Injection Of Apomorphine Research Articles

D2 receptor activation relieves pain hypersensitivity by inhibiting superficial dorsal horn neurons in parkinsonian mice.

Chronic pain is a common and undertreated nonmotor symptom in Parkinson's disease (PD). Although chronic pain is improved by L-dopa in some PD patients, the underlying mechanisms remain unclear. In this study, we established PD mice by unilateral microinjection of 6-OHDA in the medial forebrain bundle to investigate the contribution of spinal cord dopamine receptors to parkinsonian pain hypersensitivity. The von Frey filament tests and thermal pain tests revealed that these PD mice displayed decreased nociceptive thresholds in both hindpaws; intrathecal injection of L-dopa or apomorphine significantly increased the mechanical and thermal nociceptive thresholds, and the analgesic effect was mimicked by ropinirole (a D2 receptor agonist), but not SKF38393 (a D1/D5 receptor agonist), and blocked by sulpiride (a D2 receptor antagonist), but not SKF83566 (a D1/D5 receptor antagonist). Whole-cell recordings in lumber spinal cord slices showed that superficial dorsal horn (SDH) neurons in PD mice exhibited hyperexcitability, including more depolarized resting membrane potentials and more action potentials evoked by depolarizing current steps, which were mitigated by ropinirole. Furthermore, ropinirole inhibited the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in SDH neurons more strongly in PD mice than in control mice. However, sulpiride caused less disinhibition of sEPSCs in PD mice than in control mice. Taken together, our data reveal that pain hypersensitivity in PD mice is associated with hyperexcitability of SDH neurons, and both events are reversed by activation of spinal D2 receptors. Therefore, spinal D2 receptors can be promising therapeutic targets for the treatment of PD pain.

An evaluation of subcutaneous apomorphine for the treatment of Parkinson’s disease

ABSTRACT Introduction Heterogeneity of symptoms and individual variability of progression characterizes Parkinson’s disease. Unmet therapeutic needs include a cure, disease modification, and improvement of available marketed dopamine-substituting compounds. Personalized treatment, tailored to the patients’ needs and symptoms, aims to ameliorate impaired motor behavior and non-motor features. Injection or infusion of apomorphine is a therapeutic option for more advanced patients with severe levodopa associated motor complications. Areas covered This narrative review summarizes the subcutaneous administration, efficacy, and side effects of the non-ergot derivative dopamine agonist apomorphine following a non-systematic literature research. Expert opinion Subcutaneous apomorphine hydrochloride application rapidly terminates intervals with severe motor impairment with bolus injections. Oscillation of motor behavior well responds to continuous apomorphine infusions. Long-term application of the commercially available apomorphine hydrochloride solution sooner or later affects skin and oral mucosa. Onset of skin nodules associated with subcutaneous tissue inflammation probably results from the antioxidant preservative sodium metabisulfite in the apomorphine solution. Addition of another better tolerated and safer antioxidant instead of sodium metabisulphite or use of an already available concentrated apomorphine-free base formulation will enhance its future use, its tolerability, safety, and acceptance of subcutaneous and sublingual application.

Downregulation of lncRNA BACE1-AS improves dopamine-dependent oxidative stress in rats with Parkinson’s disease by upregulating microRNA-34b-5p and downregulating BACE1

ABSTRACT Objective: Long noncoding RNAs (lncRNAs) have already been proposed to function in Parkinson’s disease (PD). However, the role of lncRNA BACE1-AS in PD has never been discussed. This study aims to examine the mechanism of BACE1-AS on oxidative stress injury of dopaminergic neurons in PD rats. Methods: Rat models of PD were established through the injection of 6-hydroxydopamine. The rotation of rats was induced by intraperitoneal injection of apomorphine, and number of rotations per minute was detected. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px), glutamic acid (Glu), dopamine (DA), tyrosine hydroxylase (TH), α-synuclein and inducible nitric oxide synthase (iNOS) in the substantia nigra of rats in each group were detected. Apoptosis and pathological changes in the substantia nigra were also observed. BACE1-AS, miR-34b-5p, BACE1, Bax and Bcl-2 expression in the substantia nigra were detected. The binding of BACE1-AS and miR-34b-5p and the targeting relationship of miR-34b-5p and BACE1 were further determined. Results: Downregulated BACE1-AS reduced iNOS, α-synuclein and Glu levels and elevated DA and TH levels in the substantia nigra of PD rats. Downregulated BACE1-AS repressed apoptosis and oxidative stress injury in the substantia nigra neurons of PD rats. BACE1-AS specifically bound to miR-34b-5p. BACE1 was a direct target gene of miR-34b-5p. Conclusion: Collectively, our study reveals that downregulation of lncRNA BACE1-AS inhibits iNOS activation in the substantial nigra and improve oxidative stress injury in PD rats by upregulating miR-34b-5p and downregulating BACE1.

