These results offer a more reliable and safe therapeutic approach to deliver continuous DA selectively in the brain.

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.

Lisuride treatment of restless legs syndrome: first studies with monotherapy in de novo patients and in combination with levodopa in advanced disease.

In two 4-week polysomnography pilot studies with 10 patients each, we investigated the efficacy of oral lisuride as monotherapy in de novo RLS patients as well as in combination with levodopa in advanced RLS. Daily doses at study end were 0.3 mg lisuride, plus 150 mg levodopa in the combination study. Marked improvements occurred in both studies in different PLM indexes and in the CGI. Levodopa dose could be decreased by 27%. Lisuride might be an efficacious treatment for RLS in general, and in combination with levodopa in advanced stage.

Transdermal lisuride delivery in the treatment of Parkinson's disease.

Transdermal delivery of dopamine agonists (DA) is a promising therapeutic concept, which aims to ameliorate frequency and intensity of motor fluctuations in patients with Parkinson's disease (PD). We treated 8 PD patients with unpredictable on-off phenomena with lisuride patches (release: 2-5 microg lisuride base/cm2/hour in mice) in addition to their preexisting antiparkinsonian drug regime up to a period of 8 days. In order to quantify the intensity and frequency of motor fluctuations, we determined the motor changing rate (MCR), which corresponds to the patient's self rating of motor function, performed every thirty minutes, divided through the number of scored intervals minus 1. Additional lisuride patch application significantly (p = 0.023) improved the MCR compared to baseline. Relevant side effects were transient skin irritations in four patients. Our observational study demonstrates the safety, tolerability and efficacy of transdermal lisuride delivery in the treatment of motor complications.

Management of restless legs syndrome by the partial D2-agonist terguride.

BACKGROUND: Terguride as a partial D2-receptors agonist seems suitable for treatment of restless legs syndrome (RLS). METHODS: Nine RLS patients without previous dopaminergic therapy received a daily dose of terguride (0.25 mg) 29.9+/-16.9 (SD) days. RESULTS: Two patients enrolled in the study failed to turn up for a successive check up. The seven subjects who were re-examined complied with the therapy. Their RLS symptoms improved (as measured on the International RLS intensity scale), decreasing from 24.3+/-5.3 to 14+/-4.7 (p=0.014). However, the terguride treatment did not significantly alter the daytime sleepiness or the subjective duration of nocturnal sleep. The daily dose was doubled in three patients who reported insufficient RLS improvement. One of the three patients later reported augmentation.

[Pharmacokinetic/pharmacodynamic analysis of anti-hyperprolactinemic effect of terguride based on dopamine D2 receptor occupancy].

Terguride has been widely used for the treatment of hyperprolactinemia via partial agonistic action on dopamine D2 receptors in the pituitary. The present study analyzed retrospectively the dopamine D2 receptor binding occupancy (phi) of terguride. The average phi value was estimated to be 14.1% after oral administration of the average/standard therapeutic dose of terguride. Taking the intrinsic activity (alpha) into consideration, the value of alpha. phi was 2.33%. These results suggest that the antihyperprolactinemic effect of terguride was elicited despite the low receptor occupancy. Furthermore, we developed a pharmacokinetic/pharmacodynamic model for ascertaining the serum prolactin-lowering effect of terguride, considering both the reversible binding to D2 receptors and the effect on the increase rate in the prolactin level. The developed model fit well with the actual data. Although this model could be improved, it could explain the long duration of the antihyperprolactinemic activity of terguride and might be useful for designing its rational dosage regimen.

[Arrest of lactation after 2nd trimester abortion with a single dose of cabergoline in comparison with 10-day administration of teguride]. / Zástava laktace po potratu ve II. Trimestru jednorázovým podáním cabergolinu ve srovnání s desetidenním podáváním terguridu.

OBJECTIVE: The objective of the work was to compare the effectiveness and tolerance of a single administration of 1 mg cabergoline and 10-day administration of 1.5 mg terguride divided into three doses after 8-hour intervals, in the indication of arrest of lactation after an abortion during the second trimester. TYPE OF STUDY: Prospective clinical study. NAME AND PLACE OF DEPARTMENT: Gynaecological and Obstetric Clinic. First Medical Faculty Charles University and General Faculty Hospital Prague, Apolinárská 18, Prague 2. METHOD: During the period between January and October 2000 to 41 patients after abortion induced during the 2nd trimester terguride, 0.5 mg after 8-hour intervals, was administered for a 10-day period. During the subsequent period from November 2000 to September 2001 to 43 patients cabergoline was administered in a single dose within 12 hours after the abortion. During hospitalization the patients were asked daily for their subjective evaluation of the effect of treatment (vertigo, palpitations, headache, nausea, vomiting, abdominal pain, sleepiness, secretion from the breast, tension in the breasts) and the doctor evaluated the success of treatment objectively. Within 21 days after the abortion the patients were addressed over the phone on subjective and objective effects of treatment. For statistical evaluation Fisher's exact bilateral test was used. RESULTS: The "cabergoline" group displayed, as compared with the "terguride" group, significantly fewer undesirable effects (p < 0.01). No significant difference was found between groups (p = 0.1) as regards the necessity to repeat administration of the drug. None of the undesirable effects were so serious to call for interruption of treatment. CONCLUSION: Arrest of lactation during the second trimester of gestation is an integral part of care of the patient. Symptoms associated with lactation are adversely accepted by the patient. The incidence of undesirable effects after a single dose of cabergoline is significantly lower as compared with 10-day administration of terguride. A single dose of cabergoline during hospitalization improves the patients' compliance and thus the effect of treatment. Cabergoline can be used as the drug of first choice for arrest of lactation after abortion during the second trimester of pregnancy.

