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1.  Continuous subcutaneous waking day apomorphine in the long term treatment of levodopa induced interdose dyskinesias in Parkinson's disease 
OBJECTIVES—To determine whether continous waking day dopaminergic stimulation with the dopamine agonist apomorphine can reduce levodopa induced dyskinesias in Parkinson's disease
METHODS—19 patients with severe unpredictable refractory motor fluctuations and functionally disabling levodopa induced dyskinesias were treated with continuous subcutaneoius apomorphine monotherapy for a minimum duration of 2.7 years
RESULTS—A mean 65% reduction in dyskinetic severity and a mean 85% reduction in frequency and duration occurred. On discontinuing levodopa a concomitant reduction in off period time was also seen (35% of waking day "off" reduced to 10%)
CONCLUSION—Continuous waking day dopaminergic stimulation with apomorphine reset the threshold for dyskinesias and led to a pronounced reduction in their frequency. Apomorphine should be considered as a less invasive alternative to pallidotomy or deep cerebral stimulation in controlling levodopa induced interdose dose dyskinesias.


PMCID: PMC2170072  PMID: 9598668
2.  Apomorphine induced cognitive changes in Parkinson's disease. 
Auditory event related potentials (ERPs) and visual evoked potentials (VEPs) were recorded from eight patients with Parkinson's disease, before and after a single dose of apomorphine. To assess the treatment effects, the patients' motor state, Benton visual retention test (BVRT), and digit span tests were also examined. After apomorphine, although motor performance improved, the ERP latencies were delayed and the N2-P3 ERP amplitude was significantly diminished by comparison with pretreatment values. These data suggest that apomorphine induces, besides its motor effects in patients with Parkinson's disease, a slowing down of cognitive processing. Preferential stimulation of dopamine autoreceptors in mesocortical and mesolimbic systems may represent a neural mechanism for these effects. Also, the posttreatment BVRT rotation errors significantly increased, suggesting an apomorphine induced impairment of visuospatial perception.
PMCID: PMC1073092  PMID: 8057129
3.  The on-off phenomenon. 
The on-off phenomenon is an almost invariable consequence of sustained levodopa treatment in patients with Parkinson's disease. Phases of immobility and incapacity associated with depression alternate with jubilant thaws. Both pharmacokinetic and pharmacodynamic factors are involved in its pathogenesis, but evidence is presented to indicate that the importance of levodopa handling has been underestimated and that progressive reduction in the storage capacity of surviving nigrostriatal dopamine terminals is not a critical factor. Re-distribution of levodopa dosage which may mean smaller, more frequent doses, or larger less frequent increments, may be helpful in controlling oscillations in some patients. Dietary protein restriction, the use of selegiline hydrochloride and bromocriptine may also temporarily improve motor fluctuations. New approaches to management include the use of subcutaneous apomorphine, controlled-release preparations of levodopa with a peripheral dopa decarboxylase inhibitor and the continuous intra-duodenal administration of levodopa.
PMCID: PMC1033307  PMID: 2666577
4.  Motor response to apomorphine and levodopa in asymmetric Parkinson's disease. 
The motor responses of 14 patients with Parkinson's disease (six previously untreated and eight chronically receiving levodopa) with pronounced asymmetry in the severity of motor signs between the left and right sides of the body were studied. The effects of a short (60 minutes) and a long (16-22 hours) intravenous levodopa infusion as well as of subcutaneous apomorphine (1-6 mg bolus) were assessed. Four different tapping tests were used to measure motor function. For all pharmacological tests, the more affected side showed a shorter response duration, increased latency, and greater response magnitude than the less affected side. These differences were more pronounced in those patients receiving chronic levodopa treatment. As apomorphine is not dependent on dopamine storage capacity, these findings suggest that postsynaptic mechanisms play an important part in the origin of motor fluctuations in Parkinson's disease.
PMCID: PMC1072915  PMID: 8201324
5.  Effects of a Dopamine Agonist on the Pharmacodynamics of Levodopa in Parkinson Disease 
Archives of Neurology  2010;67(1):27-32.
