Antidopaminergic Drugs Research Articles

Reversal of morphine conditioned behavior by an anti-dopaminergic post-trial drug treatment during re-consolidation

Morphine has potent pro-dopamine effects that can be manifested as hyper-locomotion and these behavioral effects can undergo conditioning and sensitization. The aim of the present study was to assess whether an inhibitory dopaminergic post-trial treatment (0.05 mg/kg apomorphine) given during re-consolidation could reduce morphine conditioning. To induce conditioned morphine hyperactivity and control for morphine exposure, a paired/unpaired Pavlovian conditioning protocol was used. The morphine paired groups received morphine in the open-field test arena and the unpaired groups received the same morphine (10 mg/kg) treatments but in a different environment. The morphine treatments were administered once per day for 5 days. With repeated treatments, the paired morphine groups developed a sensitized hyper-locomotion response whereas the unpaired morphine groups did not differ from vehicle groups. Subsequently, the paired, unpaired and vehicle groups were given four daily non-drug 5 min conditioning tests. In these conditioning tests, the paired but not the unpaired and vehicle groups exhibited a conditioned locomotor stimulant response. These groups were subdivided into matched groups and received either vehicle or 0.05 mg/kg apomorphine either during re-consolidation immediately post-test or after re-consolidation 15 min post-test. In the immediate post-trial treatment groups, the morphine conditioned response in the paired group was eliminated after only one post-trial apomorphine treatment. The same immediate 0.05 mg/kg apomorphine post-trial treatments had no effect on the unpaired morphine or vehicle groups. In the paired group that received vehicle immediately post-trial, the conditioned response remained robust and unchanged over the four conditioning tests. In the post-trial 15 min delay treatment groups, the post-trial apomorphine treatments had no effect on the morphine conditioned response. These results showed that the inhibition of dopamine activity by apomorphine during the re-consolidation of a cue activated morphine conditioned response eliminated morphine conditioned effects. In that morphine conditioned effects are important for the initiation of addiction and in triggering drug craving and relapse, this finding has potential relevance to opioid addiction treatment.

Parkinsonism in a population-based study of individuals aged 75+ years: The Pietà study

IntroductionParkinsonism is one of the most prevalent neurological syndromes in the elderly. There are only a few epidemiological studies focusing on parkinsonism in oldest-old individuals, particularly in Latin America. This study aims to investigate the prevalence and characteristics of parkinsonism in subjects aged 75 + years living in the community. MethodsThe Pietà study is a population-based investigation on brain aging conducted in Caeté, southeast Brazil. A sample composed of 610 community-dwelling individuals aged 75 + years (48.7% of the total population within this age range) underwent clinical, neurological, cognitive and functional assessments. ResultsThe sample comprised mostly women (61.5%), with mean age of 83.3 years and mean schooling of 2.5 years. Parkinsonism was identified in 65 subjects (crude prevalence = 10.7%). Parkinson's disease, Parkinsonism + dementia syndrome, drug-induced parkinsonism, vascular parkinsonism and Lewy-body dementia were identified in, respectively, 19 (29.2%), 19 (29.2%), 8 (12.3%), 4 (6.1%) and 1 (1.5%) subjects. In 14 individuals (21.5%), the etiology of parkinsonism could not be determined. The most important vascular risk factor was hypertension (64.6%). Cognitive evaluation disclosed dementia in 37 (56.9%) subjects. Mean Pfeffer's functional activities questionnaire score was 12.2 points and 22 (33.8%) subjects were impaired in basic activities of daily living. ConclusionParkinsonism was common in this oldest-old population, being associated with dementia and vascular risk factors, particularly hypertension. Different confounders, such as concomitant dementia and exposure to anti-dopaminergic drugs, were present in this population, challenging the definition of causes of parkinsonism.