Unilateral 6-Hydroxydopamine-Lesioned Rat as Relevant Model to Study the Pain Related to Parkinson’s Disease

The present study was conducted to test the use of the hemiparkinsonian rat, obtained by the unilateral injection of 6-hydroxydopamine (6-OHDA) in the substantia nigra pars compacta (SNc), as a suitable model for the study of pain associated to Parkinson’s disease (PD). For this purpose, 14 days after unilateral injection of saline or 6-OHDA, rats were assessed for behavioral function in the cylinder test, and apomorphine-induced circling test. Thereafter, at 21st day after injection, mechanical nociceptive threshold was compared between 6-OHD-lesioned and sham-operated animals using electronic von Frey test. Our results showed that injection of 6-OHDA in the SNc induced alterations of behavioral motor as ascertained by predominant use of the ipsilateral forepaw in cylinder test and by the expression of contralateral turnings after subcutaneous injection of apomorphine. The mechanical nociceptive threshold was significantly decreased in 6-OHDA-lesioned rats compared to that of sham-operated rats (p <0.05). This response was reversed by apomorphine treatment. In conclusion, hemiparkinsonian rat, obtained by the unilateral injection of the 6-OHDA in the SNc, can be used to investigate pain symptoms and central pain processing mechanisms related to PD.

Subcutaneous apomorphine in advanced Parkinson’s disease and its use in Indian population

Although subcutaneously administered apomorphine is widely used as an effective adjunct therapy for Parkinson’s disease (PD), it was approved for use in India only in 2019. This review summarizes the history, pharmacology, clinical spectrum, indications, efficacy, and side effects of subcutaneous apomorphine use in patients with PD along with clinical recommendations for its use in Indian context. Intermittent subcutaneous apomorphine injection or continuous subcutaneous apomorphine infusion is effective adjunctive treatments for patients with advanced PD with levodopa-related refractory motor complications and some specific nonmotor symptoms (NMS) as growing evidence shows apomorphine also improves aspects of NMS of PD. Common side effects of subcutaneous apomorphine are skin nodules, nausea, and somnolence with incidence being higher with infusion than that with injection. Impulse control disorders and neuropsychiatric complications common to most dopamine agonists can also occur. As per National Institute for Health and Care Excellence (NICE), United Kingdom, apomorphine, as intermittent injection or continuous subcutaneous infusion, is one of the best medical therapies and may be considered before using deep brain stimulation (DBS) or levodopa/carbidopa intestinal gel (LCIG). Head-to-head open-label comparative multicenter data suggest that apomorphine is at least as effective as DBS or LCIG in relation to nonmotor and motor benefit. More studies are needed to reduce the paucity of apomorphine data in Indian population. We also discuss criteria to select one device therapy over another and newer apomorphine delivery strategies in the pipeline.