Prospective randomized trial of lisuride infusion versus oral levodopa in patients with Parkinson's disease.

Motor complications are a major source of disability for patients with advanced Parkinson's disease. Surgical therapies provide benefit to some, but these treatments are expensive and associated with adverse effects. Current research indicates that motor complications are associated with abnormal, intermittent, pulsatile stimulation of denervated dopamine receptors using short acting dopaminergic agents such as levodopa. Retrospective studies suggest that the use of longer-acting more continuous dopaminergic therapies can improve both motor fluctuations and dyskinesia. We performed a prospective, long-term (4-year) trial comparing patients randomized to receive subcutaneous infusion of the dopamine agonist lisuride versus conventional therapy with oral levodopa and dopamine agonists. We demonstrate that patients receiving lisuride infusions experienced a significant reduction in both motor fluctuations and dyskinesia compared with patients receiving standard dopaminergic therapies. Benefits persisted for the 4-year duration of the study. Mean Unified Parkinson's Disease Rating Scale scores in "ON" and "OFF" states did not significantly change between baseline and 4 years for patients in the lisuride group, but deteriorated in patients in the levodopa group. This study indicates that continuous lisuride infusion can be beneficial for patients with advanced Parkinson's disease and reverse established motor fluctuations and dyskinesia.

Efficacy and tolerability of dopamine agonists in a parkinsonian population.

A clinical retrospective study was carried out in a population of 366 Parkinson's disease (PD) outpatients, to analyse the efficacy and tolerability of nonergoline and ergoline dopamine agonist (DA), in monotherapy or in combination with L-dopa. Safety was comparable in both groups except for higher occurrence of gastrointestinal symptoms in ergoline group and somnolence in nonergoline group. No significant difference concerning efficacy and tolerability was found during DA monotherapy. Mean age at PD onset was slightly higher in patients withdrawing DA monotherapy for adverse events comparing to patients who needed the addition of L-dopa (60.36 +/- 7.53 versus 54.88 +/- 10.75; p<0.05), suggesting that older age at the onset of the disease increases the risk for adverse events during DA monotherapy. The follow-up of the remaining patients still in monotherapy with DA will allow a better evaluation of these aspects.

The influence of personality on nicotine craving: a hierarchical multivariate statistical prediction model.

The present study proposes a hierarchical multivariate statistical prediction model which enables to determine the most prominent variables (physiological, biochemical and personality factors) related to nicotine craving and dopaminergic activation. Based on animal studies reporting a reduction of the rewarding effects of psychotropic drugs after blockade or destruction of the mesolimbic dopamine (DA) system, changes in nicotine craving after pharmacological manipulation by means of a DA agonist (lisuride 0.2 mg) and a DA antagonist (fluphenazine 2 mg) were assessed in 36 healthy male heavy smokers. The major aim was the development of a multivariate prediction model which is applicable in samples lacking variance homogeneity or the prerequisite of a multivariate normal distribution. The model proposed is a combination of multivariate parametric and nonparametric methods taking advantage of their individual merits. Especially personality variables, such as sensation seeking, impulsivity, and neuroticism showed to be important predictors of craving in this responder approach.

Five-year follow-up of early lisuride and levodopa combination therapy versus levodopa monotherapy in de novo Parkinson's disease. The French Lisuride Study Group.

The value of an early initial coadministration of levodopa (L-dopa) and lisuride in Parkinson's disease was the main goal of the present study. Eighty-two patients with recently diagnosed idiopathic Parkinson's disease were randomized into two groups for treatment with L-dopa alone or L-dopa + lisuride. The trial was double-blinded for the first year and open for the following 4 years. Selegiline (10 mg/day b.i.d.) was added in both groups at the end of the first year. Outcome measures were evolution of L-dopa dosage and Unified Parkinson's Disease Rating Scale scores and subscores, and incidence of motor complications. The dropout rate was higher in the L-dopa group (63.4%) than in the combination group. Motor improvement was better (p < 0.01) in the L-dopa + lisuride group. Expected motor complications were rare, moderate and equivalent in the two groups despite a difference in L-dopa dosage (446.7 vs. 387.5 mg/day). Long-term follow-up demonstrated the L-dopa-sparing effect of lisuride (average 1 mg/day), the beneficial effect of early combination therapy on motor status and the paucity of motor complications in both groups.

Antagonism of a PCP drug discrimination by hallucinogens and related drugs.

Drugs such as PCP and MK-801 can cause psychotic reactions in humans by antagonizing NMDA receptors. This action is ultimately toxic to certain cortical neurons and may be one mechanism underlying neurodegenerative diseases, including schizophrenia. It has been reported that hallucinogens such as LSD, DOM, and DOI can block the neurotoxic effects of NMDA antagonists, possibly by activating inhibitory 5-HT2A receptors on GABAergic interneurons that normally inhibit glutamatergic projections to the retrosplenial and cingulate cortexes. The purpose of this experiment was to determine the extent to which similar drugs might also alter the behavioral effects of one NMDA antagonist, PCP. Rats were trained to discriminate this compound (2.5 mg/kg) from saline and were then given a series of antagonist tests. It was found that LSD (0.32 mg/kg) and DOM (4.0 mg/kg) blocked the PCP cue completely; DMT (8.0 mg/kg) and a structural congener of LSD, lisuride (LHM; 0.4 mg/kg), blocked the effects of PCP partially. The 5-HT/DA antagonists spiperone and ritanserin had no effect on the PCP cue. These data suggest that LSD, DOM, and, less effectively, DMT and LHM can block the behavioral as well as the neurotoxic effects of NMDA antagonists most likely through agonist actions at 5-HT2 receptors.