Doses Of Apomorphine Research Articles

Apomorphine: A potential modifier of amyloid deposition in Parkinson's disease?

Evidence from clinical and pathological studies suggests a role for both alpha-synuclein and amyloid-beta in the pathophysiology of dementia associated with PD. Recent work demonstrated improvement in memory and reduced amyloid-beta burden in transgenic murine Alzheimer's models given subcutaneous apomorphine. The aim of this work was to determine whether antemortem exposure to apomorphine was associated with lower levels of amyloid-beta in brain tissue in a clinicopathological study of PD. The case notes of donors with pathologically proven PD who had (n = 36) and had not received apomorphine (n = 35) during life for motor complications were reviewed to determine presence or absence of cognitive impairment. The four groups were well matched for disease duration, age at death, sex, and apolipoprotein E4 genotype. The severity of amyloid-beta mature/diffuse plaque load, tau pathology, and alpha-synuclein pathology were all established. Cerebral amyloid angiopathy was determined based on a four-tier grading system. Within the cognitively normal cases, significantly reduced amyloid-beta deposition was present in those with antemortem apomorphine exposure; this finding was not replicated in those with cognitive impairment plus previous apomorphine use. In the apomorphine cognitively normal group only, a significant negative association was observed between maximum apomorphine dose received and amyloid-beta burden. Early and maximum doses of apomorphine plus apolipoprotein genotype and sex were significant predictors of total plaque load in an explanatory model. This exploratory study suggests that apomorphine may have a modifying effect on amyloid deposition in nondemented PD cases and thus may represent a potential therapy to reduce cognitive impairment in PD. © 2015 Movement Disorder Society.

Effective delivery of apomorphine in the management of Parkinson disease: practical considerations for clinicians and Parkinson nurses.

The clinical utility of long-term oral levodopa therapy in Parkinson disease (PD) is often limited by the emergence of motor complications. Over time, many patients with PD experience regular and/or unpredictable "off" periods, despite taking optimized oral medication regimens, with a major negative impact on their ability to undertake routine activities of daily living and consequently on their overall quality of life. One established approach for treating patients experiencing off periods and controlling motor fluctuations refractory to conventional oral drug therapy is the subcutaneous administration of the dopaminergic agonist apomorphine. This article outlines how the pharmacokinetic properties of apomorphine underpin its efficacy for the treatment of PD and provides practical guidance for the 3 main approaches in which it is used: subcutaneous intermittent apomorphine injection as a "rescue" therapy for off states, subcutaneous continuous apomorphine infusion for PD patients with intractable motor fluctuations as an alternative to other dopaminergic treatment, and in the apomorphine response (or challenge) test for assessment of dopamine-induced motor response in patients thought to have PD, or in establishing the optimal tolerated dose of apomorphine in patients already known to have PD. Also discussed is the management of potential adverse events with subcutaneous administration of apomorphine, the majority of which are mild and easily managed in practice. The importance of a multidisciplinary PD team in the optimal management of PD patients is now recognized, in particular the role of the specialist PD nurse.

Dopamine receptors play distinct roles in sexual behavior expression of rats with a different sexual motivational tone.

Dopamine (DA) plays a central role in the expression of male sexual behavior. The effects of DA-enhancing drugs on copulation seem to vary depending on the dose of the agonist used, the type of DA receptor activated, and the sexual condition of the animals. The aim of the present study was to carry out a systematic analysis of the effects of dopaminergic agonists on the expression of male sexual behavior by sexually competent rats in different sexual motivational states, that is when sexually active (sexually experienced) and when temporarily inhibited (sexually exhausted). To this end, the same doses of the nonselective DA receptor agonist apomorphine, the selective D2-like DA receptor agonist quinpirole, and the selective D1-like DA receptor agonist SKF38393 were injected intraperitoneally to sexually experienced or sexually exhausted male rats and their sexual behavior was recorded. Low apomorphine doses induced expression of sexual behavior in sexually satiated rats, but only reduced the intromission latency of sexually experienced rats. SKF38393 facilitated the expression of sexual behavior by sexually exhausted rats, but not that of sexually experienced males and quinpirole did not exert an effect in both types of animal. In line with these results, the apomorphine-induced reversal of sexual exhaustion was blocked by the D1-like receptor antagonist SCH23390. The data suggest that DA receptors play distinct roles in the expression of sexual behavior by male rats depending on their motivational state and that activation of D1-like receptors promotes the expression of sexual behavior in satiated rats.