Background
Treatment of Parkinson disease commonly includes levodopa and dopamine agonists; however, the interaction of these 2 drugs is poorly understood.
Objective
To examine the effects of a dopamine agonist on the motor response to levodopa.
Design
Double-blind, randomized, placebo-controlled, crossover clinical trial.
Setting
Ambulatory academic referral center.
Patients
Thirteen patients with idiopathic Parkinson disease taking levodopa and experiencing motor fluctuations and dyskinesia.
Interventions
Eligible individuals were randomly assigned to receive pramipexole dihydrochloride or placebo for 4 weeks followed by a 2-hour intravenous levodopa infusion on consecutive days at 2 rates and with blinded assessments. They were then crossed over to the alternate oral therapy for 4 weeks followed by levodopa infusion and reassessment.
Main Outcome Measures
Change in finger-tapping speed, measured using the area under the curve (AUC) for finger taps per minute across time; peak finger-tapping speed; duration of response; time to “ON” (defined as a 10% increase in finger-tapping speed above baseline); walking speed; and dyskinesia AUC.
Results
Pramipexole with levodopa infusion increased finger-tapping speed beyond the change in baseline by a mean (SE) of 170 (47.2) per minute×minutes (P=.006) and more than doubled the AUC for finger-tapping speed. Pramipexole increased peak finger-tapping speed by a mean (SE) of 18 (8.5) taps per minute (P=.02) and improved mean (SE) walking speed (15.9 [0.70] vs 18.9 [0.70] seconds, P=.004). Pramipexole prolonged duration of response after levodopa infusion and shortened time to ON. Pramipexole increased mean (SE) baseline dyskinesia scores (26.0 [5.85] vs 12.1 [5.85] points, P = .05) and peak dyskinesia scores with levodopa infusion.
Conclusions
Pramipexole augmented the motor response to levodopa beyond a simple additive effect and increased the severity of levodopa-induced dyskinesia. When considering a combination of these therapies, an appropriate balance should be maintained regarding gain of motor function vs worsening of dyskinesia.
Trial Registration
clinicaltrials.gov Identifier: NCT00666653
doi:10.1001/archneurol.2009.287
PMCID: PMC3390306  PMID: 20065126
6.  The apomorphine test in parkinsonian syndromes. 
The dopamine receptor agonist apomorphine has been used successfully to treat on-off swings in Parkinson's disease. Its value as a predictor of dopa responsiveness in idiopathic Parkinson's disease (IPD) was assessed and its potential role in differentiating IPD from the Parkinsonian plus syndromes (PPS) of multisystem atrophy, progressive supranuclear palsy and olivopontocerebellar atrophy was investigated. The response to an injection of apomorphine was observed in 20 patients with IPD and eight with PPS after being off levodopa for 12 hours. Patients were reassessed after taking levodopa for one month. Nineteen of the 20 patients (95%) with IPD showed a positive response to apomorphine and 18 (90%) to oral levodopa. In the PPS group, two patients (25%) responded to the apomorphine injection but not to oral levodopa. Apomorphine produced severe drowsiness in the PPS patients. It is suggested that the test can predict dopa responsiveness in IPD and may be of help in confirming a doubtful diagnosis. It has potential value in differentiating IPD from PPS.
PMCID: PMC1014569  PMID: 1744640
7.  Apomorphine and the dopamine hypothesis of schizophrenia: a dilemma? 
The dopamine (DA) hypothesis of schizophrenia implicates an enhancement of DA function in the pathophysiology of the disorder, at least in the genesis of positive symptoms. Accordingly, apomorphine, a directly acting DA receptor agonist, should display psychotomimetic properties. A review of the literature shows little or no evidence that apomorphine, in doses that stimulate postsynaptic DA receptors, induces psychosis in non-schizophrenic subjects or a relapse or exacerbation of psychotic symptoms in patients with schizophrenia. After a detailed review of the literature reporting psychotogenic effects of apomorphine in patients with Parkinson's disease, an interpretation of these data is difficult, in part because of several confounding factors, such as the concomitant use of drugs known to induce psychosis and the advanced state of the progressive neurological disorder. In the context of the DA hypothesis of schizophrenia, the limited ability of apomorphine to induce psychosis, in contrast to indirectly acting DA agonists that increase synaptic DA, may be explained by the relatively weak affinity of apomorphine for the D3 receptor compared with DA. Alternatively, enhancement of DA function, though necessary, may be insufficient by itself to induce psychosis.
