Suprathreshold Dose Research Articles

3D Kinematics Quantifies Gait Response to Levodopa earlier and to a more Comprehensive Extent than the MDS-Unified Parkinson's Disease Rating Scale in Patients with Motor Complications.

Quantitative 3D movement analysis using inertial measurement units (IMUs) allows for a more detailed characterization of motor patterns than clinical assessment alone. It is essential to discriminate between gait features that are responsive or unresponsive to current therapies to better understand the underlying pathophysiological basis and identify potential therapeutic strategies. This study aims to characterize the responsiveness and temporal evolution of different gait subcomponents in Parkinson's disease (PD) patients in their OFF and various ON states following levodopa administration, utilizing both wearable sensors and the gold-standard MDS-UPDRS motor part III. Seventeen PD patients were assessed while wearing a full-body set of 15 IMUs in their OFF state and at 20-minute intervals following the administration of a supra-threshold levodopa dose. Gait was reconstructed using a biomechanical model of the human body to quantify how each feature was modulated. Comparisons with non-PD control subjects were conducted in parallel. Significant motor changes were observed in both the upper and lower limbs according to the MDS-UPDRS III, 40 minutes after levodopa intake. IMU-assisted 3D kinematics detected significant motor alterations as early as 20 minutes after levodopa administration, particularly in upper limbs metrics. Although all "pace-domain" gait features showed significant improvement in the Best-ON state, most rhythmicity, asymmetry, and variability features did not. IMUs are capable of detecting motor alterations earlier and in a more comprehensive manner than the MDS-UPDRS III. The upper limbs respond more rapidly to levodopa, possibly reflecting distinct thresholds to levodopa across striatal regions.

MORPHOLOGICAL ASYMMETRY OF ANTENNAE AND BEHAVIORAL ASYMMETRIES DURING GROOMING IN THE COCKROACH <i>PERIPLANETA AMERICANA</i> L.

Animal behaviors are often characterized by behavioral asymmetry, or lateralization, which is caused in part by the morphological asymmetry of the body and/or brain. To test the hypothesis that functional asymmetry of grooming is connected with morphological asymmetry of the antennae in American cockroach Periplaneta americana, we measured the length of the antennae, scapus diameter, pedicel diameter and length, and segment’s diameter and length. The data obtained indicate statistically significant differences: segment length is greater on the left antennae, and segment width is greater on the right antennae, except for a short region near the base. Correlation analysis revealed the following relationships: longer right antenna corresponds to more time spent cleaning it; scapus diameter larger on the right antenna correlates with antenna cleaning frequency; asymmetry of flagellum segments has no effect on cleaning asymmetry. Presenting sex pheromone at a suprathreshold dose increased asymmetry of antennal grooming, while asymmetry for leg grooming was generally unchanged. Thus, the asymmetry of antennal grooming, resulting at least in part from morphological asymmetry, significantly changes in the presence of a biologically important olfactory stimulus, the sex pheromone.

Clinical Practice Guidelines for the Use of Electroconvulsive Therapy.

Clinical Practice Guidelines for the Use of Electroconvulsive Therapy.

Selecting right unilateral placement to facilitate continuation of electroconvulsive therapy following prolonged seizures

Available literature remains limited in the identification of risk factors for prolonged seizures in electroconvulsive therapy and much less is reported about the continuation of electroconvulsive therapy after prolonged seizures. We describe two cases with prolonged seizures early in their course of electroconvulsive therapy and the subsequent adjustment made that allowed for safe and effective continuation of electroconvulsive therapy. In both cases, right unilateral electroconvulsive therapy was continued at a suprathreshold stimulus dose of six times relative to seizure threshold. Both patients continued their course of electroconvulsive therapy with no further episodes of prolonged seizures. They did not experience significant cognitive side effects and were discharged after showing marked improvement in their clinical symptoms. Prolonged seizures do not preclude the use of electroconvulsive therapy. The selection of ultrabrief right unilateral electroconvulsive therapy allows for a higher suprathreshold dose with less cognitive side effects compared to bilateral placements. This mitigates the risk of prolonged seizures, allowing for safe and effective continuation of electroconvulsive therapy.