Anti-dopaminergic drug could help ease postoperative nausea and vomiting in high-risk patents

Anti-dopaminergic drug could help ease postoperative nausea and vomiting in high-risk patents

Hormonal induction of ovulation using Ovaprim™ [(D-Arg6, Pro9NEt)-sGnRH + domperidone] and its impact on embryonic development of wild-caught Longspine scraper, Capoeta trutta (Heckel, 1843)

Knowledge of gamete quality is a prerequisite for developing techniques to fertilize eggs and rear offspring for hatchery production. Our objective was to develop assisted reproductive techniques, via hormonal induction of final oocyte maturation (FOM), for Longspine scraper, Capoeta trutta. Fish were administered injections of salmon gonadotropin-releasing hormone analogue containing anti-dopaminergic drug (Ovaprim™) or saline (control). Effects of Ovaprim on induction of ovulation, gamete quality, embryonic development, and larval survival were later examined with serum steroid hormone levels and ovarian histology. The saline group failed to spawn, whereas Ovaprim accelerated FOM and induced spawning. Fish treated with Ovaprim showed an increase in gonadosomatic index, egg diameter, and wet weight relative to controls. Average absolute fecundity, relative fecundity, fertilization, and hatching rates were 8823 eggs/spawn, 53 eggs/g body weight, 95%, and 91%, respectively. Serum 17α,20β-dihydroxy-4-pregnen-3-one (DHP) levels were significantly enhanced by ∼4-fold in Ovaprim-treated fish compared to the saline-injected fish, while 17β-estradiol levels declined upon FOM in hormone treated fish. Embryonic development closely resembled the teleost scheme, despite variations in timing. Larval survival at 6 and 12days post-hatch were 98% and 95%, respectively. Results suggest that Ovaprim is efficient for inducing spawning in C. trutta for stock enhancement or hatchery purposes.

266 The Relative Frequency of Akathisia from Parenteral Antidopaminergics: A Systematic Review and Meta-Analysis

Parenteral antidopaminergic medications are frequently administered in the acute setting for nausea, vomiting, and headache. Extrapyramidal symptoms, which are extremely distressing to patients, may develop in the near term after parenteral administration of these medications. In this study, we performed a systematic review and meta-analysis to determine how frequently these symptoms arise in the aftermath of antidopaminergic medication use. PubMed, EmBase, Web of Science, and the Cochrane Library were searched in January 2017 for randomized controlled trials and prospective cohort studies in which a parenteral antidopaminergic drug was administered for headache, migraine, nausea, or vomiting. Articles were selected based on independent determinations of two investigators. Data was abstracted into a standardized form. Evidence was graded using the Cochrane risk of bias tool. Weighted mean frequencies were calculated for each type of extrapyramidal symptom. Meta-analysis, using random effects models, was performed, when appropriate—results are reported as OR (95% CI). A total of 36 studies with 4643 participants were included (median number of participants=98). Most were set in the emergency department. Baseline demographics were generally comparable amongst the included studies. In general, the quality of the studies was good with low risk of bias. Akathisia was the only consistently reported extrapyramidal side effect. The overall rate of acute drug-induced akathisia was 16.3% (642/3942). Prochlorperazine induced the highest rates of akathisia at 27.3% (95% CI [24.8%, 30.0%]), followed by haloperidol at 19.6% (95% CI [10.8%, 32.7%]), droperidol at 13.1% (95% CI [10.4%, 16.4%]), promethazine at 11.6% (95% CI [6.4, 19.7%]), and metoclopramide at 11.0% (95% CI [9.5%, 12.2%]). Overall, dystonic reactions occurred in 2.9% (6/206) of antidopaminergic administrations. For metoclopramide the frequency of dystonic reactions was 3.9% (95% CI [1.2%, 10.0%]) and for droperidol 1.9% (95% CI [0.1%, 7.2%]). There were no reported cases of tardive dyskinesia. Metoclopramide was more likely to cause akathisia than non-antidopaminergic standard therapy (OR 15.5 95% CI [2.1, 117.1]). Similarly, prochlorperazine was more likely to cause akathisia than non-antidopaminergic therapy (OR 4.7 95% CI [1.2, 18.8]). Slow infusion was less likely to cause akathisia than bolus administration for both metoclopramide (OR 3.0 95% CI [2.0, 4.6]) and prochlorperazine (OR 1.3 95% CI [0.8, 2.2]). Antidopaminergics other than metoclopramide were more likely to cause akathisia than metoclopramide itself (OR 2.2 95% CI [1.0, 5.1]), while antidopaminergics other than prochlorperazine were less likely than prochlorperazine to cause akathisia (OR 0.6 95% CI [0.4, 1.0]). Overall, akathisia occurs in 16.3% of patients administered a parenteral antidopaminergic. Other extrapyramidal side effects were much less common. Akathisia is much more common after administration of antidopaminergics than when non-antidopaminergic therapy is given. Metoclopramide is less likely to cause akathisia than other antidopaminergics while prochlorperazine is more likely to cause akathisia.