Place conditioning to apomorphine in rat models of Parkinson's disease: Differences by dose and side-effect expression

One potential complication of treating Parkinson's Disease (PD) with dopaminergic drugs is dopamine dysregulation syndrome, an addiction-like response to the drug therapy. Here, we assessed whether rats given parkinsonian-like symptoms with a unilateral injection of 6-hydroxydopamine into the medial forebrain bundle (6-OHDA-MFB), exhibit similar behavior. To examine this, we injected these rats or sham-lesioned rats subcutaneously (sc) with apomorphine (APO) at low (0.05mg/kg) and high (1mg/kg) dosage and monitored their conditioned place preference Saline was administered on alternating days. After 4 and 8 conditioned pairings, both rat groups underwent post-conditioning tests in a drug-free state 6-OHDA rats exhibited positive place conditioning to the low dose of APO after 4 and 8 pairings whereas sham-lesioned rats did not (p<0.01). At the high APO dose, sham-lesioned rats showed consistent positive place conditioning, but preferences in 6-OHDA rats were more variable although they all exhibited rotation behavior. Upon further inspection, we noted that contraversive rotation increased over time and this negatively correlated with place conditioning scores. While the absolute number of rotations did not negatively affect preference for the APO-paired chamber, an increase in rotation numbers between pairings did (r=−0.634, p=0.027). Taken together, 6-OHDA rats were more sensitive to the rewarding aspects of APO, but the adverse consequence of rotation diminished this response This model may be ideal to study addiction-like responses in PD.

Electrophysiological characterization of dopamine neuronal activity in the ventral tegmental area across the light-dark cycle.

Direct evidence that dopamine (DA) neurotransmission varies during the 24 h of the day is lacking. Here, we have characterized the firing activity of DA neurons located in the ventral tegmental area (VTA) using single-unit extracellular recordings in anesthetized rats kept on a standard light-dark cycle. DA neuronal firing activity was measured under basal conditions and in response to intravenous administration of increasing doses of amphetamine (AMPH: 0.5, 1, 2, 5 mg/kg), apomorphine (APO: 25, 50, 100, 200 µg/kg) and melatonin (MLT: 0.1, 1, 10 mg/kg) at different time intervals of the light-dark cycle. DA firing activity peaked between 07:00 and 11:00 h (3.5 ± 0.3 Hz) and between 19:00 and 23:00 h (4.1 ± 0.7 Hz), with lowest activity occurring between 11:00 and 15:00 h (2.4 ± 0.2 Hz) and between 23:00 and 03:00 h (2.6 ± 0.2 Hz). The highest number of spontaneously active neurons was observed between 03:00 and 06:00 h (2.5 ± 0.3 neurons/track), whereas the lowest was between 19:00 and 23:00 h (1.5 ± 0.2 neurons/track). The inhibitory effect of AMPH on DA firing rate was similar in both phases. The inhibitory effect of low dose of APO (25 μg/kg, dose selective for D2 autoreceptor) was more potent in the dark phase, whereas APO effects at higher doses were similar in both phases. Finally, MLT administration (1 mg/kg) produced a moderate inhibition of DA cell firing in both phases. These experiments demonstrate the existence of an intradiurnal rhythmic pattern of VTA DA neuronal firing activity and a higher pharmacological response of D2 autoreceptors in the dark phase.

TAAR1-dependent effects of apomorphine in mice.