Effectiveness of home-based and remotely supervised aerobic exercise in Parkinson's disease: a double-blind, randomised controlled trial

High-intensity aerobic exercise might attenuate the symptoms of Parkinson's disease, but high-quality evidence is scarce. Moreover, long-term adherence remains challenging. We aimed to evaluate the effectiveness of aerobic exercise-gamified and delivered at home, to promote adherence-on relieving motor symptoms in patients with Parkinson's disease with mild disease severity who were on common treatment regimes. In this single-centre, double-blind, randomised controlled trial (Park-in-Shape), we recruited sedentary patients with Parkinson's disease from the outpatient clinic at Radboudumc, Nijmegen, Netherlands. Patients were made aware of the study either by their treating neurologist or via information in the waiting room. Patients could also contact the study team via social media. We included patients aged 30-75 years with a Hoehn and Yahr stage of 2 or lower, who were on stable dopaminergic medication. Patients were randomly assigned (in a 1:1 ratio) to either aerobic exercise done on a stationary home-trainer (aerobic intervention group) or stretching (active control group) by means of a web-based system with minimisation for sex and medication status (treated or untreated) and permuted blocks of varying sizes of more than two (unknown to study personnel). Patients were only aware of the content of their assigned programme. Assessors were unaware of group assignments. Both interventions were home based, requiring 30-45 min training three times per week for 6 months. Both groups received a motivational app and remote supervision. Home trainers were enhanced with virtual reality software and real-life videos providing a so-called exergaming experience (ie, exercise enhanced by gamified elements). The primary outcome was the between-group difference in the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor section at 6 months, tested during the off state (≥12 h after last dopaminergic medication). The analysis was done on an intention-to-treat basis in patients who completed the follow-up assessment, regardless of whether they completed the assigned intervention. Patients reported adverse events directly to their coach and also after the 6-month visit retrospectively. A between-group difference of 3·5 points or more was deemed a-priori clinically relevant. The study is concluded and registered with the Dutch Trial Registry, NTR4743. Between Feb 2, 2015, and Oct 27, 2017, 139 patients were assessed for eligibility in person, of whom 130 were randomly assigned to either the aerobic intervention group (n=65) or the active control group (n=65). Data from 125 (96%) patients were available for the primary analysis; five patients were lost to follow-up (four in the intervention group; one in the control group). 20 patients (ten in each group) did not complete their assigned programme. The off-state MDS-UPDRS motor score revealed a between-group difference of 4·2 points (95% CI 1·6-6·9, p=0·0020) in favour of aerobic exercise (mean 1·3 points [SE 1·8] in the intervention group and 5·6 points [SE 1·9] for the control group). 11 patients had potentially related adverse events (seven [11%] in the intervention group, four [6%] in the control group) and seven had unrelated serious adverse events (three in the intervention group [vestibilar disorder, vasovagal collapse, knee injury during gardening that required surgery; 6%], four in the control group [supraventricular tachycardia, hip fracture, fall related injury, severe dyskinesias after suprathreshold dose levodopa in a patient with deep brain stimulation; 7%]). Aerobic exercise can be done at home by patients with Parkinson's disease with mild disease severity and it attenuates off-state motor signs. Future studies should establish long-term effectiveness and possible disease-modifying effects. Netherlands Organization for Health Research and Development.

Palmatine plays a role in sedation and hypnosis by increasing 5-hydroxytryptamine

Objective of this study was to investigate the sedative and hypnotic effects of palmatine and to observe whether its mechanism is related to 5-hydroxytryptamine (5-HT) and GABA. The sedative and hypnotic effects of palmatine on mice were observed with mouse autonomic activity test, direct sleep test, pentobarbital sodium in suprathreshold and subthreshold dose sleep test. The content of GABA and 5-HT in brain homogenate was determined by ELISA method. Mouse brain specimens were observed by immunohistochemistry for 5-HT expression in the nucleus of mouse brain. Palmatine could reduce spontaneous activities of mice, prolong the sleep time of mice induced by pentobarbital sodium in suprathreshold dose and shorten the sleep latency. And it could increase the number of mice falling asleep induced by pentobarbital sodium in subthreshold dose and the incidence of falling asleep, but with no direct sleep effect. In addition, it enhanced the 5-HT content in brain, but had no effect on GABA content, and had no toxicity to PC12 cells. Palmatine plays a significant role in sedation and hypnosis, which may be associated with the increase of intra-cerebral 5-HT.