Incidental Findings of Intense Radioiodine Uptake in Struma Ovarii and Bilateral Nonlactating Breasts Simultaneously on Postablation 131I SPECT/CT for Papillary Thyroid Cancer.

A 52-year-old woman diagnosed with papillary thyroid carcinoma was referred for 131I therapy following total thyroidectomy. She was given 4,810MBq (130mCi) of 131I following 4weeks of thyroid hormone withdrawal. A posttherapy scan showed intense, focal activity in the pelvis and intense, diffuse activity on both sides of the chest, which was localized to the right ovary and both breasts on SPECT/CT examination. She had bilateral nipple pain and a history of antidopaminergic drugs as combination medication for her rheumatoid arthritis and prokinetics during radioiodine therapy. On a 123I whole-body scan 9months later after stopping the drugs, bilateral breast uptake was not visible; however, right ovarian focal uptake was still visualized. Bilateral salpingo-oophorectomy was performed, and revealed struma ovarii with substantial internal necrosis due to radioiodine therapy. This case is interesting as two rare entities, 131I therapy-related struma ovarii and drug-related breast uptake, were simultaneously visualized.

Postnatal development of the dopaminergic signaling involved in the modulation of intestinal motility in mice.

Since antidopaminergic drugs are pharmacological agents employed in the management of gastrointestinal motor disorders at all ages, we investigated whether the enteric dopaminergic system may undergo developmental changes after birth. Intestinal mechanical activity was examined in vitro as changes in isometric tension. In 2-d-old (P2) mice, dopamine induced a contractile effect, decreasing in intensity with age, replaced, at the weaning (day 20), by a relaxant response. Both responses were tetrodotoxin (TTX)-insensitive. In P2, dopaminergic contraction was inhibited by D1-like receptor antagonist and mimicked by D1-like receptor agonist. In 90-d-old (P90) mice, the relaxation was reduced by both D1- and D2-like receptor antagonists, and mimicked by D1- and D2-like receptor agonists. In P2, contraction was antagonized by phospholipase C inhibitor, while in P90 relaxation was antagonized by adenylyl cyclase inhibitor and potentiated by phospholipase C inhibitor. The presence of dopamine receptors was assessed by immunofluorescence. Quantitative real-time polymerase chain reaction (qRT-PCR) revealed a significant increase in D1, D2, and D3 receptor expression in proximal intestine with the age. In mouse small intestine, the response to dopamine undergoes developmental changes shifting from contraction to relaxation at weaning, as the consequence of D2-like receptor recruitment and increased expression of D1 receptors.

A Review and Update on Tourette Syndrome: Where Is the Field Headed?

Tourette syndrome (TS) is a childhood onset neurologic disorder with manifestations including multiple motor and phonic tics, and in most cases a variety of behavioral comorbidities such as attention deficit hyperactivity disorder, obsessive compulsive disorder, and other impulse control disorders. Although it is considered a hereditary disorder, likely modified by environmental factors, genetic studies have yet to uncover relevant causative genes and there is no animal model that mimics the broad clinical phenomenology of TS. There has been a marked increase in the number of neurophysiological, neuroimaging, and other studies on TS. The findings from these studies, however, have been difficult to interpret because of small sample sizes, variability of symptoms across patients, and comorbidities. Although anti-dopaminergic drugs are the most widely used medications in the treatment of TS, there has been increasing interest in other drugs, behavioral therapies, and surgical approaches including deep brain stimulation. Herein, we review the current literature and discuss the complexities of TS and the challenges in understanding its pathophysiology and in selecting the most appropriate treatment. We also offer an expert's view of where the field of TS may be headed.

