Treatment of subcutaneous nodules after infusion of apomorphine; a biopsy-controlled study comparing 4 frequently used therapies.

This study aimed to provide clinical evidence for existing treatments of subcutaneous nodules after subcutaneous infusion of apomorphine, using a biopsy-controlled prospective crossover design of four treatments. We demonstrated that dilution of apomorphine significantly improved patient satisfaction, while subcutaneous hydrocortisone reduced nodule size, however with no differences in the histopathology.

An update on the use of non-ergot dopamine agonists for the treatment of Parkinson's disease.

INTRODUCTION: Long-term treatment of Parkinson's disease (PD) with levodopa is hampered by motor complications related to the inability of residual nigrostriatal neurons to convert levodopa to dopamine (DA) and use it appropriately. This generated a tendency to postpone levodopa, favoring the initial use of DA agonists, which directly stimulate striatal dopaminergic receptors. Use of DA agonists, however, is associated with multiple side effects and their efficacy is limited by suboptimal bioavailability. AREAS COVERED: This paper reviewed the latest preclinical and clinical findings on the efficacy and adverse effects of non-ergot DA agonists, discussing the present and future of this class of compounds in PD therapy. EXPERT OPINION: The latest findings confirm the effectiveness of DA agonists as initial treatment or adjunctive therapy to levodopa in advanced PD, but a more conservative approach to their use is emerging, due to the complexity and repercussions of their side effects. As various factors may increase the individual risk to side effects, assessing such risk and calibrating the use of DA agonists accordingly may become extremely important in the clinical management of PD, as well as the availability of new DA agonists with better profiles of safety and efficacy.

Neurochemical and behavioral effects of Nigella sativa and Olea europaea oil in rats.

OBJECTIVES: In the last few decades, therapeutic uses of medicinal compounds present in food as a normal constituent has risen substantially, largely because of their fewer side effects and adequate efficacy. This study is designed to investigate a role of brain serotonin (5-HT) and dopamine (DA) in the potential nootropic, anxiolytic, and other beneficial effects of Nigella sativa (NS) and Olea europaea (OE) oil in rat models. METHODS: Animals were treated with NS and OE oil orally at doses of 0.1 ml/kg and 0.25 ml/kg for 5 weeks. Food intake and body weight change, anxiety-like effects in elevated plus maze and activity in a novel and familiar environment were monitored weekly. Effects on learning and memory after 5 weeks treatment were monitored using Morris water maze test. Neurochemical analysis was carried using HPLC-ECD method. RESULTS: NS and OE oil administration enhanced learning and memory in Morris water maze test and the effects were greater in NS than OE oil-treated animals. Low dose of OE oil increased exploration in an open field, higher dose of OE oil and both doses of NS oil produced no consistent effect on open field exploration. Effects of both oils on anxiety-like behavior, food and water intake, and activity in activity box were either not consistent or did not occur. The treatment increased homovanillic acid (HVA). 5-HT levels increased in high dose of NS oil and low dose of OE oil-treated groups. Low dose NS oil decreased 5-HT. DISCUSSION: The present study suggests that active components in NS and OE oil may prove useful in treating impaired cognition. OE oil may produce psychostimulant-like effect. Modulation of DA and serotonin neurotransmission seems important in the pharmacological effect of these oils.

Neuroprotective Effects of Drug-Induced Therapeutic Hypothermia in Central Nervous System Diseases.

OBJECTIVE: This review article focuses on the neuroprotective effect of drug-induced hypothermia in cerebrovascular diseases and discusses its related side effects. METHOD: A systematic literature search was performed using Pubmed and Embase electronic databases for a retrospective analysis. RESULTS: Experimental studies have shown that drug-induced hypothermia alleviates brain damage and plays a neuroprotective role, thereby reducing mortality and ameliorating neurological deficits. Therefore, drug-induced hypothermia has an important research value and is worth further consideration in the clinical setting. However, drug-induced hypothermia is also associated with side effects, such as ventricular tachycardia, ventricular fibrillation, suppressed immune function, infection, electrolyte imbalance, glucose metabolism disorders, and skeletal muscle tremor. Existing drugs with cooling effects belong to the following categories: (1) dopamine receptor agonists; (2) cannabis; (3) opioid receptors; (4) vanilloid receptors; (5) vasopressins (potent neurotensin receptor agonists); (6) thyroid drugs; (7) adenosine drugs; and (8) purine drugs.