PMCID: PMC1408306  PMID: 11394190
8.  Dopamine Transporter Genotype Dependent Effects of Apomorphine on Cold Pain Tolerance in Healthy Volunteers 
PLoS ONE  2013;8(5):e63808.
The aims of this study were to assess the effects of the dopamine agonist apomorphine on experimental pain models in healthy subjects and to explore the possible association between these effects and a common polymorphism within the dopamine transporter gene. Healthy volunteers (n = 105) participated in this randomized double-blind, placebo-controlled, cross-over trial. Heat pain threshold and intensity, cold pain threshold, and the response to tonic cold pain (latency, intensity, and tolerance) were evaluated before and for up to 120 min after the administration of 1.5 mg apomorphine/placebo. A polymorphism (3′-UTR 40-bp VNTR) within the dopamine transporter gene (SLC6A3) was investigated. Apomorphine had an effect only on tolerance to cold pain, which consisted of an initial decrease and a subsequent increase in tolerance. An association was found between the enhancing effect of apomorphine on pain tolerance (120 min after its administration) and the DAT-1 polymorphism. Subjects with two copies of the 10-allele demonstrated significantly greater tolerance prolongation than the 9-allele homozygote carriers and the heterozygote carriers (p = 0.007 and p = 0.003 in comparison to the placebo, respectively). In conclusion, apomorphine administration produced a decrease followed by a genetically associated increase in cold pain tolerance.
doi:10.1371/journal.pone.0063808
PMCID: PMC3660379  PMID: 23704939
9.  Pen injected apomorphine against off phenomena in late Parkinson's disease: a double blind, placebo controlled study. 
The effect, therapeutic dose range, and pharmacokinetics of apomorphine, given as subcutaneous injections by a single use pen, were evaluated in the treatment of off phenomena in 22 patients with idiopathic Parkinson's disease. At study entry a placebo controlled apomorphine test was performed, and apomorphine doses were then individually titrated (mean 3.4 (range 0.8-6.0) mg) and compared with placebo in a double blind cross over phase. With apomorphine compared with placebo the mean daily duration of off periods was reduced by 51% as assessed by the patients and by 58% as assessed by the staff. The severity of off periods was also significantly reduced. The effect was unchanged after a maintenance phase of eight weeks. At study termination 13 of 14 patients were able to inject themselves and 11 of 14 patients found that their feeling of freedom had increased. The most common adverse events were nausea, subcutaneous nodules, and increased frequency of involuntary movements. Pharmacokinetics were linear and did not change with repeat dosing. The tmax ranged from five to 45 minutes (16 patients). It is concluded that pen injected apomorphine is a valuable treatment for patients with advanced Parkinson's disease with on-off phenomena.
PMCID: PMC1073544  PMID: 7608665
10.  Subcutaneous apomorphine in the treatment of Parkinson's disease. 
Apomorphine a dopamine receptor agonist was given subcutaneously to 57 levodopa treated parkinsonian patients with refractory off-period disabilities for a median period of 16 months. In 30 given intermittent suprathreshold injections the mean number of hours spent in a disabling off state fell from 6.9 to 2.9. Similar benefit was observed in 21 patients receiving continuous infusions with additional boluses on demand by mini-pump (mean reduction of hours off from 9.9 to 4.5). Twelve patients have been treated for over two years without tachyphylaxis or loss of response. The incidence of neuropsychiatric side-effects has been low (7%). Six patients failed to show a sustained worthwhile response; severe disabilities during "on" periods being the major problem. Subcutaneous apomorphine is proposed as an effective treatment for patients with incapacitating "off" period disabilities refractory to oral medication and should be considered before experimental implantation procedures.