The Effects of Dopamine and Serotonin on Yawning Behavior in the Rat Model of Social Isolation

A sample of 80 Male rats (21-day post weaning) were chosen, and were put for 6 weeks in separate cages with black plastic buffers. Eight rats were put in one group of 8 rats in a single cage (the control group) and the rest were put in individual cages: one male rat in each cage. In group 1 or the control group (social conditions) 8 rats were put in one cage. They received saline carrier and their yawning behavior was recorded for 60 minutes. Group 2 (n=8; in separate cages) (social isolation conditions) received no treatment with serotonin and dopamine agonist and antagonist and were kept in separate cages with one rat in each cage. Their yawning behavior was also recorded for 60 minutes. Group 3 (n=8; in separate cages) included the rats that received Apomorphine (dopamine agonist) at a dose of 0.08 mg/kg via subcutaneous injection (SC), and their yawning behavior was recorded for 60 minutes. Rats in group 4 (n=8; in separate cages) received serotonin agonist (m-CPP) at a dose of 0.5 mg/kg via subcutaneous injection, and their yawning behavior was recorded for 60 minutes. Group 5 (n=8; in separate cages) included rats that received Serotonin Antagonist (Mianserin) at a dose of 0.2 mg/kg via subcutaneous injection, and their yawning behavior was recorded for 60 minutes. Group 6 (n=8; in separate cages) included rats receiving dopamine antagonist (haloperidol) at a dose of 0.1 mg/kg via Intraperitoneal (IP) injection, and their yawning behavior was recorded for 60 minutes. Group 7 (n=8; in separate cages) included rats receiving Serotonin antagonist (Mianserin) at a dose of 0.2 mg/kg via subcutaneous injection 15 minutes before injection of apomorphine (dopamine agonist) and their yawning behavior was recorded for 60 minutes. Rats in group 8 (n=8; in separate cages) received dopamine antagonist (haloperidol) at a dose of 0.1 mg/kg via intraperitoneal injection (IP) 15 minutes before the injection of serotonin agonist (m-ccp), and their yawning behavior was recorded for 60 minutes. Rats in group 9 (n=8; in separate cages) received Apomorphine (dopamine agonist) at a dose of 0.08 mg/kg and Serotonin agonist (m-CPP) injected subcutaneously (SC) at a dose of 0.5 mg/kg and their yawning behavior was recorded for 60 minutes. Group 10 (n=8; in separate cages) included rats that received dopamine antagonists (haloperidol) at 0.1 mg/kg via intraperitoneal injection (IP) and antagonist serotonin (Mianserin) at 0.2 mg/kg injected subcutaneously and their yawning belabor was recorded for 60 minutes. Dopamine agonist (apomorphine) and serotonin antagonist (Mianserin) induce yawning in the social conditions and injection of haloperidol (dopamine antagonist) before serotonin agonist (m-ccp) reduces yawning in social conditions. Yawning is different in social conditions and social isolation conditions. Using Meta-Chlorophenylpiperazineserotonin (serotonin agonist), Mianserin (serotonin antagonist), apomorphine (dopamine agonist), haloperidol (dopamine antagonist) the role of serotonin and dopamine in yawning, fear, erection etc. can be investigated as a model for human studies.

Deep brain stimulation of the thalamic centromedian-parafascicular nucleus improves behavioural and neuronal traits in a rat model of Tourette

Deficient prepulse inhibition (PPI) of the acoustic startle reaction after injection of the dopamine receptor agonist apomorphine has been experimentally used to model certain aspects of Tourette syndrome (TS) in rats. Deep brain stimulation (DBS) of the centromedian-parafascicular (CM-Pf) complex alleviates tics in patients with TS. The CM-Pf projects to striatal regions, which might mediate the effect of DBS via the cortico basal-ganglia circuitry implicated in the pathophysiology of TS. We tested the effect of CM-Pf DBS on apomorphine-induced deficient PPI and on striatal neuronal activity in rats.Electrodes were stereotaxically implanted bilaterally in the CM-Pf of adult male Sprague Dawley rats. Thereafter, rats were stimulated (150 μA and 130 Hz) or sham-stimulated (no application of current) to test the effect on apomorphine-induced deficient PPI (vehicle and 1.0 mg/kg). Additionally, the neuronal activity of the dorsomedial striatum (DMS) and the nucleus accumbens (NAC), as well as its coherence with the sensorimotor cortex (SM-Ctx) was recorded after apomorphine injection and CM-Pf DBS.CM-Pf DBS prevented the apomorphine-induced PPI-deficit. In striatal neurons apomorphine enhanced burst activity, as well as oscillatory theta band coherence with SM-Ctx electrocorticogram (SM-Ctx ECoG), which was reduced by CM-Pf DBS. Overall, the effect was stronger in the NAC than in the DMS.Modulation of neuronal activity in striatal regions may mediate the effects of CM-Pf DBS on PPI. This model may be used to test and improve novel neuro-modulation strategies.