Pharmacokinetic drug evaluation of safinamide mesylate for the treatment of mid-to-late stage Parkinson's disease.

INTRODUCTION: Patients with Parkinson's disease suffer from a heterogeneous expression of neurotransmitter deficits. They cause an individual variable expression of motor and non-motor symptoms. Thus, drugs with various mechanisms of actions are suitable to counteract these disease related neurotransmitter alterations. Areas covered: This invited review suggests safinamide as an ideal compound for therapy of Parkinson's disease, as its pharmacological profile includes reversible monoamine oxidase B inhibition, blockage of voltage-dependent sodium channels, modulation of calcium channels and abnormal glutamate release. Safinamide may provide benefits effects on non-motor symptoms in addition to the demonstrated amelioration of motor impairment in levodopa treated patients with Parkinson's disease. Safinamide was well tolerated and safe when administered in dose of 50 or 100 mg daily in pivotal trials. Expert opinion: Clinical handling, safety and tolerability of Safinamide are better than of dopamine agonists or levodopa. Safinamide supplements the existing armamentarium of drugs for Parkinson's disease. Safinamide will help to reduce dosing of levodopa but also of dopamine agonists during long term treatment in patients with Parkinson's disease.

Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation.

A Task Force was established by the International Restless Legs Syndrome Study Group (IRLSSG) in conjunction with the European Restless Legs Syndrome Study Group (EURLSSG) and the RLS Foundation (RLS-F) to develop evidence-based and consensus-based recommendations for the prevention and treatment of long-term pharmacologic treatment of dopaminergic-induced augmentation in restless legs syndrome/Willis-Ekbom disease (RLS/WED). The Task Force made the following prevention and treatment recommendations: As a means to prevent augmentation, medications such as α2δ ligands may be considered for initial RLS/WED treatment; these drugs are effective and have little risk of augmentation. Alternatively, if dopaminergic drugs are elected as initial treatment, then the daily dose should be as low as possible and not exceed that recommended for RLS/WED treatment. However, the physician should be aware that even low dose dopaminergics can cause augmentation. Patients with low iron stores should be given appropriate iron supplementation. Daily treatment by either medication should start only when symptoms have a significant impact on quality of life in terms of frequency and severity; intermittent treatment might be considered in intermediate cases. Treatment of existing augmentation should be initiated, where possible, with the elimination/correction of extrinsic exacerbating factors (iron levels, antidepressants, antihistamines, etc.). In cases of mild augmentation, dopamine agonist therapy can be continued by dividing or advancing the dose, or increasing the dose if there are breakthrough night-time symptoms. Alternatively, the patient can be switched to an α2δ ligand or rotigotine. For severe augmentation the patient can be switched either to an α2δ ligand or rotigotine, noting that rotigotine may also produce augmentation at higher doses with long-term use. In more severe cases of augmentation an opioid may be considered, bypassing α2δ ligands and rotigotine.

Cancer risks among the users of ergot-derived dopamine agonists for Parkinson's disease, a nationwide population-based survey.

BACKGROUND: Factors of cancer occurrence among Parkinson disease patients are still not well known, although genetic predilection has been investigated. The aim of this study is to evaluate the medication effect of dopamine agonists of Parkinson disease on incidence of cancers from the Taiwan National Health Insurance Research Database. METHODS: We conducted a population-based nested case-control study by using the resources of the Taiwanese National Health Insurance from 1996 to 2000 and analyzed the prevalence of cancer among patients with Parkinson disease. A nested analysis was then implemented among those patients with both Parkinson disease and cancer, focusing separately on the use of ergot- and nonergot-derived-dopamine agonists. RESULTS: We reviewed 6211 patients with Parkinson's disease and found 329 patients with cancer. The ergot-derived dopamine agonists users were associated with an increased odds ratio for cancer, compared with nonergot-derived dopamine agonist users, with an adjusted odds ratio of 2.16 (95% confidence interval, 1.55-2.99). Among all the cancer types, we observed the higher occurrence of liver cancer among the ergot-derived dopamine agonist users. CONCLUSION: The association of ergot-derived-dopamine agonist use and cancers, especially the liver cancers, has provided us the information to further understand the drug-cancer interaction. We hope this result would prompt further investigations on the risk and benefit of the dopamine agonists use among the Parkinson's disease patients.

Psychiatric disorders and sleep issues.