Paroxysmal dyskinesia on waking: two case reports

Until recently, paroxysmal hypnogenic dyskinesia was thought to be a rare movement disorder characterized by intermittent dystonia and/or choreoathetoid movements that occur during non-rapid eye movement sleep, with consciousness preserved once the patient is awakened during the episodes. Recent investigations have revealed that most, but not all, paroxysmal hypnogenic dyskinesia cases are actually frontal lobe epilepsy. Here, we present two cases with paroxysmal choreoathetoid movements on waking during non-rapid eye movement sleep. Although they did not respond to antiepileptic drugs, they did respond to antidopaminergic drugs. This supports the opinion that non-epileptic paroxysmal hypnogenic dyskinesia does exist.

A proposal to prevent omissions and delays of antiparkinsonian drug administration in hospitals.

A prospective study carried out in the Netherlands showed that the most important risk factor for motor function deterioration in Parkinson's disease (PD) during hospital admission was medication error, including both incorrect timing of levodopa administration and prescription of contraindicated antidopaminergic drugs.1 Indeed, one of the reported reasons for omitting or delaying levodopa administration has been medication unavailability on time where needed, that is, in medical wards where the patient is admitted. Skelly et al in a recent study carried out in Derby Hospital (National Parkinson Foundation Centre of Excellence for Parkinson’s Disease) report that even in a ward specially designed to treat patients with PD, with an enhanced stock of anti-PD medications, 2.5% of all doses were not administered because the drug was not available on time.2 It is likely this problem is compounded in other nonspecialized wards and especially in smaller hospitals. To counteract this problem, Parkinson's United Kingdom “Get it on time campaign,”3 among others, has suggested that all commercially available antiparkinsonian drugs should be available in all hospital wards and on time. Given the data described previously, this seems unfeasible, especially in small hospitals where having available all the anti-PD drugs would certainly result in the expiration of many of these drugs before they are used. We think a possible solution can be found in Skelly et al’s reflections: “The available stock was not used as flexibly as we had hoped: e.g. doses of modified release medications were omitted rather than a temporary switch to available standard release drugs.”2 (p. 1246) We agree and propose a therapeutic interchange protocol (Figure 1) where the unavailable PD drug is first converted to the equivalent levodopa dose according to published dose equivalency.4 Then an immediate release levodopa dose could be administered until the original drug is available. Immediate release levodopa is cheap. Thus, having it in each hospital ward is a realistic approach. Figure 1. An example of applying the proposed protocol to prevent Parkinson’s disease (PD) drug omissions. It has to be kept in mind that dose equivalencies proposed by Tomlinson et al were developed to compare dose intensities of antiparkinsonian drugs in clinical trials rather than to use them in clinical practice and were catalogued by the authors as mere approximations. Paraphrasing Magdalinou et al5: “PD medications should be regarded as important as insulin is for diabetics.” (p. 540) Using short-acting insulin instead of the patient’s chronic insulin treatment is now routine clinical practice in hospitals. Although there may be some limitations to this approach, we think changing to an equivalent dose of immediate release levodopa could help to prevent PD drug omissions and delays.

Temporomandibular joint dislocation due to atypical antipsychotic-induced acute dystonia: a case report.

Dystonia is a movement disorder that causes sustained muscle contractions, repetitive twisting movements, and abnormal postures of the trunk, neck, face, arms or legs [Fahn et al. 1987]. It may be focal, segmental (multifocal), or generalized and may also be primary or secondary based on their etiology. It may manifest as oculogyric crisis, deviation of eyes in all directions, protrusion of tongue, trismus, lock jaw, torticolis, laryngeal spasm, difficulty in speaking, facial grimacing, opisthotonus, lordosis or scoliosis and tortipelvic crisis. Drug-induced dystonia are secondary dystonias which occur commonly with drugs with antidopaminergic effects such as antipsychotics and metoclopramide [Ropper and Samuels, 2009; Fadare and Owolabi, 2009]. They reportedly arise from a drug-induced alteration of dopaminergic–cholinergic balance in the nigrostriatum (i.e. basal ganglia). Most drugs produce dystonic reactions by nigrostriatal dopamine D2 receptor blockade, which leads to an excess of striatal cholinergic output. High-potency D2 receptor antagonists are most likely to produce an acute dystonic reaction [Marsden and Jenner, 1980]. Agents that balance dopamine blockade with muscarinic M1 receptor blockade, such as atypical antipsychotics, are less likely to cause dystonic reactions [Marsden and Jenner, 1980; Volkow et al. 1998]. The incidence of acute dystonic reactions varies according to individual susceptibility, drug identity and dose of the drug. Increased age may carry less risk for the development of dystonia because of diminished numbers of D2 receptors. It occurs commonly to young males who are naive to antidopaminergic drugs [Volkow et al. 1998]. Oromandibular dystonia is one of the focal dystonias, which can be presented as jaw clenching, jaw opening or jaw deviation and leads to impaired speech and swallowing [Eken et al. 2009]. At times, oromandibular dystonia is so severe that it can cause temporomandibular joint (TMJ) dislocation. So far, few case reports have been published about TMJ dislocation due to antipsychotic medications [Ibrahim and Brooks, 1996]. Among antipsychotic-induced TMJ dislocation, case reports were mainly for high-potency first-generation antipsychotics such as haloperidol [Eken et al. 2009; Ibrahim and Brooks, 1996; Zakariaei et al. 2012]. It has been proposed that drugs such as risperidone and amisulpride which block specific receptors of serotonin (the S-HT2 receptors) and dopamine (the D2 receptors) are less likely to cause these effects [Owens, 1994]. Therefore, the present paper reports a case of oromandibular dystonia with TMJ dislocation with atypical antipsychotics such as risperidone and amisulpride.