The role of dopamine in eye growth responses to color and luminance flicker in chicks

Stroboscopic luminance flicker has been found to prevent the increase in eye growth normally associated with form deprivation through the release of retinal dopamine. In this study, we sought to investigate whether dopamine plays a role in the decreased growth observed with 2 Hz sine-wave luminance flicker and increased growth with color flicker. Starting 5–7 days after hatching, chicks were exposed to 2 Hz sinusoidally modulated illumination (Mean: 680 lux) for 4 days and were otherwise in the dark. Chicks were exposed to color-modulated red and green (RG) light, to luminance modulated RGB components (LUM), or to a no-flicker (NF) control. Chicks received daily 10 μL intravitreal injections of apomorphine, spiperone, or saline. Fellow eyes received no injection. Spiperone injections prevented the decrease in eye growth typically seen with LUM flicker, with a relative increase in eye length, but no other significant effects compared with saline controls. Apomorphine injections prevented the increase in eye growth typically seen with RG flicker, with a relative decrease in eye length compared to saline controls. These results indicate a role for the activation of D2-receptor types in the inhibition of eye growth in response to luminance flicker, and a lack of dopamine receptor activation associated with the increase in eye growth with color flicker.

Apomorphine-induced reorganization of striato-frontal connectivity in patients with tremor-dominant Parkinson's disease

IntroductionApomorphine is a dopamine agonist used in Parkinson's disease (PD), which matches levodopa in terms of the magnitude of effect on the cardinal motor features, such as tremor and bradykinesia. The beneficial effect of this treatment on PD patients with tremor-dominant has widely been demonstrated, although the underlying neural correlates are unknown. We sought to examine the effects of apomorphine on topological characteristics of resting-state functional connectivity networks in tremor-dominant PD (tdPD) patients. MethodsSixteen tdPD patients were examined using a combined electromyography-functional magnetic resonance imaging approach. Patients were scanned twice following either placebo (subcutaneous injection of 1 mL saline solution) or 1 mg of apomorphine injection. Graph analysis methods were employed to investigate the modular organization of functional connectivity networks before and after drug treatment. ResultsAfter injection of apomorphine, evident reduction of tremor symptoms was mirrored by a significant increase in overall connectivity strength and reorganization of the modular structure of the basal ganglia and of the fronto-striatal module. Moreover, we found an increase in the centrality of motor and premotor regions. No differences were found between pre- and post-placebo sessions. ConclusionThese results provide new evidence about the effects of apomorphine at a large-scale neural network level showing that drug treatment modifies the brain functional organization of tdPD, increasing the overall resting-state functional connectivity strength, the segregation of striato-frontal regions and the integrative role of motor areas.

Apomorphine for Parkinson's Disease: Efficacy and Safety of Current and New Formulations.

Satisfactory management of Parkinson’s disease is a challenge that requires a tailored approach for each individual. In the advanced phase of the disease, patients may experience motor complications despite optimized pharmacological therapy. Apomorphine, a short-acting D1- and D2-like receptor agonist, is the only drug proven to have an efficacy equal to that of levodopa, albeit with a shorter time to onset and effect duration. Clinical trials have shown that intermittent apomorphine injections provide rapid and effective relief from unpredictable “off” periods. Continuous apomorphine infusion reduced around 50% of the daily “off” time in several studies. Dopaminergic side effects such as nausea, somnolence and hypotonia, as well as administration site reactions, are often mild or treatable, but somnolence and skin reactions in particular can sometimes be reasons for premature discontinuation. We provide an overview of the pharmacological mechanism of action of the drug in light of its effects on Parkinson’s disease symptoms. We then summarize the evidence regarding the efficacy and tolerability of apomorphine, both in its established formulations (subcutaneous intermittent injection and continuous infusion) and in the new preparations currently under investigation.