G protein-coupled trace amine-associated receptor 1 (TAAR1) is expressed in several brain regions and modulates dopaminergic activity partially by affecting D2 dopamine receptor function. In vitro, the nonselective dopamine agonist apomorphine can activate mouse and rat TAAR1. The aim of the present study was to evaluate whether apomorphine activity at the rodent TAAR1 observed in in vitro studies contributes to its behavioral manifestation in mice. For this purpose, we compared the behavioral effects of a wide range of apomorphine doses in wild type (WT) and TAAR1 knockout (TAAR1-KO) mice. Apomorphine-induced locomotor responses (0.01-4.0mg/kg) were tested in locomotor activity boxes, and stereotypic behavior at 5mg/kg was tested by ethological methods. A gnawing test was used to analyze the effects of the highest dose of apomorphine (10mg/kg). No statistically significant differences were observed between TAAR1-KO and WT mice following inhibitory pre-synaptic low doses of apomorphine. At higher doses (2.0-5.0mg/kg), apomorphine-induced climbing behavior was significantly reduced in TAAR1 mutants relative to WT controls. Moreover, the lack of TAAR1 receptors decreased certain types of stereotypies (as reflected in by measures of the global stereotypy score, licking but not sniffing or gnawing) that were induced by high doses of apomorphine. These data indicate that apomorphine activity at TAAR1 contributes to some behavioral manifestations, particularly climbing, in rodents following high doses of this drug. The contribution of TAAR1 to apomorphine-induced climbing in rodents should be considered when apomorphine is used as a screening tool in the search for potential antipsychotics.

Le traitement par apomorphine en perfusion continue sous-cutanée dans la maladie de Parkinson : analyse rétrospective d’une série de 81 patients

BackgroundContinuous subcutaneous infusion of apomorphine (CAI) has shown efficacy in the treatment of motor fluctuations but its place in the therapeutic arsenal remains poorly defined in terms of indication, acceptability and long-term tolerance. Indeed, few studies have been carried out with a follow-up greater than 12 months. The main objective was to assess the quality of life of Parkinson's disease (PD) patients treated with CAI. We also evaluate the effectiveness on the motor fluctuations, the long-term tolerance of this treatment with its causes of discontinuation and the treatment regimens used. MethodsWe conducted a retrospective study of 81 PD patients treated with CAI between April 2003 and June 2012. Data were collected from medical records. A repeated measures analysis of variance by the linear mixed model was used (significance level: 5%). ResultsIn August 2012, 27/81 patients were still treated with CAI with a mean duration of 28 months, 46/81 discontinued CAI (9 precociously), and 8 were lost to view. We didn’t show improvement in the quality of life nor efficacy of CAI on the UPDRS IV score (P=0.54) and dyskinesia score (P=0.95). The CGI score patient also reflects this result with a majority response suggesting no significant change with CAI. We observed relative good cognitive and psychiatric tolerance. Adverse events were frequent but often benign. The average (±SD) rate of apomorphine was 3.15±1.71mg/h and the oral dopaminergic treatment was decreased by 37.8%. DiscussionThe results are consistent with the literature except for the lack of efficiency on motor fluctuations which may be due to the use of too small doses of apomorphine. This seems to be a leading cause of discontinuation of CAI, especially when it is associated with side effects or important constraints. For better efficiency on motor fluctuations, we recommend the use of apomorphine at higher doses to obtain an optimal continuous dopaminergic stimulation.