I08 The association of Body Composition with Huntington Disease severity. A case-control study

<h3>Introduction</h3> Determination of body composition is important in nutritional assessment and an indirect marker for skeletal muscle mass (SMM). Low SMM has been associated with morbidity and mortality. Animal models of HD exhibit muscle atrophy but the relevance of muscle wasting and its association with HD severity is unknown. <h3>Objectives</h3> To analyse and to compare the body composition of patients with HD with healthy controls, and to analyse the association of SMM with HD severity, energy expenditure and the use of antidopaminergic drugs. <h3>Methods</h3> Case-control, cross sectional study. Body composition was measured using bioimpedance, and energy expenditure with indirect calorimetry and actigraphy. Anthropometrics, biochemical and nutritional data were also collected. HD severity was measured using the UHDRS. <h3>Results</h3> Twenty two patients with HD [36% males, mean age 50.2 + 15.6 years, motor UHDRS 27.9 + 23.7, TFC 10.4 (IR 6), cognitive UHDRS 155 (IQR 125), CAG 43 + 6.0, caloric food intake 1946.4 + 756.7 Kcal/day, BMI 24.4 + 3.0], and 17 controls (50% males, mean age 47.4 + 13.7, food caloric intake 2056.5 + 548.8, BMI 25.8 + 4.0) were included. Both groups were homogeneous in terms of age, gender and BMI. No significant differences were found in terms of SMM, fat mass, creatin kinase or proteic catabolism (urinary nitrogen), and similarly correlated with energy expenditure. In HD patients, body composition was similar in terms of antidopaminergic drugs use, and SMM was not correlated with UHDRS scores. In both groups BMI was only correlated with fat mass (not with SMM), and SMM was only moderately correlated with subscapular skinfold r=-0.53, p = 0.01). <h3>Conclusions</h3> Compared to controls, patients with HD have similar body composition, SMM and proteic catabolism. In HD, BMI only estimates fat mass. Longitudinal studies are warranted to confirm these results.

Differentiating drug-induced parkinsonism from Parkinson's disease: an update on non-motor symptoms and investigations.

Drug-induced parkinsonism is the second most common cause of parkinsonism after Parkinson's disease and their distinction has crucial implications in terms of management and prognosis. However, differentiating between these conditions can be challenging on a clinical ground, especially in the early stages. We therefore performed a review to ascertain whether assessment of non-motor symptoms, or use of ancillary investigations, namely dopamine transporter imaging, transcranial sonography of the substantia nigra, and scintigraphy for myocardial sympathetic innervation, can be recommended to distinguish between these conditions. Among non-motor symptoms, there is evidence that hyposmia can differentiate between patients with "pure" drug-induced parkinsonism and those with degenerative parkinsonism unmasked by an anti-dopaminergic drug. However, several issues, including smoking history and cognitive functions, can influence smell function assessment. Higher diagnostic accuracy has been demonstrated for dopamine transporter imaging. Finally, preliminary evidence exists for sympathetic cardiac scintigraphy to predict dopaminergic pathway abnormalities and to differentiate between drug-induced parkinsonism and Parkinson's disease. Imaging of the dopaminergic pathway seems to be the only, reasonably available, technique to aid the differential diagnosis between drug-induced parkinsonism and Parkinson's disease.