Вплив N-ацетилцистеїну на рухову активність геміпаркінсо-нічних щурів, викликану ін’єкцією агоніста дофамінових рецепторів

Мета роботи – виявити профілактичний ефект попередньої ін’єкції N-АЦ на розвиток м’язової втоми в неанестезованої тварини з експериментальним геміпаркінсонізмом під час тривалих циркуляторних рухів, викликаних ін’єкцією апоморфіну (АМ).Дослідження проводили на щурах лінії Вістар-Кіото, у яких викликали однобічне руйнування дофамінергічної (ДА) висхідної системи мозку за допомогою ін’єкції 8 мкг 6-гідроксидофаміну, розчиненого в 4 мкл фізіологічного розчину з додатком 0,1 % аскорбінової кислоти, яка гальмує окислення нейротоксину. Поведінкові реакції тварин на ін’єкцію дофаміноміметика апоморфіну були непрямим тестом на ступінь дегенерації ДА-нейронів середнього мозку. Через сім днів після введення 6-гідроксидофаміну тварин розділили на такі групи: 1 – контрольні тварини, у яких викликали інтенсивні циркуляторні рухи за допомогою ін’єкції апоморфіну (0,5 мг/кг) (n = 6); 2 – щури, яким за годину до ін’єкції АМ вводили 0,5 мл фізіологічного розчину (n = 6); 3 – тварини, яким за годину до ін’єкції АМ вводили розчин N-ацетилцистеїну (150 мг/кг) (n = 6).Порівнюючи поведінкові тести на щурах у трьох групах, можемо припустити, що зменшення числа обертів щурів контрольної групи й тварин із попередньою ін’єкцією фізіологічного розчину відбувалося не через припинення дії апоморфіну, а через розвиток м’язової втоми під час тривалих циркуляторних рухів. Водночас у щурів третьої групи після застосування N-АЦ зниження середньої кількості обертів не спостерігали. Це може вказувати на активацію захисної дії антиоксидантної системи у відповідь на тривалу м’язову активність, а N-АЦ можна розглядати як потужний активатор захисних механізмів, спрямованих на зниження втоми скелетних м’язів.

Efficacy of intravenous administration of apomorphine for removal of gastric foreign material in dogs: 495 cases (2010–2015)

To evaluate the efficacy of IV administration of apomorphine for removal of gastric foreign bodies in dogs. 495 dogs with gastric foreign bodies. Records of a veterinary hospital were searched to identify dogs that received an injectable formulation of apomorphine between January 1, 2010, and July 30, 2015. Dogs with a gastric foreign body that received an IV injection of apomorphine were included in the study. Information extracted from the record of each dog included signalment, type of foreign material ingested, duration between foreign material ingestion and emesis, dose and number of doses of apomorphine administered, and whether emesis occurred and did or did not result in successful removal of the foreign body. Descriptive data were compared between dogs with and without successful foreign body removal. Emesis with successful foreign body removal was achieved in 363 and 11 dogs after administration of 1 and 2 doses of apomorphine, respectively. Successful removal was more likely for young dogs and dogs that had ingested fabric, leather, or bathroom waste. Successful removal was less likely as the duration between foreign body ingestion and emesis increased and for dogs that received opioids, sedatives, or antiemetics before apomorphine administration. Minor adverse effects were recorded for only 4 dogs. IV administration of apomorphine was a viable alternative for induction of emesis and removal of gastric foreign bodies in dogs. Dogs should be examined as soon as possible after foreign body ingestion and should not receive any medications that might affect apomorphine efficacy.

Protective effect of chlorogenic acid in an experimental model of Parkinson’s disease induced by 6-hydroxydopamine in rats