Drug memory substitution during re-consolidation: A single inhibitory autoreceptor apomorphine treatment given during psychostimulant memory re-consolidation replaces psychostimulant conditioning with conditioned inhibition and reverses psychostimulant sensitization

Psychostimulant conditioning and sensitization effects have proven to be difficult to eliminate using behavioral methods. We used a low autoreceptor dose of apomorphine in counter-conditioning and memory re-consolidation protocols to modify conditioned and sensitized responses induced by a high dose of apomorphine. Rats received five daily treatments of apomorphine (2.0mg/kg) and were tested in an arena for 30min to induce conditioning and sensitization. Conditioning was validated in a brief 5min non-drug conditioning test and sensitization by a 2.0 apomorphine challenge test. Next, the counter-conditioning and memory re-consolidation protocols were initiated. In counter-conditioning, vehicle or 0.05mg/kg apomorphine was given either 15min or immediately before a 5min arena test. In the memory re-consolidation protocol, the vehicle and 0.05 apomorphine treatments were administered post-trial either immediately after or 15min after the 5min arena test. Effects were assessed with a 5min saline conditioning test and a second 2.0mg/kg apomorphine challenge test. The counter-conditioning protocol induced hypolocomotion and but did not induce a conditioned hypo-locomotion and did not alter the sensitized response. The 15min post-trial treatment did not affect either the conditioned or the sensitized responses. The immediate post-trial treatment eliminated sensitization and induced a conditioned hypoactivity response. These results highlight the memory re-consolidation period as a critical target for drug memory substitution and suggest the potential utility of the pharmacological inhibition of dopamine activity given as a therapeutic drug memory replacement during addictive drug memory re-consolidation.

Clinical effects of an intravenous apomorphine protocol in Parkinson disease

protocol of apomorphine produces detectable biological effect (increased growth hormone concentration) but negligible clinical effect (tapping speed and expert rated of parkinsonism) • We do not have much power to detect a difference in tapping scores in 8 subjects, however the difference likely does not exceed 5 taps/min • Although this dose produces reliable increases of GH in PD and controls, a higher dose of apomorphine, or a larger sample size, may be needed to detect significant motor improvement in PD. • The results suggest there are advantages and disadvantages to this dosing schedule: • Disadvantage: minimal effect in the clinical assay • Advantages: • well tolerated • detectable effect on hypothalamic DA receptors • imaging changes with this protocol could be interpreted as directly drug-induced rather than as indirect effects of a change in PD motor function or patient comfort • Moderately severe PD (modified UPDRS, apo day 22.1 + 6.3; saline day 21.7 + 7.7, mean + SD) • No significant differences between post infusion drug and saline UPDRS scores (apo: 21.7 + 7.7; saline 24.0 + 2.2) • No significant improvement in tapping speed with apomorphine (apo 2.2 + 7.2 clicks/min; saline 2.3 + 5.0 [95% C.I. for difference = -5.1 to +4.9]) • GH level was significantly higher after apomorphine than after saline (apo: 1.43 + 2.1 ng/mL; saline: 0.27 + 0.5, p = 0.04; see graph)

Dopamine agonist-induced penile erection and yawning: A comparative study in outbred Roman high- and low-avoidance rats

The effects on penile erection and yawning of subcutaneous (SC) injections of the mixed dopamine D1/D2-like agonist apomorphine (0.02–0.2mg/kg) were studied in outbred Roman high- (RHA) and low-avoidance (RLA) male rats, two lines selectively bred for their respectively rapid versus poor acquisition of the active avoidance response in the shuttle-box, and compared with the effects observed in male Sprague–Dawley (SD) rats. Apomorphine dose–response curves were bell-shaped in all rat lines/strains. Notably, more penile erections and yawns were recorded mainly in the ascending part of these curves (e.g., apomorphine 0.02–0.08mg/kg) in both RLA and RHA rats compared to SD rats, with RLA rats showing the higher response (especially for yawning) with respect to RHA rats. Similar results were found with PD-168,077 (0.02–0.2mg/kg SC), a D4 receptor agonist, which induced penile erection but not yawning. In all rat lines/strains, apomorphine responses were markedly reduced by the D2 antagonist L-741,626, but not by the D3 antagonist, SB277011A, whereas the D4 antagonists L-745,870 and FAUC213 elicited a partial, yet statistically significant, inhibitory effect. In contrast, the pro-erectile effect of PD-168,077 was completely abolished by L-745,870 and FAUC213, as expected. The present study confirms and extends previously reported differences in dopamine transmission between RLA and RHA rats and between the SD strain and the Roman lines. Moreover, it confirms previous studies supporting the view that dopamine receptors of the D2 subtype play a predominant role in the pro-yawning and pro-erectile effect of apomorphine, and that the selective stimulation of D4 receptors induces penile erection.