Images
PMCID: PMC487943  PMID: 2313313
11.  The motor response to sequential apomorphine in parkinsonian fluctuations. 
Fifteen patients with Parkinson's disease and levodopa-induced motor fluctuations, were studied with repeated injections of apomorphine using two protocols to explore possible changes in the duration of motor response. One involved different interdose intervals; in the other, doses were given when the motor effects induced by the previous dose had just worn off. No significant change in the duration of motor response to sequential subcutaneous apomorphine with either protocol was found. The results suggest that rapid changes in receptor sensitivity during repeated intermittent dopaminergic stimulation do not contribute to the pathogenesis of Parkinsonian motor fluctuations.
PMCID: PMC488493  PMID: 2056323
12.  Deep brain stimulation of the subthalamic nucleus: effectiveness in advanced Parkinson's disease patients previously reliant on apomorphine 
Objectives: To assess the efficacy of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with advanced Parkinson's disease previously reliant on apomorphine as their main antiparkinsonian medication.
Methods: Seven patients with motor fluctuations despite optimal medical treatment given as predominantly apomorphine infusion (n=6), or intermittent apomorphine injections (n=1) underwent bilateral STN DBS using frameless stereotactic surgery. Standard assessments of parkinsonism and motor fluctuations, using Unified Parkinson's Disease Rating Scale (UPDRS) were performed before and six months after surgery. Assessments were performed both on and off medication, and postoperative with the stimulators switched on and off.
Results: Bilateral STN DBS improved motor scores (UPDRS III) by 61% when off medication (p<0.05). Clinical fluctuations (UPDRS IV items 36–39) were reduced by 46.2% (p<0.05). Total daily apomorphine dose was reduced by 68.9% (p<0.05) and apomorphine infusion via a pump was no longer required in four patients. There were no operative complications. Two patients required treatment for hallucinations postoperatively but there was no significant change in mini-mental state examination.
Conclusions: In patients with advanced Parkinson's disease, previously reliant on apomorphine, bilateral STN DBS is an effective treatment to reduce motor fluctuations and enable a reduction in apomorphine use.
doi:10.1136/jnnp.74.2.170
PMCID: PMC1738303  PMID: 12531942
13.  Comparison of motor response to apomorphine and levodopa in Parkinson's disease. 
The magnitude and pattern of motor responses to single doses of subcutaneous apomorphine and oral levodopa were compared in 14 patients with Parkinson's disease. Although apomorphine produced much shorter motor responses than levodopa, the quality of response to the two drugs was virtually indistinguishable. These clinical observations support the notion that integrity of striatal post-synaptic dopamine receptors is a key determinant of responsiveness to dopaminergic treatment in Parkinson's disease.
PMCID: PMC488286  PMID: 2283512
14.  Subcutaneous apomorphine in late stage Parkinson's disease: a long term follow up 
OBJECTIVES—Despite the recent introduction of new peroral drugs as well as neurosurgical methods for Parkinson's disease, treatment of late stage parkinsonian patients remains difficult and many patients become severely handicapped because of fluctuations in their motor status. Injections and infusions of apomorphine has been suggested as an alternative in the treatment of these patients, but the number of studies describing the effects of such a treatment over longer time periods is still limited. The objective was to investigate the therapeutic response and range of side effects during long term treatment with apomorphine in advanced Parkinson's disease.
METHODS—Forty nine patients (30 men, 19 women; age range 42-80 years) with Parkinson's disease were treated for 3 to 66 months with intermittent subcutaneous injections or continuous infusions of apomorphine.
RESULTS—Most of the patients experienced a long term symptomatic improvement. The time spent in "off" was significantly reduced from 50 to 29.5% with injections and from 50 to 25% with infusions of apomorphine. The quality of the remaining "off" periods was improved with infusion treatment, but was relatively unaffected by apomorphine injections. The overall frequency and intensity of dyskinesias did not change. The therapeutic effects of apomorphine were stable over time. The most common side effect was local inflammation at the subcutaneous infusion site, whereas the most severe were psychiatric side effects occurring in 44% of the infusion and 12% of the injection treated patients.