Concomitant Transcranial Direct Current Stimulation With Ultrabrief Electroconvulsive Therapy: A 2-Week Double-Blind Randomized Sham-Controlled Trial.

The feasibility and effectiveness of concomitant use of transcranial direct current stimulation (tDCS) with electroconvulsive therapy (ECT) has not been investigated. The study principally aimed at determining whether tDCS when combined with ECT improved the speed of antidepressant response. Secondarily, the ease of generation of seizures during electroconvulsive therapy and cognitive outcomes were investigated. Consecutive patients referred for ECT to treat major depression were randomized to tDCS with dorsolateral prefrontal electrode placements (n = 8) or sham (n = 8) used daily and just before thrice weekly, 6 times threshold, right unilateral ultrabrief (0.3 ms) pulse width ECT. Change of depression severity was determined using the Montgomery Asberg Depression Rating Scale along with cognitive assessments using Montreal Cognitive Assessment and visual memory testing at weeks 1 and 2, which were compared with baseline. Change of depression severity from baseline was similar in tDCS and ECT compared with sham tDCS and ECT at week1 (mean [standard deviation {SD}] = 16.00 [6.78]; 13.75 [7.83]; P = 0.89) and at week 2 (mean [SD] = 23.00 [4.96]; 19.75 [9.85], P = 0.08). No between-group differences were obtained in the cognitive tests at weeks 1 and 2. Combining tDCS with ECT resulted in higher restimulation: 62.5% requiring 3 stimulations to achieve threshold in contrast to 12.5% with sham tDCS and ECT (P = 0.04). The mean suprathreshold dose was higher in the tDCS and ECT group compared with sham tDCS and ECT: mean [SD] = 144.0 [43.54] and mean [SD] = 122.4 [20.36], P = 0.04, respectively. Concomitant use of tDCS with ultrabrief right unilateral ECT is feasible and safe albeit with higher rates of restimulation when tDCS was combined with ECT. However, there were no statistically significant differences in the speed of antidepressant response or cognitive outcomes at weeks 1 and 2 after the commencement of treatments.

Interactions between whole-body heating and citalopram on body temperature, antidepressant-like behaviour, and neurochemistry in adolescent male rats

Evidence suggests that affective disorders are associated with altered thermoregulation, and it has been hypothesized that therapeutic strategies targeting body-to-brain thermosensory systems may be effective for treating depression. Consistent with this hypothesis, a recent randomized, double blind, placebo-controlled clinical trial has suggested that infrared whole-body hyperthermia has therapeutic potential for the treatment of depression. Preclinical models may help uncover the mechanism(s) underlying the antidepressant-like effects of whole-body heating. We have previously shown that exposure to whole-body heating potentiates antidepressant-like behavioural responses following administration of a behaviourally subthreshold dose of the selective serotonin reuptake inhibitor citalopram, but the neurochemical and behavioural interactions between whole body heating and behaviourally effective doses of citalopram are not known. In these experiments, we examined the effects of whole-body heating, either with or without treatment of a suprathreshold dose of citalopram (20 mg/kg, s.c.), on body temperature, antidepressant-like behavioural responses in the forced swim test, and tissue concentrations of serotonin and its metabolite, 5-hydoxyindoleacetic acid (5-HIAA), in the prefrontal cortex of adolescent male Wistar rats. Although whole-body heating did not potentiate the behavioural effects of suprathreshold citalopram, citalopram was observed to increase body temperature and potentiate the effects of whole-body heating on body temperature. Whole-body heating, by itself, decreased serotonin concentrations in the infralimbic cortex to a level similar to that observed following treatment with citalopram, suggesting that these treatments have convergent effects on a mesolimbocortical system innervating the medial prefrontal cortex, an effect that was correlated with effects of treatment on body temperature.

Attitudes of community pharmacists to off-label prescribing of baclofen in Northern France.