Sleep issues are common in people with psychiatric disorders, and the interaction is complex. Sleep disorders, particularly insomnia, can precede and predispose to psychiatric disorders, can be comorbid with and exacerbate psychiatric disorders, and can occur as part of psychiatric disorders. Sleep disorders can mimic psychiatric disorders or result from medication given for psychiatric disorders. Impairment of sleep and of mental health may be different manifestations of the same underlying neurobiological processes. For the primary care physician, key tools include recognition of potential sleep effects of psychiatric medications and familiarity with treatment approaches for insomnia in depression and anxiety.

Effects of rotigotine on Parkinson's disease-related sleep disturbances.

INTRODUCTION: Sleep abnormalities are a frequent non-motor symptom and a prominent cause of disability in patients with Parkinson's disease (PD). AREAS COVERED: This review discusses what is currently known about the characteristics of sleep disturbances in PD patients and attempts to clarify the role of dopaminergic pathways in their pathogenesis as well as the beneficial effect of dopaminergic agents in their treatment. In particular, this review will focus on the effects of transdermal rotigotine on improving PD-related sleep disorders. EXPERT OPINION: Sleep disturbances are common in PD, and these disturbances can be reduced or resolved, in large part, by preventing or attenuating nocturnal and early morning motor and non-motor symptoms of PD. The studies discussed within this review suggest that sleep disorders are not just a consequence of motor impairment and dopaminergic therapy but are an integral part of the neurodegenerative process of PD. This is supported by the appearance of specific sleep disturbances, which are related to degeneration of the brainstem areas involved in the regulation of sleep/wake states in advance of typical PD symptoms. Development of more detailed diagnostic tools aimed at detecting sleep disturbances and at defining the main causative factors of sleep disturbances in PD will lead to improved treatment of these disturbances.

Do not use drugs to prevent onset of lactation. Relieve the discomfort and wait.

Breast-feeding is not advisable in certain situations and some women do not want to breast-feed. If the woman does not breast-feed, lactation ceases after one or two weeks. Where does the evaluation of methods used to prevent onset of lactation stand in 2012? To answer this question, we reviewed the available evidence, based on the standard Prescrire methodology. Among the physical methods sometimes proposed, breast binding causes greater discomfort than wearing a bra. Dopamine agonists, such as bromocriptine, are effective in inhibiting lactation. But the serious, mainly cardiovascular, adverse effects they provoke are disproportionate to the discomfort they prevent.These drugs are best avoided. High doses of oestrogens inhibit lactation, but the risk of thromboembolism they pose is unreasonable in the postpartum setting. Neither diuretics nor homeopathy have been shown to have any tangible efficacy against the discomfort associated with onset of lactation. In practice, a standard analgesic such as paracetamol generally eases the few days of discomfort or pain associated with the onset of lactation. Wearing a bra is risk-free and sometimes provides relief. Breast discomfort, however intense, does not justify exposing women to the serious adverse effects linked to postpartum administration of dopamine agonists or oestrogens.

Detoxification and antioxidative therapy for levodopa-induced neurodegeneration in Parkinson's disease.

Levodopa is the most efficacious drug treatment option for Parkinson's disease. However, in particular, high levodopa dosing may contribute to disease progression. Chronic levodopa metabolism reduces the methylation capacity and the antioxidant defense. Thus, this levodopa-induced free radical production complements the disease process, which considerably depends on free radical-induced, apoptotic neuronal cell death. Accordingly, clinical long-term studies with in the laboratory neuroprotective compounds failed in clinical investigations, as these studies were performed in levodopa-naive patients with Parkinson's disease over a relative short interval. Therefore, the likelihood for a positive outcome was rather low, since trials only focused on the disease process in levodopa-naive patients. However, studies on antioxidant therapeutic strategies were positive in levodopa-treated Parkinson's disease patients. To counteract these metabolic long-term levodopa-associated effects, chronic levodopa therapy should be combined with supplemental application of free radical scavengers and methyl group donating vitamins.

Neurostimulation for Parkinson's disease with early motor complications.