CONCLUSION—Subcutaneous apomorphine is a highly effective treatment which can substantially improve the symptomatology in patients with advanced stage Parkinson's disease over a prolonged period of time.


PMCID: PMC2170363  PMID: 9810943
15.  Subcutaneous apomorphine infusion in Parkinson's disease: does it have a role? 
Postgraduate Medical Journal  1994;70(823):344-346.
Apomorphine is a potent dopamine agonist at both D1 and D2 receptors and has been used successfully for treating the 'on/off' phenomenon in Parkinson's disease. We report our experience with apomorphine in treating the 'on/off' phenomenon in L-dopa responsive idiopathic Parkinson's disease. Thirteen such patients were commenced on apomorphine infusions. Their mean age was 69 (range 53-80) years and the mean duration of the disease was 15 (range 6-28) years. The clinical response to apomorphine was good in four patients, fair in two, unchanged in five and worse in two. Activities of daily living improved in six, were unchanged in five and worse in two. When the response was poor or showed no change, apomorphine was discontinued. In addition, apomorphine was also discontinued in three patients who had had a fair/good response but suffered side effects of hallucinations, delusions and psychosis, lack of cooperation or found the pump inconvenient. Apomorphine was continued in only three patients out of 13.
PMCID: PMC2397604  PMID: 8016004
16.  Motor response to acute dopaminergic challenge with apomorphine and levodopa in Parkinson's disease: implications for the pathogenesis of the on-off phenomenon. 
OBJECTIVES--To evaluate the contribution of postsynaptic changes to motor fluctuations, three groups of parkinsonian patients with differing responses to treatment were acutely challenged with two dopaminergic drugs-apomorphine and levodopa-having different mechanisms of action. METHODS--Forty two patients with Parkinson's disease (14 untreated, eight with a stable response to levodopa, and 20 with levodopa induced motor fluctuations) were challenged on two consecutive days with apomorphine and levodopa. The latency, duration, and magnitude of motor response was measured. RESULTS--A progressive shortening of mean latency after levodopa challenge was found passing from the untreated to the stable and fluctuating groups; the difference between untreated and fluctuating patients was statistically significant (P < 0.01). Response duration after levodopa challenge was similar in untreated and stable patients, whereas it showed a significant shortening in patients with motor fluctuations (P < 0.05 v both untreated and stable patients). When subcutaneous apomorphine was given, untreated patients had a longer response duration than those who had developed motor fluctuations (P < 0.05). Although baseline disability was significantly greater in the fluctuating patients than in the untreated and stable patients, the severity of residual parkinsonian signs after both apomorphine and levodopa challenge was similar for all three groups; as a result, the degree of improvement in parkinsonian signs after dopaminergic stimulation was substantially greater in more advanced than in early cases. Linear regression analysis also indicated that latency and duration after apomorphine challenge did not significantly correlate with those after levodopa challenge, whereas magnitude of response to apomorphine showed a strong positive correlation with that after levodopa challenge (r = 0.9, P < 0.001). CONCLUSION--The progressive shortening of motor response after both apomorphine and levodopa suggests that pharmacodynamic factors play an important part in determining the duration of motor response and argue against altered central pharmacokinetics of levodopa being principally responsible for the on-off effect. The widening response amplitude and increasing off phase disability occurring during disease progression are also critical factors in determining the appearance of motor fluctuations.