Community pharmacists' liability is involved when they dispense off-label prescriptions (OLPs). However, their attitudes to off-label prescribing are little known, while in France off-label baclofen use for alcohol dependence is increasing. To determine community pharmacists' attitudes to off-label prescribing of baclofen. A postal questionnaire was sent to 219 community pharmacies in the Nord-Pas-de-Calais region, France, previously identified as delivering at least five boxes of oral baclofen monthly. The questionnaire examined whether pharmacists delivered baclofen for alcohol dependence, how pharmacists detected off-label prescribing of baclofen, who were the most frequent prescribers (general practitioners or specialists), and pharmacists' attitudes to OLPs. Eighty pharmacies responded (36.5 %). Detection criteria for OLPs were supra-threshold dose (77.3 %) and "off-label" written on prescription (52.5 %). General practitioners were the most frequent prescribers of off-label baclofen. Pharmacists were more likely to refuse to fill prescriptions not marked "off-label" (6.0 %) than correctly marked prescriptions (1.5 %). 85 % of respondents considered they lacked information on off-label use. Although community pharmacists felt they were poorly informed on off-label baclofen, the majority nevertheless delivered the drug. Since our survey, off-label baclofen prescribing has been strictly controlled in France. Pharmacists' current attitudes will need further evaluation.

Sedative and hypnotic effect of freeze-dried paeoniflorin and Sini San freeze-dried powder in pentobarbital sodium-induced mice

ObjectiveTo investigate the sedative and hypnotic activity of paeoniflorin and freeze-dried Sini San powder on mice and provide a reliable method for determining the pharmacodynamic material basis of Sini San. MethodsMale adult mice weighing 20–22 g were used in this study. Three experiments were carried out. Synergism with pentobarbital was used as an index for hypnotic effect. Loss of the righting reflex was used to determine the start of sleep. Sleep latency and sleeping time were recorded in each experiment. ResultsThe coefficient of variation of the supra-threshold dose (55 mg/kg) was significantly lower than that of the threshold dose. The sleep latency of mice was significantly decreased, and the sleeping time of mice was significantly prolonged. The effects of paeoniflorin and Sini San on prolonging the sleeping time of mice induced by pentobarbital sodium were significantly stronger than those in the control group. ConclusionPaeoniflorin produces significant sedative and hypnotic effects, and there is an obvious dose-effect relationship.

Parkinson's disease and pain-Nondopaminergic mechanisms are likely to be important too

Anecdotally, clinicians have known that Parkinson’s disease (PD) patients may report alleviation of what appears to be pain arising from peripheral structures, in response to dopaminergic medication. Drs. Nebe and Ebersbach 1 contribute to the small literature 2 documenting this phenomenon. They report that 14 of 15 PD patients with motor fluctuations experience less intense pain (of various types, the majority with degenerative osteoarticular changes) after administration of a supra-threshold dose of levodopa (L-dopa). So-called ‘‘central’’ pain has been reported in various studies to account for as little as 0–10% of pain/sensory complaints in PD 3 ; however, central mechanisms underlying primary PD pain are also likely to mediate pain arising from peripheral structures. In a recent study, 50 PD outpatients were carefully classified according to L-dopa response (stable responders, fluctuators, and patients with dyskinesia). We reported a marked improvement in experimentally evoked pain responses after L-dopa administration in patients with dyskinesia, but not in stable responders. 4 We would like to expand on our investigations of the response of spontaneous pain to L-dopa, which were previously reported in brief only. After L-dopa challenge, we found a � 6-point reduction in Gracely pain scores (range of scale 0– 20) for spontaneous pain that was not clearly nociceptive in origin in 21 patients. Taking patients who endorsed Gracely scores � 6 in the off-medication state as the denominator, the proportion of patients whose pain improved with L-dopa was 50% (2 of 4), 89% (8 of 9), and 100% (11 of 11) for the stable responder, fluctuator, and dyskinetic groups, respectively (P ¼ 0.029, Fisher’s Exact Test). The commonest complaint was shoulder/upper limb pain (9 of 21 cases; in all but one patient,

Subthalamic nucleus stimulation and levodopa-resistant postural instability in Parkinson's disease

We examined the effect of bilateral subthalamic nucleus stimulation on levodopa-resistant balance impairment in 14 patients with Parkinson's disease and 18 matched controls. Instability was quantitatively assessed using standardized multidirectional dynamic posturography. Patients were tested after taking a suprathreshold dose of levodopa, both with stimulators turned on and off. Patients with stimulators turned off were more unstable than controls following backward directed perturbations. Overall, patients' instability did not improve with STN stimulation, and considerable inter-individual variability was noted. Of note, marked levodopa- resistant axial motor symptoms before surgery correlated with an adverse treatment effect. We conclude that STN stimulation does not alleviate levodopa-resistant postural instability in Parkinson's disease.