Introdution: Parkinson's disease is the second most common neurodegenerative disease. Considering the antioxidant and neuroprotective properties of chlorogenic acid, the purpose of this study was to evaluate the neuroprotective effect of this substance in an experimental model of Parkinson's disease. Methods: In this experimental study, Wisar male rats (n = 32) were divided into 4 groups: sham, chlorogenic acid-treated sham, lesion and chlorogenic-acid-treated lesion. The experimental model of Parkinson's disease was made by injecting 12.5 microgram of 6-hydroxydopamine dissolved in a saline-ascorbate solution into the left side of neostriatum. The chlorogenic acid-treated sham and the chlorogenic-acid-treated lesion groups received 10 mg/kg of the drug intraperitoneally daily during a week before stereotaxic surgery and the last injection was given one hour before stereotaxic surgery. In the second week after surgery, the rotational behavior induced by apomorphine injection within one hour and the number of dopaminergic neurons in the substantia nigra compacta was examined and counted. For statistical analysis, one-way ANOVA and Tukey post-host tests were used in Sigmaplot 12. Results: Chlorogenic acid-pretreated lesion group showed significantly lower rotations versus lesion group (p<0.01). In addition, chlorogenic acid-treated lesion group had a higher number of dopaminergic neurons relative to lesion group (p<0.05). Conclusion: Pretreatment with chlorogenic acid reduces motor asymmetry in an experimental model of Parkinson's disease and has also protective effect on nigral dopaminergic neurons.

Medial prefrontal cortex ERK and conditioning: Evidence for the association of increased medial prefrontal cortex ERK with the presence/absence of apomorphine conditioned behavior using a unique post-trial conditioning/extinction protocol

Increases in medial prefrontal cortex ERK have been linked to learning and memory processes. In the present study separate groups of rats initially underwent testing in an open-field paired with either 2.0 mg/kg apomorphine or vehicle injections. Subsequently, in a brief conditioning 5 min. test the paired apomorphine group manifested a conditioned hyperactivity response. The vehicle/apomorphine groups were then subdivided into two vehicle and two apomorphine subgroups matched for their activity scores in this conditioning test. Following another apomorphine/vehicle pairing in the test environment the groups received 3 additional 5 min. non-drug conditioning tests in which the groups received post-trial vehicle/apomorphine treatments. The vehicle groups received vehicle either immediately or 15 min. after the first two of the three conditioning tests and the apomorphine groups received 2.0 mg/kg either immediately or 15 min. after the first two of the three conditioning tests. In the first conditioning test both of the apomorphine groups exhibited equivalent conditioned responses. By the third test, the conditioned response of the immediate post-trial apomorphine group remained robust whereas conditioned response of the 15 min. apomorphine post-trial group was extinguished. Immediately following the third conditioning test, the animals were euthanized and ERK was measured in the medial prefrontal cortex and the nucleus accumbens. ERK was enhanced in both brain areas, selectively in the immediate apomorphine post-trial group. Increased ERK activity linked to the presence of the apomorphine conditioned response coupled with the absence of increased ERK activity following extinction of the apomorphine conditioned response suggests that ERK activity immediately following a conditioning test is an indicator of activity in brain systems with substantial dopaminergic input that are important in learning and memory. The facilitative effects of the immediate post-trial apomorphine treatment on the conditioned response are also consistent with the proposition that immediate post-trial dopaminergic drug treatments can modify the re-consolidation of conditioned behavior.

Effects of agomelatine in rotenone-induced Parkinson’s disease in rats

The effects of melatonin and melatonin analogs in experimental Parkinson’s disease (PD) models remain controversial. Agomelatine, a novel analog of melatonin, is both agonists for melatonin-1 and melatonin-2 receptors and antagonist of 5-HT2C receptors. While agomelatine has been commonly used as an anti-depressant and sleep drug, information about effects of agomelatine in PD are still lacking. Male Sprague-Dawley rats (220–260 g) were injected with rotenone (0.5 μg, n = 16) or vehicle (1 μl DMSO, n = 8) into the left substantia nigra (SN) and ventral tegmental area under stereotaxic surgery. After ten days, the rats were assessed for the confirmation of PD by the rotational test following apomorphine injection (2 mg/kg, i.p.).The confirmed rats were divided into two groups which received daily p.o. agomelatine (40 mg/kg, n = 8) or saline (2 ml/rat, n = 8) for consecutively 18 days. Twenty-four hours after the last drug administration, the rotational test was repeated and motor coordination was assesed just before the decapitation. Brain tissues were taken for biochemical, molecular and histopathological evaluations. Agomelatine treated animals showed augmented apomorphine-induced rotation response and impaired motor coordination compared to the rotenone group. Furthermore, agomelatine treatment significantly induced apoptosis with an increase in caspase-3 expression independent from PARP-1 activation. Agomelatine treatment caused increased protein oxidation levels, in addition to a decrease in neuron number in the striatum. Although we investigated the effects of the agomelatine in the manner of ameliorating the rotenone toxicity in animals, agomelatine exacerbates rotenone-induced toxicity which mimics Parkinson’s disease pathology.