PMCID: PMC1073946  PMID: 8648329
17.  The Role of Dopamine in Reinforcement: Changes in Reinforcement Sensitivity Induced by D1-type, D2-type, and Nonselective Dopamine Receptor Agonists 
Dose-dependent changes in sensitivity to reinforcement were found when rats were treated with low, moderate, and high doses of the partial dopamine D1-type receptor agonist SKF38393 and with the nonselective dopamine agonist apomorphine, but did not change when rats were treated with similar doses of the selective dopamine D2-type receptor agonist quinpirole. Estimates of bias did not differ significantly across exposure to SKF38393 or quinpirole, but did change significantly at the high dose of apomorphine. Estimates of goodness of fit (r2) did not change significantly during quinpirole exposure. Poor goodness of fit was obtained for the high doses of SKF38393 and apomorphine. Decrements in absolute rates of responding were observed at the high dose of quinpirole and at the moderate and high doses of SKF38393 and apomorphine. Changes in r2 and absolute responding may be due to increases in stereotyped behavior during SKF38393 and apomorphine exposure that, in contrast to quinpirole, were distant from the response lever. The present data provide evidence that sensitivity to reward is affected more strongly by dopamine D1-like receptors rather than D2-like receptors, consistent with evidence from other studies investigating consummatory dopamine behavior and the tonic/phasic dopamine hypothesis.
doi:10.1901/jeab.2005.82-04
PMCID: PMC1389773  PMID: 16596971
dopamine D1-like and D2-like receptors; quinpirole; SKF38393; apomorphine; matching; sensitivity to reward; lever press; rat
18.  Drug treatment of Parkinson's disease. 
BMJ : British Medical Journal  1995;310(6979):575-579.
A wide variety of drugs is available for treating Parkinson's disease, including anticholinergics, amantadine levodopa, dopamine agonists, and selegiline. In younger patients (less than 50) levodopa is usually delayed provided that adequate relief of symptoms can be achieved with other drugs. In older patients (greater than 70) levodopa should be started as soon as symptom relief is required. Between these ages there is no consensus, but at present most such patients should probably be given controlled release levodopa before a dopamine agonist is added. Fluctuations can often be alleviated by giving controlled release preparations of levodopa, by giving small doses at frequent intervals, by adding selegiline or a long acting oral agonist, or by subcutaneous apomorphine. Dyskinesia can be peak dose, diphasic, or "off period." The diphasic form is hardest to alleviate. Psychiatric side effects should initially be managed by changing the antiparkinsonian treatment before resorting to antipsychotic drugs.
PMCID: PMC2548944  PMID: 7888935
19.  Dopamine-transporter levels drive striatal responses to apomorphine in Parkinson's disease 
Brain and Behavior  2013;3(3):249-262.
Dopaminergic therapy in Parkinson's disease (PD) can improve some cognitive functions while worsening others. These opposite effects might reflect different levels of residual dopamine in distinct parts of the striatum, although the underlying mechanisms remain poorly understood. We used functional magnetic resonance imaging (fMRI) to address how apomorphine, a potent dopamine agonist, influences brain activity associated with working memory in PD patients with variable levels of nigrostriatal degeneration, as assessed via dopamine-transporter (DAT) scan. Twelve PD patients underwent two fMRI sessions (Off-, On-apomorphine) and one DAT-scan session. Twelve sex-, age-, and education-matched healthy controls underwent one fMRI session. The core fMRI analyses explored: (1) the main effect of group; (2) the main effect of treatment; and (3) linear and nonlinear interactions between treatment and DAT levels. Relative to controls, PD-Off patients showed greater activations within posterior attentional regions (e.g., precuneus). PD-On versus PD-Off patients displayed reduced left superior frontal gyrus activation and enhanced striatal activation during working-memory task. The relation between DAT levels and striatal responses to apomorphine followed an inverted-U-shaped model (i.e., the apomorphine effect on striatal activity in PD patients with intermediate DAT levels was opposite to that observed in PD patients with higher and lower DAT levels). Previous research in PD demonstrated that the nigrostriatal degeneration (tracked via DAT scan) is associated with inverted-U-shaped rearrangements of postsynaptic D2-receptors sensitivity. Hence, it can be hypothesized that individual differences in DAT levels drove striatal responses to apomorphine via D2-receptor-mediated mechanisms.
doi:10.1002/brb3.115
PMCID: PMC3683285  PMID: 23785657
Cognition; DAT; dopamine-agonist; fMRI; Parkinson's disease; working memory
20.  Relationship of Dopamine of the Nucleus Accumbens with Intra-infralimbic Apomorphine Microinjection  
Objective(s): The dopamine level of the nucleus accumbens changes during some stereotyped behaviors. To study dopamine level of the nucleus accumbens in intra infralimbic apomorphine-induced climbing, microdialysis probes were implanted into the nucleus accumbens shell of male Sprague Dawley rats weighting 275–400 g.