BACKGROUND: Subthalamic stimulation reduces motor disability and improves quality of life in patients with advanced Parkinson's disease who have severe levodopa-induced motor complications. We hypothesized that neurostimulation would be beneficial at an earlier stage of Parkinson's disease. METHODS: In this 2-year trial, we randomly assigned 251 patients with Parkinson's disease and early motor complications (mean age, 52 years; mean duration of disease, 7.5 years) to undergo neurostimulation plus medical therapy or medical therapy alone. The primary end point was quality of life, as assessed with the use of the Parkinson's Disease Questionnaire (PDQ-39) summary index (with scores ranging from 0 to 100 and higher scores indicating worse function). Major secondary outcomes included parkinsonian motor disability, activities of daily living, levodopa-induced motor complications (as assessed with the use of the Unified Parkinson's Disease Rating Scale, parts III, II, and IV, respectively), and time with good mobility and no dyskinesia. RESULTS: For the primary outcome of quality of life, the mean score for the neurostimulation group improved by 7.8 points, and that for the medical-therapy group worsened by 0.2 points (between-group difference in mean change from baseline to 2 years, 8.0 points; P=0.002). Neurostimulation was superior to medical therapy with respect to motor disability (P<0.001), activities of daily living (P<0.001), levodopa-induced motor complications (P<0.001), and time with good mobility and no dyskinesia (P=0.01). Serious adverse events occurred in 54.8% of the patients in the neurostimulation group and in 44.1% of those in the medical-therapy group. Serious adverse events related to surgical implantation or the neurostimulation device occurred in 17.7% of patients. An expert panel confirmed that medical therapy was consistent with practice guidelines for 96.8% of the patients in the neurostimulation group and for 94.5% of those in the medical-therapy group. CONCLUSIONS: Subthalamic stimulation was superior to medical therapy in patients with Parkinson's disease and early motor complications. (Funded by the German Ministry of Research and others; EARLYSTIM ClinicalTrials.gov number, NCT00354133.).

A historical justification for and retrospective analysis of the systematic application of light therapy in Parkinson's disease.

For the past 40 years the primary purpose of therapeutics for Parkinson's disease (PD) has been to replace deficient dopamine (DA) in the nigrostriatal dopamine (NSD) system. Even in the presence of limited efficacy, abundant side effects and impoverished quality of life, the involvement of other systems in the aetiology and treatment of this disorder has been sorely neglected and the excessive use of DA replacement therapy (DART) continues on a global basis. Recent scientific work suggests that the retina plays a major role in NSD function and intimates light therapy in the management of PD. After a thorough review of historical evidence supporting this contention, a retrospective, open-label study on 129 PD patients, whereby they were monitored for a period extending for a few months to eight years, was carried out. Primary motor and non-motor symptoms were monitored using an objectified global rating scale and timed motor tests that were assessed at regular intervals for the duration of the study. Thirty-one patients with other neurological disorders (OND) served as controls to determine whether any therapeutic effects seen with light were generalizable across other conditions. Patients were classified as compliant (COM), semi-compliant (SCOM), or early quit (EQUIT; prematurely discontinued treatment). EQUIT patients showed deterioration, while the COM group improved on most parameters. The SCOM patients were not as good as the COM group. The OND group showed significant improvement in depression and insomnia, but exposure to light did not improve motor function. The total drug burden of PD patients maintained on light was less with fewer side effects than SCOM or EQUIT groups. These results confirm the value of the strategic application of light therapy with controlled doses of DART in PD and warrants further controlled investigation. That the symptomatic improvement continued as long patients remained in the program suggests that exposure to light, under a strict daily regimen, combined with controlled DART, actively slows or arrests the progressive degenerative process underlying PD.

Síndrome de Otelo (delirio celotípico monosintomático) inducido por agonistas dopaminérgicos / Othelo syndrome (monosymptomatic jealousy delusion) related with dopaminergic agonists

La enfermedad de Parkinson (EP) es un trastorno neurodegenerativo crónico que produce un grado variable de destrucción de neuronas de los ganglios basales, con la consecuente reducción de la transmisión dopaminérgica. Clínicamente se traduce principalmente en temblor de reposo, rigidez muscular, bradicinesia y alteraciones de la marcha. También aparecen otros síntomas motores y no motores. Entre los no motores se encuentra un amplio espectro de sintomatología psiquiátrica, entre la que destacan la depresión, la ansiedad, la agitación, el delirium, los trastornos del sueño, la hipersexualidad, los trastornos del control de impulsos y diversos síntomas psicóticos. Estos últimos presentan una prevalencia del 45-60% en la EP, predominando los «síntomas menores» (ilusiones visuales y sensaciones de presencia) sobre las alucinaciones y delirios. Entre los delirios destacamos el síndrome de Otelo (SO), un trastorno delirante con síntomas celotípicos poco frecuente en pacientes con EP. Su aparición se relaciona con el tratamiento agonista dopaminérgico, y en la mayoría de los casos se resuelve tras la disminución de la dosis del fármaco agonista. Solo en algunos casos es necesario añadir tratamiento antipsicótico, siendo de elección los atípicos. Por último, nuevos fármacos como la pimavanserina (un agonista inverso selectivo 5-HT2A) están siendo estudiados en el tratamiento de la psicosis asociada a la EP, con resultados prometedores. Presentamos un caso de EP que, tras varios años de tratamiento agonista dopaminérgico, desarrolló un SO que se resolvió tras recibir tratamiento antipsicótico atípico y ajustar el tratamiento antiparkinsoniano (AU)