Blockade of 5-HT2a Receptors Reduces Haloperidol-Induced Attenuation of Reward

Previous studies have shown that effective antipsychotic medications attenuate reward, an effect that is generally attributed to their effectiveness at blocking the dopamine D2-like receptors. As blockade of the serotonin type 2a (5-HT2a) receptors is a common property of the newer antipsychotics, the present study compared the effect of haloperidol, clozapine, and M100907 (a selective 5-HT2a antagonist) and the combined effect of haloperidol and M100907 treatment on brain stimulation reward (BSR). Experiments were performed on male Sprague-Dawley rats trained to produce an operant response to obtain electrical stimulation in the lateral hypothalamus. Measures of reward threshold were determined in different groups of rats using the curve-shift method using fixed current intensity and variable frequency before and at different times after injection of haloperidol (0.01, 0.05, 0.1, and 0.25 mg/kg), clozapine (1, 7.5, 15, and 30 mg/kg), M100907 (0.033, 0.1, and 0.3 mg/kg), or their vehicle. The effect of M100907 (0.3 mg/kg) on the attenuation of BSR by a sub- and suprathreshold dose of haloperidol was studied in another group of rats. Clozapine produced a dose-orderly increase in reward threshold with a mean maximal increase of 50%; at high doses, clozapine induced cessation of responding in several animals at different time periods. Haloperidol induced a dose-dependent increase in reward threshold, with the mean maximal increase (75%) being observed at the highest dose; it also produced a dose-dependent reduction of maximum rates of responding. M100907 failed to alter reward at any of the doses tested and had no effect on the subthreshold dose (0.01 mg/kg) of haloperidol. But when combined with a suprathreshold dose of haloperidol, M100907 reduced the reward-attenuating effect of haloperidol. These results show that 5-HT2a receptors are unlikely to constitute a component of the reward-relevant pathway activated by lateral hypothalamic stimulation. However, blockade of 5-HT2a receptors may account for the relatively lower level of reward attenuation produced by clozapine, and predict that antipsychotic medications that have a high affinity for the 5-HT2a receptor may be less likely to induce dysphoria.

Pyridostigmine Treatment Trial in Neurogenic Orthostatic Hypotension

Midodrine hydrochloride is the only drug demonstrated in a placebo-controlled treatment trial to improve orthostatic hypotension (OH) but it significantly worsens supine hypertension. By enhancing ganglionic transmission, pyridostigmine bromide can potentially ameliorate OH without worsening supine hypertension. To evaluate the efficacy of a single 60-mg dose of pyridostigmine bromide, alone or in combination with a subthreshold (2.5 mg) or suprathreshold (5 mg) dose of midodrine hydrochloride, compared with placebo. We report a double-blind, randomized, 4-way cross-over study of pyridostigmine in the treatment of neurogenic OH. A total of 58 patients with neurogenic OH were enrolled. After 1 day of baseline measurements, patients were given 4 treatments (3 active treatments [60 mg of pyridostigmine bromide; 60 mg of pyridostigmine bromide and 2.5 mg of midodrine hydrochloride; 60 mg of pyridostigmine bromide and 5 mg of midodrine hydrochloride] and a placebo) in random order on successive days. Blood pressure (BP) and heart rate were measured, both supine and standing, immediately before treatment and hourly for 6 hours after the treatment was given. No significant differences were seen in the supine BP, either systolic (P = .36) or diastolic (P = .85). In contrast, the primary end point of the fall in standing diastolic BP was significantly reduced (P = .02) with treatment. Pairwise comparison showed significant reduction by pyridostigmine alone (BP fall of 27.6 mm Hg vs 34.0 mm Hg with placebo; P = .04) and pyridostigmine and 5 mg of midodrine hydrochloride (BP fall of 27.2 mm Hg vs 34.0 mm Hg with placebo; P = .002). Standing BP improvement significantly regressed with improvement in OH symptoms. Pyridostigmine significantly improves standing BP in patients with OH without worsening supine hypertension. The greatest effect is on diastolic BP, suggesting that the improvement is due to increased total peripheral resistance.