Materials and Methods: The rats were divided into two groups (apomorphine and control) of least eleven rats in each group. Apomorphine at dose of 5 μg/0.5 μl or its vehicle was microinjected into the infralimbic in apomorphine and control groups respectively. Then, changes in dopamine levels in the nucleus accumbens shell were monitored. The concentration of dopamine was measured by High-Performance Liquid Chromatography-Electochemical (HPLC-ECD). Finally, the stereotyped behaviors were recorded.
Results: The mean of dopamine levels for all of after microinjection period in control and drug groups were 450% and 150% respectively compared to those of before microinjection period. However, there was no significant difference between groups of apomorphine and control. In addition, the return of dopamine level to the baseline was faster in apomorphine group than the control group.
Conclusion: The intra infralimbic apomorphine -induced climbing at dose of 5 μg/0.5 μl was not modulated via the increase of dopamine level in the nucleus accumbens area.
PMCID: PMC3758028  PMID: 23997899
Apomorphine; Dopamine; Microdialysis; The nucleus accumbens; The prefrontal cortex
21.  Urocortin, a CRF-like peptide, restores key indicators of damage in the substantia nigra in a neuroinflammatory model of Parkinson's disease 
We have recently observed that the corticotrophin releasing hormone (CRF) related peptide urocortin (UCN) reverses key features of nigrostriatal damage in the hemiparkinsonian 6-hydroxydopamine lesioned rat. Here we have studied whether similar effects are also evident in the lipopolysaccaride (LPS) neuroinflammatory paradigm of Parkinson's disease (PD). To do this we have measured restoration of normal motor behaviour, retention of nigral dopamine (DA) and also tyrosine hydroxylase (TH) activity. Fourteen days following intranigral injections of LPS and UCN, rats showed only modest circling after DA receptor stimulation with apomorphine, in contrast to those given LPS and vehicle where circling was pronounced. In separate experiments, rats received UCN seven days following LPS, and here apomorphine challenge caused near identical circling intensity to those that received LPS and UCN concomitantly. In a similar and consistent manner with the preservation of motor function, UCN 'protected' the nigra from both DA depletion and loss of TH activity, indicating preservation of DA cells. The effects of UCN were antagonised by the non-selective CRF receptor antagonist α-helical CRF and were not replicated by the selective CRF2 ligand UCN III. This suggests that UCN is acting via CRF1 receptors, which have been shown to be anti-inflammatory in the periphery. Our data therefore indicate that UCN is capable of maintaining adequate nigrostriatal function in vivo, via CRF1 receptors following a neuro-inflammatory challenge. This has potential therapeutic implications in PD.
doi:10.1186/1742-2094-4-19
PMCID: PMC1976313  PMID: 17659087
22.  Apomorphine reduces subthalamic neuronal entropy in parkinsonian patients 
Experimental neurology  2010;225(2):455-458.
Dopamine depletion in Parkinson's disease (PD) alters the neuronal activity in basal ganglia circuits. Characterizing these changes in network activity is an important step in understanding the disease and how therapies mitigate symptoms. Non-linear analysis methods can complement the traditional description of neuronal firing characteristics. Here we examine the entropy of subthalamic neurons in PD patients undergoing stereotactic surgery for deep brain stimulation (DBS). The activity of 8 neurons was recorded prior to, during, and following systemic administration of the dopamine agonist apomorphine at clinically effective doses. Apomorphine induced a decrease in entropy measured in the inter-spike intervals of subthalamic neurons in 6 of the 8 neurons. This is the first report that anti-parkinsonian drugs affect non-linear features of neuronal firing in the basal ganglia of parkinsonian patients.
doi:10.1016/j.expneurol.2010.07.016
PMCID: PMC2939318  PMID: 20659454
nonlinear; firing pattern; interspike interval
23.  Dendritic Distributions of Dopamine D1 Receptors in the Rat Nucleus Accumbens are Synergistically Affected by Startle-Evoking Auditory Stimulation and Apomorphine 
Neuroscience  2007;146(4):1593-1605.