Sensor-based gait analysis of individualized improvement during apomorphine titration in Parkinson's disease.

Mobile, sensor-based gait analysis in Parkinson's disease (PD) facilitates the objective measurement of gait parameters in cross-sectional studies. Besides becoming outcome measures for clinical studies, the application of gait parameters in personalized clinical decision support is limited. Therefore, the aim of this study was to evaluate whether the individual response of PD patients to dopaminergic treatment may be measured by sensor-based gait analysis. 13 PD patients received apomorphine every 15min to incrementally increase the bioavailable apomorphine dose. Motor performance (UPDRS III) was assessed 10min after each apomorphine injection. Gait parameters were obtained after each UPDRS III rating from a 2×10m gait sequence, providing 41.2 ± 9.2 strides per patient and injection. Gait parameters and UPDRS III ratings were compared cross-sectionally after apomorphine titration, and more importantly between consecutive injections for each patient individually. For the individual response, the effect size Cohen's d for gait parameter changes was calculated based on the stride variations of each gait sequence after each injection. Cross-sectionally, apomorphine improved stride speed, length, gait velocity, maximum toe clearance, and toe off angle. Between injections, the effect size for individual changes in stride speed, length, and maximum toe clearance correlated to the motor improvement in each patient. In addition, significant changes of stride length between injections were significantly associated with UPDRS III improvements. We therefore show, that sensor-based gait analysis provides objective gait parameters that support clinical assessment of individual PD patients during dopaminergic treatment. We propose clinically relevant instrumented gait parameters for treatment studies and especially clinical care.

Phase-coherence classification: A new wavelet-based method to separate local field potentials into local (in)coherent and volume-conducted components

BackgroundLocal field potentials (LFP) reflect the integrated electrophysiological activity of large neuron populations and may thus reflect the dynamics of spatially and functionally different networks. New methodWe introduce the wavelet-based phase-coherence classification (PCC), which separates LFP into volume-conducted, local incoherent and local coherent components. It allows to compute power spectral densities for each component associated with local or remote electrophysiological activity. ResultsWe use synthetic time series to estimate optimal parameters for the application to LFP from within the subthalamic nucleus of eight Parkinson patients. With PCC we identify multiple local tremor clusters and quantify the relative power of local and volume-conducted components. We analyze the electrophysiological response to an apomorphine injection during rest and hold. Here we show medication-induced significant decrease of incoherent activity in the low beta band and increase of coherent activity in the high beta band. On medication significant movement-induced changes occur in the high beta band of the local coherent signal. It increases during isometric hold tasks and decreases during phasic wrist movement. Comparison with existing methodsThe power spectra of local PCC components is compared to bipolar recordings. In contrast to bipolar recordings PCC can distinguish local incoherent and coherent signals. We further compare our results with classification based on the imaginary part of coherency and the weighted phase lag index. ConclusionsThe low and high beta band are more susceptible to medication- and movement-related changes reflected by incoherent and local coherent activity, respectively. PCC components may thus reflect functionally different networks.

Influence of Gonadal Hormones on Motivation for a Sucrose Reward in Female Rats: Alterations following Exposure to Haloperidol and Apomorphine