MCH and apomorphine in combination enhance action potential firing of nucleus accumbens shell neuronsin vitro

The MCH and dopamine receptor systems have been shown to modulate a number of behaviors related to reward processing, addiction, and neuropsychiatric conditions such as schizophrenia and depression. In addition, MCH and dopamine receptors can interact in a positive manner, for example in the expression of cocaine self-administration. A recent report (Chung et al., 2011a) showed that the DA1/DA2 dopamine receptor activator apomorphine suppresses pre-pulse inhibition, a preclinical model for some aspects of schizophrenia. Importantly, MCH can enhance the effects of lower doses of apomorphine, suggesting that co-modulation of dopamine and MCH receptors might alleviate some symptoms of schizophrenia with a lower dose of dopamine receptor modulator and thus fewer potential side effects. Here, we investigated whether MCH and apomorphine could enhance action potential firing in vitro in the nucleus accumbens shell (NAshell), a region which has previously been shown to mediate some behavioral effects of MCH. Using whole-cell patch-clamp electrophysiology, we found that MCH, which has no effect on firing on its own, was able to increase NAshell firing when combined with a subthreshold dose of apomorphine. Further, this MCH/apomorphine increase in firing was prevented by an antagonist of either a DA1 or a DA2 receptor, suggesting that apomorphine acts through both receptor types to enhance NAshell firing. The MCH/apomorphine-mediated firing increase was also prevented by an MCH receptor antagonist or a PKA inhibitor. Taken together, our results suggest that MCH can interact with lower doses of apomorphine to enhance NAshell firing, and thus that MCH and apomorphine might interact in vivo within the NAshell to suppress pre-pulse inhibition.

Postnatal manganese exposure does not alter dopamine autoreceptor sensitivity in adult and adolescent male rats

Administering manganese chloride (Mn) to rats on postnatal day (PD) 1–21 causes long-term reductions in dopamine transporter levels in the dorsal striatum, as well as a persistent increase in D1 and D2 receptor concentrations. Whether dopamine autoreceptors change in number or sensitivity is uncertain, although D2S receptors, which may be presynaptic in origin, are elevated in Mn-exposed rats. The purpose of this study was to determine if early Mn exposure causes long-term changes in dopamine autoreceptor sensitivity that persist into adolescence and adulthood. To this end, male rats were exposed to Mn on PD 1–21 and autoreceptor functioning was tested 7 or 70 days later by measuring (a) dopamine synthesis (i.e., DOPA accumulation) in the dorsal striatum after quinpirole or haloperidol treatment and (b) behavioral responsiveness after low-dose apomorphine treatment. Results showed that low doses (i.e., “autoreceptor” doses) of apomorphine (0.06 and 0.12mg/kg) decreased the locomotor activity of adolescent and adult rats, while higher doses increased locomotion. The dopamine synthesis experiment also produced classic autoreceptor effects, because quinpirole decreased dorsal striatal DOPA accumulation; whereas, haloperidol increased DOPA levels in control rats, but not in rats given the nerve impulse inhibitor γ-butyrolactone. Importantly, early Mn exposure did not alter autoreceptor sensitivity when assessed in early adolescence or adulthood. The lack of Mn-induced effects was evident in both the dopamine synthesis and behavioral experiments. When considered together with past studies, it is clear that early Mn exposure alters the functioning of various dopaminergic presynaptic mechanisms, while dopamine autoreceptors remain unimpaired.