Prepulse inhibition of the startle response to auditory stimulation (AS) is a measure of sensorimotor gating that is disrupted by the dopamine D1/D2 receptor agonist, apomorphine. The apomorphine effect on prepulse inhibition is ascribed in part to altered synaptic transmission in the limbic-associated shell and motor-associated core subregions of the nucleus accumbens (Acb). We used electron microscopic immunolabeling of dopamine D1 receptors (D1Rs) in the Acb shell and core to test the hypothesis that region-specific redistribution of D1Rs is a short-term consequence of AS and/or apomorphine administration. Thus, comparisons were made in the Acb of rats sacrificed one hour after receiving a single subcutaneous injection of vehicle (VEH) or apomorphine (APO) alone or in combination with startle-evoking AS (VEH+AS, APO+AS). In both regions of all animals, the D1R immunoreactivity was present in somata and large, as well as small, presumably more distal dendrites and dendritic spines. In the Acb shell, compared with the VEH+AS group, the APO+AS group had more spines containing D1R immunogold particles, and these particles were more prevalent on the plasma membranes. This suggests movement of D1Rs from distal dendrites to the plasma membrane of dendritic spines. Small- and medium-sized dendrites also showed a higher plasmalemmal density of D1R in the Acb shell of the APO+AS group compared with the APO group. In the Acb core, the APO+AS group had a higher plasmalemmal density of D1R in medium-sized dendrites compared with the APO or VEH+AS group. Also in the Acb core, D1R-labeled dendrites were significantly smaller in the VEH+AS group compared to all other groups. These results suggest that alerting stimuli and apomorphine synergistically affect distributions of D1R in Acb shell and core. Thus adaptations in D1R distribution may contribute to sensorimotor gating deficits that can be induced acutely by apomorphine or develop over time in schizophrenia.
doi:10.1016/j.neuroscience.2007.04.005
PMCID: PMC1978178  PMID: 17490822
accumbens shell; immunogold; receptor trafficking; schizophrenia; sensorimotor gating; spine
24.  Apomorphine and psychopathology. 
Forty men, mainly alcoholics, were administered either the dopamine receptor agonist, apomorphine HCl (1 mg), or distilled water subcutaneously three times a day for 14 days in a double blind study. None of the subjects developed an endogenous depression or schizophrenic symptoms. Scores on the Hamilton Rating Scale, Zung Self Rating Scale, and Brief Psychiatric Rating Scale showed improvement with both apomorphine and placebo. There were no significant differences between the two treatments on these rating scales. A significant incidence of spontaneous penile erections occurred after apomorphine treatment compared with placebo. Both treatments eliminated subjective craving for alcohol. Acute administration of apomorphine had no effect on psychomotor retardation or depressed mood in two patients with endogenous depression.
PMCID: PMC1083255  PMID: 1099172
25.  The effects of acute levodopa withdrawal on motor performance and dopaminergic receptor sensitivity in patients with Parkinson's disease. 
The effects of acute levodopa withdrawal were studied in nine patients with levodopa related on-off oscillations. One patient withdrew from the study due to off period confusion and hallucinations. A marked deterioration in motor disability occurred in all patients following overnight withdrawal of levodopa and a further mild delayed deterioration was present over a mean withdrawal period of 44 hours. Patients with more severe disease were able to tolerate levodopa withdrawal for a shorter period of time than those with milder disease severity. The minimum therapeutic dose of subcutaneous apomorphine needed to produce a similar improvement in patients' mobility, before and after several days of drug withdrawal, did not differ, thus providing no clinical evidence for alterations in striatal dopamine receptor sensitivity after acute levodopa withdrawal.
PMCID: PMC1015058  PMID: 8331352

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