Can Antipsychotic Agents be Considered as Real Antimanic Treatments?

Until now, in various parts of the world, no consensus has been reached with regard to the treatment of acute mania. Controlled clinical trials have at last provided irrefutable evidence for the effectiveness of lithium, which had long been used alone, as well as that of divalproate or its derivatives and, to a lesser extent, carbamazepine (1). In Europe, haloperidol is still the reference compound used in clinical trials while it has never been officially approved in the treatment of mania. In the USA, lithium, divalproate, or second-generation-antipsychotics can be prescribed as first-line treatments. As dopamine was reported to be involved in the pathophysiology of mania in the 1970s and as changes in dopaminergic neurotransmission have consistently been reported in bipolar disorders (BDs), the question of the antimanic properties of antidopaminergic drugs such as antipsychotics is a fair one (2).

Elucidation of in vitro phase I metabolites of droperidol using UPLC-QTOF MS

Droperidol, an antidopaminergic drug clinically used as an antiemetic and antipsychotic, has been reported to induce cardiac toxicity in patients. Due to the close relationship between drug metabolism and efficiency and toxicity, the present study aims to investigate the phase I metabolites using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. The NADPH-supplemented phase I incubation system was used to elucidate the in vitro phase I metabolites. Five metabolites were detected after droperidol was incubated with phase I incubation mixture, including one hydrogenated droperidol, three oxidative metabolites, and one N-dealkylated droperidol, elucidated by individual retention time and MS/MS fragmentation. Due to the existed phase II metabolic reaction, further phase II metabolism should be investigated in the future. In conclusion, the phase I metabolism of droperidol was investigated in the present study, and five new metabolites were identified. The efficiency and toxicity of these phase I metabolites should be investigated in the future.

Enhancing Dissolution of Domperidone By Spray-Drying: Effect of Different Storage Conditions on Stability

Domperidone is an antidopaminergic drug that facilitates a function of the digestive smooth muscle. Depending on the Biopharmaceutical Classification System, domperidone is classified as class II with poor solubility and high permeability. Solid dispersions were prepared by spray-drying with a polymer. The characterization of prepared solid dispersions was analyzed by scanning electron microscope, Fourier transform infrared spectroscopy, x-ray diffraction and differential scanning calorimeter. In vitro dissolution behavior was carried out in gastric juice (pH 1.2) and these results were compared with pure domperidone (active pharmaceutical ingredient). The dissolution rate was improved due to the influence of polymers. Stability assays were conducted by the same pre-experiment. Storage conditions of the solid dispersions were as follows: 25°C relative humidity 25% and 65°C relative humidity 80%. In this study, the goal is to improve the dissolution rate of domperidone by solid dispersions and to confirm stability of the prepared solid dispersions. It suggests that the content of polymers added in solid dispersions can affect the dissolution behavior and change dissolution rate of drug.

The Addenbrooke’s Cognitive Examination-Revised accurately detects cognitive decline in Huntington’s disease

Cognitive features, which begin before manifestation of the motor features, are an integral part of Huntington's disease and profoundly affect quality of life. A number of neuropsychological batteries have been used to assess this aspect of the condition, many of which are difficult to administer and time consuming, especially in advanced disease. We, therefore, investigated a simple and practical way to monitor cognition using the Addenbrooke's Cognitive Examination-Revised (ACE-R) in 126 manifest Huntington's disease patients, 28 premanifest gene carriers and 21 controls. Using this test, we demonstrated a selective decrease in phonemic, but not semantic, fluency in premanifest participants Cognitive decline in manifest Huntington's disease varied according to disease severity with extensive cognitive decline observed in early-stage Huntington's disease patients, indicating that this would be an optimal stage for interventions designed to halt cognitive decline, and lesser changes in the advanced cases. We next examined cognitive performance in patients prescribed antidopaminergic drugs as these drugs are known to decrease cognition when administered to healthy volunteers. We paradoxically found that these drugs may be beneficial, as early-stage Huntington's disease participants in receipt of them had improved attention and Mini-Mental State Examination scores. In conclusion, this is the first study to test the usefulness of the ACE-R in a Huntington's disease population and demonstrates that this is a brief, inexpensive and practical way to measure global cognitive performance in clinical practice with potential use in clinical trials.