Parkinson disease (PD) is a chronic, neurodegenerative disorder that produces a degeneration of the basal ganglia, with a variable reduction of dopamine neurotransmission activity. In a clinical point of view, these impairments are translated into tremor, rigidity, bradykinesia, and shuffling gait. Both motor and nonmotor symptoms are characteristics of PD. Nonmotor symptoms include a wide spectrum of psychiatric features: depression, anxiety, delirium, sleep disorders, hipersexuality, impulsivity disorders, and psychotic symptoms. Prevalence of psychotic symptoms in PD is high (45-60%), although "minor symptoms" (visual illusions and "sense of presence") are more frequent than "major" ones (hallucinations and delusions). Considering the delusional disorders, Othelo syndrome (OS) (jealousy delusion) represents a scarce clinical presentation in PD. Jealousy delusion has been related with dopaminergic agonists, and a reduction of dose is the first-line treatment. In several cases, it may be also necessary to add atypical antipsychotics as complementary therapy. Finally, pimavanserine (a selective, inverse agonist 5-HT2A) is currently on research, and it may be a promising option in the treatment of PD related-psychosis in the next future. We present a case-report of PD which developed an OS after several years of agonistic dopaminergic treatment. The dose-adjustment of antiparkinsonian drugs plus atypical antipsychotics was the option played, obtaining resolution of jealousy delusion (AU)

Lesions of the entopeduncular nucleus in rats prevent apomorphine-induced deficient sensorimotor gating.

Dopamine-induced hyperactivity and deficient sensorimotor gating, measured as prepulse inhibition (PPI) of the acoustic startle response (ASR), are used as animal models for neuropsychiatric disorders such as schizophrenia and Tourette's syndrome. We here investigated whether excitotoxic lesions of the rat entopeduncular nucleus (EPN), the equivalent to the human globus pallidus internus (GPi), would improve apomorphine-induced PPI-deficits and hyperactivity. Additionally, we investigated the effect of EPN lesions on cognition, motivation and motor skills. In male Sprague Dawley rats bilateral EPN lesions were induced by stereotactic injection of ibotenate (4 µg in 0.4 µl phosphate buffered saline, PBS) or sham-lesions by injection of vehicle PBS. After one week, rats were tested for learning and memory (continuous and delayed alternation, T-maze), for motivation (progressive ratio test with breakpoint of 3 min inactivity, Skinner box), and for motor skills (rotating rod). Thereafter, rats were tested for PPI of ASR (startle response system) after subcutaneous injection of apomorphine (1.0mg/kg and vehicle) and for locomotor activity (0.5mg/kg and vehicle). Ibotenate-induced EPN lesions did not affect learning and memory, motivation or motor skills. Basal locomotor activity and PPI was also not affected, but EPN lesions ameliorated apomorphine-induced hyperlocomotion and deficient PPI. This work indicates an important role of the EPN for the modulation of dopamine agonist-induced deficient sensorimotor gating and hyperlocomotion, without affecting normal behavioral function.

Partial agonists in schizophrenia--why some work and others do not: insights from preclinical animal models.

While dopamine D2 receptor partial agonists (PAs) have been long considered for treating schizophrenia, only one, aripiprazole, is clinically available for therapeutic use. This raises critically important questions as to what is unique about aripiprazole and to what extent animal models can predict therapeutic success. A number of PAs whose clinical fate is known: aripiprazole, preclamol, terguride, OPC-4392 and bifeprunox were compared to haloperidol (a reference antipsychotic) in several convergent preclinical animal models; i.e. amphetamine-induced locomotion (AIL) and conditioned avoidance response (CAR), predictive of antipsychotic effects; unilateral nigrostriatal lesioned rats, a model of hypo-dopaminergia; striatal Fos induction, a molecular marker for antipsychotic activity; and side-effects common to this class of drugs: catalepsy (motor side-effects) and prolactaemia. The results were compared across drugs with reference to their measured striatal D2 receptor occupancy. All the PAs occupied striatal D2 receptors in a dose dependent manner, inhibited AIL and CAR, and lacked motor side-effects or prolactinaemia despite D2 receptor occupancy exceeding 80%. At comparative doses, aripiprazole distinguished itself from the other PAs by causing the least rotation in the hypo-dopaminergic model (indicating the least intrinsic activity) and showed the highest Fos expression in the nucleus accumbens (indicating functional D2 antagonism). Although a number of PAs are active in antipsychotic animal models, not all of them succeed. Given that only aripiprazole is clinically available, it can be inferred that low functional intrinsic activity coupled with sufficient functional antagonism as reflected in the animal models may be a marker of success.