IntroductionSex differences in dysfunction of motivational systems for natural rewards has been implicated in several disorders, including depression, obesity, and substance abuse (Pulcu & Elliott, 2015; Volkow & Wise, 2005). Sex differences are evident in these motivational disorders, and our lab has previously shown that female rats work harder for a natural sucrose reward compared to male rats. Interestingly, dopamine regulates motivated behaviors and may be important for understanding these sex differences in motivation. Previous research has found that haloperidol and apomorphine decrease responding for sucrose rewards, and gonadal hormones may influence sensitivity to these dopaminergic alterations. Although the role of gonadal hormones on motivation for drug rewards such as cocaine has been studied, little research has measured motivation for a natural sucrose reward following hormone manipulation. Further, it is not known if gonadal hormones alter sensitivity to haloperidol and apomorphine, as measured by responding for a sucrose reward. Therefore, the current study investigated the role estrogen and progesterone had on motivation for a sucrose reward and how these hormones alter sensitivity to dopaminergic manipulations (i.e. haloperidol and apomorphine injections).MethodsSeventy adult female rats were randomly assigned to one of five experimental groups: intact, ovariectomized (ovx) that received vehicle, ovx that received estradiol benzoate, ovx that received progesterone, or ovx that received both estradiol benzoate and progesterone. All rats were trained to lever press on an autoshaping schedule followed by an increasing fixed ratio schedule (FR1, FR3, FR5). Rats were then given three progressive ratio (PR) tests to assess motivation following gonadal hormone manipulation, a .032 mg/kg haloperidol injection, or a .032 mg/kg apomorphine injection. Throughout training and testing, hormones were administered every four to five days to mimic the endogenous estrous cycle. Estradiol benzoate was administered 48 hours and progesterone administered 4 hours prior to each PR test.ResultsNeither ovx nor hormone restoration altered the number of active lever presses, suggesting similar motivational responding across all groups. The dopamine antagonist haloperidol decreased active lever responding overall compared to PR responding without drug, but hormone condition did not influence this change. The dopamine agonist apomorphine differentially altered responding, depending on the hormone condition. Ovx females receiving estradiol with progesterone had significantly greater active lever responding compared to ovx females receiving vehicle following apomorphine. However, neither estradiol benzoate nor progesterone treated females differed from ovx with vehicle.DiscussionGonadal hormones do not seem to influence motivation for a sucrose reward in female rats or responding following haloperidol exposure. However, gonadal hormones alter behavioral sensitivity to apomorphine. These findings suggest gonadal hormones may contribute to altered sensitivity to dopaminergic manipulations, which has implications for disorders such as depression, obesity, and substance abuse.

Understanding the role of the Parkinson's disease nurse specialist in the delivery of apomorphine therapy

Optimal care of Parkinson's disease (PD) patients should involve a multidisciplinary team (MDT) of which a PD nurse specialist (PDNS) is a key member. The role of a PDNS is particularly prominent in the care of advanced PD patients suitable for apomorphine because, in addition to nursing skills, apomorphine treatment requires liaison, training, interaction and coordination with patients, caregivers and other members of the MDT as well as the interface with primary care physicians. The therapeutic success of apomorphine therapy depends not only upon the pharmacologic drug response, but also on how well the patient understands his/her disease and how to handle the therapy. In this respect, a PDNS is a vital member of the MDT who provides education and training, support, and is available for consultation when problems arise. In this article, we review the literature on the contribution of PDNSs in both continuous subcutaneous apomorphine infusion and intermittent subcutaneous apomorphine injection and highlight the various beneficial aspects of PDNS care, supported by scientific evidence when available. Despite a low level of published evidence, there is strong clinical evidence that the impact of PDNSs on the management of apomorphine therapy is vital and indispensable for the success of this treatment.

Apomorphine therapy in Parkinson's disease and future directions

Apomorphine infusion or injection is an important dopamine agonist non-oral therapy usually used in advanced Parkinson's disease (PD) with refractory motor fluctuations. The drug also has appreciable efficacy for nonmotor fluctuations and is the quickest to reverse predictable “off” periods. Current subcutaneous administration, however, is complicated by problems associated with needle-based therapies, such as skin nodule formation, skin irritation, and avoidance of this treatment option by needle-phobic subjects.In this review we focus on what the future might hold for apomorphine injection/infusion. We discuss interesting and novel delivery strategies of apomorphine or esters via oral, buccal, inhalation and a novel pump-patch route. We also discuss recent research that has highlighted some important properties of apomorphine in animal models, such as a potential anti-amyloid effect and its potential impact in the management of PD dementia or perhaps even Alzheimer's disease. A potential role for apomorphine infusion in cases with impulse control disorders and other nonmotor issues is also discussed.