Lithium normalizes amphetamine-induced changes in striatal FoxO1 phosphorylation and behaviors in rats

Administration of the psychostimulant drug amphetamine (AMPH) to animals causes hyperactivity and deficit in prepulse inhibition (PPI) of startle, behaviors that are often observed in neuropsychiatric disorders such as schizophrenia and bipolar disorder. Enhanced central dopamine (DA) transmission is believed to mediate AMPH-induced behavioral alterations. Lithium, a drug used primarily in the treatment of bipolar disorder, is reported to interact with the DA system and antagonize some DA-related behaviors. Here, we provide evidence that AMPH and lithium reciprocally regulate the activity of the transcription factor forkhead box, class O1 (FoxO1), a downstream target of Akt. Administration of d-AMPH (3 mg/kg, intraperitoneally) to Sprague-Dawley rats resulted in a concomitant decrease in levels of phosphorylated (p) Akt as well as p-FoxO1 in the striatum, whereas lithium chloride (LiCl,100 mg/kg, intraperitoneally) exerted the opposite effect, that is, it increased levels of p-Akt and p-FoxO1. Pretreatment of animals with lithium prevented an AMPH-induced decrease in striatal p-Akt and p-FoxO1 levels. Pretreatment of animals with lithium also attenuated AMPH-induced locomotor activity and decreased prepulse inhibition. These in-vivo data suggest that the Akt-FoxO1 pathway may be a common target for the action of dopaminergic and antidopaminergic drugs, and its modulation may be relevant to the treatment of neuropsychiatric disorders.

Domperidone in Parkinson’s Disease: A Perilous Arrhythmogenic or the Gold Standard?

Domperidone, a dopamine antagonist that does not easily cross the blood-brain barrier, is considered the gold standard for treating gastrointestinal symptoms in patients with Parkinson's disease (PD) because the risk of developing extrapyramidal adverse effects is considered minimal. On the other hand, cardiotoxicity related to domperidone is not a new issue. In fact, arrhythmias, sudden death and cardiac arrest were reported with high intravenous doses in the 80s. Concern about the cardiotoxicity of oral domperidone has arisen more recently after the publication of two case-control studies which have questioned domperidone's safety even further, especially in patients > 60 years and in doses >30 mg/day. Very little is known about domperidone's cardiac effects in patients with PD. In addtion, pharmacoepidemiological data about specific antiemetic use in these patients is scarce, with almost anecdotal reports of inappropriate centrally acting antidopaminergic drugs like metoclopramide in the hospital setting. As a result, and even no cases of serious arrhythmias or sudden cardiac death associated with domperidone concerning patients with PD have been reported, no definitive conclusions can be drawn about its safety. In conclusion, despite domperidone is still recognized as the first choice for treating gastrointestinal symptoms PD, doses above 30 mg/daily should only be considered with special caution taking into account its potential cardiotoxic effects.

The influence of sGnRH-A and antidopaminergic drug - pimozide - on prolactin mRNA synthesis in female Prussian carp (Carassius gibelio Bloch) in vivo

Effects of salmon gonadotropin releasing hormone analogue (sGnRH-A) and antidopaminergic drug, pimozide, on the synthesis of prolactin mRNA in vivo in female Prussian carp (Carassius gibelio Bloch) during two different stages of the reproductive cycle were evaluated. The results showed that the lowest dose of sGnRH-A (5 &amp;mu;g/kg body weight) significantly stimulated the mRNA synthesis in fish during the recrudescence as well as during the preovulatory period, higher doses of this compound having no significant effect on prolactin mRNA synthesis. The blocker of dopamine receptors, pimozide, also potentiated prolactin mRNA synthesis &amp;ndash; in recrudescent females it increased mRNA levels at the dose of 1 mg/kg, while in the preovulatory period all of the used pimozide doses (1, 5, and 10 mg/kg) were responsible for the increase of prolactin mRNA levels. Taken together, the above results suggest that gonadotropin releasing hormone (GnRH) is the factor responsible for the stimulation of prolactin synthesis, while dopamine has an inhibitory influence on the prolactin production. &amp;nbsp;