Differential effects of subthalamic nucleus stimulation in advanced Parkinson disease on reaction time performance

The aim of the present study was to assess the effect of bilateral subthalamic nucleus (STN) stimulation and dopaminergic medication on speed of mental processing and motor function. Thirty-nine patients suffering from advanced Parkinson disease (PD) were operated on. Motor function and reaction time (RT) performance [simple RT (SRT) and complex RT (CRT)] were evaluated under four experimental conditions with stimulation (stim) and medication (med) on and off: stim-on/med-on, stim-on/med-off, stim-off/med-off and stim-off/med-on. In the last condition, the patients received either low medication (usual dose) or high medication (suprathreshold dose). STN stimulation improved the motor performance in the SRT and CRT tasks. Furthermore, STN deep brain stimulation (DBS) also improved response preparation as shown by the significant improvement of the RT performance in the SRT task. This effect of STN DBS on the RT performance in the SRT task was greater as compared with the CRT task. This is due to the more complex information processing that is required in the CRT task as compared to the SRT task. These data suggest that treatment of STN hyperactivity by DBS improves motor function, confirming earlier reports, but has a differential effect on cognitive functions. The STN seems to be an important modulator of cognitive processing and STN DBS can differentially affect motor and associative circuits.

Acute psychotropic effects of bilateral subthalamic nucleus stimulation and levodopa in Parkinson's disease.

High-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves the motor symptoms of Parkinson's disease (PD). Opposite changes in mood, such as mania or depression, have been reported after surgery, but it is not known whether these side effects are specifically related to STN DBS. To learn whether STN DBS also influences the limbic loop, we investigated acute subjective psychotropic effects related to levodopa or bilateral STN DBS. After a median postoperative follow-up of 12 months, 50 PD patients completed the Addiction Research Center Inventory (ARCI), assessing subjective psychotropic effects in four conditions: off-drug/on-stimulation; off-drug/off-stimulation; on-drug/off-stimulation; and on-drug/on-stimulation. Both levodopa and STN DBS improved all the ARCI subscales, indicating subjective feelings of well being, euphoria, increase in motivation, and decrease in fatigue, anxiety, and tension. A suprathreshold dose of levodopa was significantly more effective than STN DBS, using the same electrical parameters as for chronic stimulation, on four of the five ARCI subscales. We concluded that 1) both STN DBS and levodopa have synergistic acute beneficial psychotropic effects in PD, 2) the psychotropic effects of both treatments need to be considered in the long-term management of chronic STN DBS, and 3) the results indicate an involvement of the limbic STN in mood disorders of PD.

An antihypokinesic action of alpha2-adrenoceptors upon MPTP-induced behaviour deficits in mice.

The effects of co-administration of either the dopamine precursor, L-Dopa, or the directly-acting, mixed dopamine (DA) agonist, apomorphine, with the alpha-adrenoceptor agonists, clonidine and guanfacine, upon the motor activity of hypoactive L-Dopa-tolerant MPTP-treated C57 BL/6 mice were measured in four experiments. In each case, MPTP (2 x 40 mg/kg, s.c., separated by a 24-hr interval) was administered eight-to-ten weeks before behavioural testing. It was found that clonidine co-administered with L-Dopa (20 mg/kg) restored motor activity in a dose- and parameter-related manner: locomotion and total activity were restored by the 1 mg/kg dose, rearing behaviour by the 0.3 and 1 mg/kg doses. The restorative effects of clonidine (1 mg/kg), co-administered with L-Dopa, were antagonised completely by pretreatment with yohimbine (1 mg/kg), but not by prazosin (1 mg/kg). Guanfacine (1 mg/kg) co-administered with L-Dopa (20 mg/kg) restored locomotor, but not rearing, behaviour in L-Dopa-tolerant MPTP-treated mice. The antikinesic action of guanfacine was antagonised completely by yohimbine (1 mg/kg), but not prazosin (1 mg/kg). Clonidine (1 or 3 mg/kg) co-administered with apomorphine (0.1, 0.3, 1.0 or 3.0 mg/kg), directly-acting DA agonist, did not restore motor behaviour in the hypokinesic L-Dopa-tolerant MPTP-treated mice. Nor did apomorphine, by itself, affect the motor activity of these animals. Neurochemical analysis indicated marked DA, DOPAC and HVA depletions in the striatum, and to a much lesser extent in the frontal cortex, of MPTP-treated mice. The synergistic antiparkinsonian action of clonidine with L-Dopa, but not apomorphine, in hypokinetic MPTP mice for the restoration of responding to a suprathreshold dose of L-Dopa, to which "wearing-off" had been induced previously, is discussed.