Clinical review and treatment of select adverse effects of dopamine receptor agonists in Parkinson's disease.

Dopamine receptor agonists provide a viable alternative or adjunct to levodopa therapy in Parkinson's disease and are associated with fewer motor complications and dyskinesia. However, all available dopamine agonists may cause profound adverse effects in some patients. In many cases, these adverse effects amplify non-motor symptoms that people with Parkinson's disease may already be experiencing. Nausea from dopamine agonists generally lessens with time and may be responsive to both antiemetic therapy and complementary remedies, such as ginger, peppermint and chamomile. Unfortunately, compulsive behaviours, as well as peripheral oedema caused by dopamine agonists, are poorly responsive to pharmacological therapy and require a reduction or discontinuation of agonist therapy. Somnolence and associated sleep attacks generally require elimination of the agonist or the use of a stimulating agent. The necessity of treatment for hallucinations and psychosis associated with dopamine agonists must be thoroughly evaluated prior to initiating therapy. If a medication is initiated for hallucinations or psychosis, quetiapine or clozapine are agents of choice. Orthostatic hypotension, though not always symptomatic, responds well to nonpharmacological strategies and medications, including indometacin, midodrine and fludrocortisone. Care must be taken to educate patients with Parkinson's disease about the common adverse effects of dopamine agonists and what can be done to lessen them.

Comparison of apomorphine and levodopa infusions in four patients with Parkinson's disease with symptom fluctuations.

BACKGROUND: Motor fluctuations in patients with advanced Parkinson's disease may be successfully treated with subcutaneous apomorphine infusion or intraduodenal levodopa/carbidopa infusion. No comparative trials of these two alternatives were performed. AIMS OF THE STUDY: We present a subanalysis from a randomized crossover clinical trial where levodopa infusion as monotherapy was compared with any other combination of pharmacotherapy in fluctuating patients. Four patients used apomorphine infusion and oral levodopa in the comparator arm. The results of these four patients are presented in detail. METHODS: The duration of the trial was 3 + 3 weeks. Patients were video-recorded half-hourly on two non-consecutive days of both treatment arms. Blinded video ratings were used. Patient self-assessments of motor function and quality-of-life (QoL) parameters were captured using an electronic diary. RESULTS: Ratings in moderate to severe "off" state ranged 0-44% on apomorphine infusion and 0-6% on levodopa infusion. Moderate to severe dyskinesias were not recorded in any of the treatments. QoL was reported to be improved in all patients on duodenal levodopa infusion. CONCLUSIONS: Monotherapy with duodenal infusion of levodopa was more efficacious and brought greater QoL than combination therapy with apomorphine infusion in these fluctuating patients.

Hypothesis-driven medication discovery for the treatment of psychostimulant addiction.

Psychostimulant abuse is a serious social and health problem, for which no effective treatments currently exist. A number of review articles have described predominantly 'clinic'-based pharmacotherapies for the treatment of psychostimulant addiction, but none have yet been shown to be definitively effective for use in humans. In the present article, we review various 'hypothesis'- or 'mechanism'-based pharmacological agents that have been studied at the preclinical level and evaluate their potential use in the treatment of psychostimulant addiction in humans. These compounds target brain neurotransmitter or neuromodulator systems, including dopamine (DA), gamma-aminobutyric acid (GABA), endocannabinoid, glutamate, opioid and serotonin, which have been shown to be critically involved in drug reward and addiction. For drugs in each category, we first briefly review the role of each neurotransmitter system in psychostimulant actions, and then discuss the mechanistic rationale for each drug's potential anti-addiction efficacy, major findings with each drug in animal models of psychostimulant addiction, abuse liability and potential problems, and future research directions. We conclude that hypothesis-based medication development strategies could significantly promote medication discovery for the effective treatment of psychostimulant addiction.