Predictors of effective bilateral subthalamic nucleus stimulation for PD.

To identify factors predictive of effective bilateral subthalamic nucleus (STN) stimulation for PD with severe motor complications, pre- and postoperative Unified PD Rating Scale (UPDRS) scores were analyzed in a series of 54 patients who received bilateral STN stimulation. Younger age and levodopa responsiveness predict a favorable response to bilateral STN stimulation. For individual PD symptoms, those that improve with a suprathreshold dose levodopa challenge are likely to improve with stimulation.

Principles for interpreting interactions among the multiple systems that influence food intake.

The widespread use of molecular biological tools has led to a pronounced increase in the number of signals that are now implicated in the controls of food intake and body weight. However, a complete understanding of the roles of these multiple signals requires that we assess how they interact with one another to alter ingestive behavior. Although many such experiments are being conducted, the methods employed to delineate these interactions are often fraught with interpretive difficulties. The purpose of this article is to explore these difficulties and offer practical advice for minimizing these issues in experiments that seek to explore the important interactions among these signals. In particular, the issues of additive vs. nonadditive results, the use of sub- or suprathreshold dose combinations, and the choosing of multiple-dose analyses are all addressed. Furthermore, the possibilities of using intake measures other than cumulative intake and complementary nonbehavioral endpoints are encouraged.

Co-administration of memantine and amantadine with sub/suprathreshold doses of L-Dopa restores motor behaviour of MPTP-treated mice.

The antiparkinsonian effects of the uncompetitive NMDA antagonists, memantine, amantadine and MK-801, in combination with an acute subthreshold dose of L-Dopa (5 mg/kg) in drug-naive MPTP-treated mice or a suprathreshold dose (20 mg/kg) in L-Dopa tolerant MPTP-treated mice were investigated. In the former case, memantine (locomotion: 3 mg/kg; rearing: 1 mg/kg) and amantadine (locomotion and rearing: 10 mg/kg) injected 60 min before the subthreshold dose of L-Dopa (5 mg/kg), each induced an antiparkinsonian action in hypokinesic MPTP-treated mice that consisted of dose-specific, as opposed to dose-related, elevations of locomotion and rearing behaviour. At the same time, higher doses of memantine reduced further the rearing (10 and 30 mg/kg) and locomotor (30mg/kg) behaviour of the MPTP-treated mice. MK-801 plus L-Dopa elevated locomotion (0.1 mg/kg) but reduced rearing at the 0.3 mg/kg dose. In control, saline-treated mice, memantine (3, 10 and 30 mg/kg) and MK-801 (0.1 and 0.3 mg/kg) increased locomotor behaviour but decreased rearing behaviour, while amantadine produced no effects. Memantine increased locomotor (1 and 3 mg/kg, s.c.; 1 mg/kg dose restored activity) and rearing (0.3 and 3 mg/kg) activity in the L-Dopa tolerant MPTP-treated mice, whereas amantadine (3 and 10 mg/kg) restored both locomotor (30 mg/kg significantly increased locomotion but did not restore the activity level) and rearing (3 mg/kg only) activity. MK-801 (0.1 and 0.3 mg/kg, s.c.) also increased significantly locomotor activity of L-Dopa-tolerant MPTP mice although the antikinetic action was not reversed, thereby precluding a restorative effect of the compound. These results, demonstrating both a synergistic and a restorative effect of the NMDA antagonists in coadministration with L-Dopa, demonstrate a putative antiparkinson action by these compounds in a functional animal model that incorporates the "wearing-off" complications of L-Dopa administration in the disorder.