Effects of dopamine receptor agonist and antagonists on cholestasis-induced anxiolytic-like behaviors in rats

Dysfunctions in the dopamine transmission system have been suggested to contribute to the pathogenesis of hepatic encephalopathy. In an experimental animal model, cholestasis induction through bile duct ligation may present several main pathological features of hepatic encephalopathy. Dopaminergic systems are shown to play pivotal roles in regulation of anxiety-like behaviors. The main bile duct in male Wistar rats, weighing 220–240g, was ligated using two ligatures plus duct transection in between. Anxiety-like behaviors were measured using the elevated plus maze task. Cholestasis increased the open arm time percentage (%OAT), 13 but not 10 days after bile duct ligation, indicating an anxiolytic-like effect. Sole intraperitoneal injection of apomorphine (dopamine D1/D2 receptor agonist, 0.25mg/kg), SCH23390 (dopamine D1 receptor antagonist, 0.005, 0.01 and 0.02mg/kg) or sulpiride (dopamine D2 receptor antagonist, 0.125, 0.25 and 0.5mg/kg) did not alter %OAT, open arm entries percentage (%OAE) and locomotor activity in the sham-operated rats. Meanwhile, the higher dose apomorphine (0.5mg/kg) induced anxiolytic-like behaviors in this group. The subthreshold dose injection of SCH23390 or sulpiride, partially reversed the anxiolytic-like behaviors induced by cholestasis (13 days after bile duct ligation). On the other hand, subthreshold dose of apomorphine in cholestatic rats (10 days post bile duct ligation) induced anxiolytic-like effects which could be blocked by SCH23390 or sulpiride. The effective doses of above drugs did not alter locomotor activity, number of rearings, groomings and defections. These findings suggested that the dopaminergic system may potentially be involved in the modulation of cholestasis-induced anxiolytic-like behaviors in rats.

Phase IIa randomized double‐blind, placebo‐controlled study of inhaled apomorphine as acute challenge for rescuing ‘off’ periods in patients with established Parkinson's disease

In this first study of inhaled apomorphine (VR040) in patients with Parkinson's disease, the primary objective was to find the minimum efficacious dose of apomorphine that was useful in rescuing patients during 'off' periods. Safety, tolerability and pharmacokinetics of inhaled apomorphine were assessed during the study. A double-blind, placebo-controlled, randomized trial of three escalating single doses of inhaled apomorphine (0.2, 0.5 and 0.8 mg fine particle dose) versus placebo (3 : 1 active:placebo) was performed. Parkinson's motor severity assessments by a clinician, and disease state assessment by the patient, were performed at baseline during an 'off' state, and at specified times after test drug administration. Safety assessments (including vital signs, electrocardiogram and forced expiratory volume) were performed, and plasma apomorphine levels measured. All 24 patients completed the study, and considering the three dose levels together, inhaled apomorphine did not significantly increase the proportion of patients switching from 'off' to 'on' (0/6 at 0.2 mg, 3/6 at 0.5 mg and 2/6 at 0.8 mg vs. 1/6 for placebo), or decrease the time from 'off' to 'on' post-treatment (10 min for 0.5 mg, 40 min for 0.8 mg, vs. 20 min for placebo). However, there was a suggestion of benefit at the higher doses (5/12 switched 'on' at the 0.5 or 0.8 mg doses, vs. 1/6 for placebo). There were no serious adverse events and treatment was well tolerated. Peak plasma concentration was 1-3 min post-dose, and plasma level dose proportionality was observed. Inhaled apomorphine was safe and well tolerated at the doses tested for an acute challenge to rescue 'off' periods, but efficacy at these doses was limited. A follow-up study at higher doses is appropriate given these initial findings.

Antidepressant-like effect of ursolic acid isolated from Rosmarinus officinalis L. in mice: Evidence for the involvement of the dopaminergic system

Ursolic acid, a constituent from Rosmarinus officinalis, is a triterpenoid compound which has been extensively known for its anticancer and antioxidant properties. In the present study, we investigated the antidepressant-like effect of ursolic acid isolated from this plant in two predictive tests of antidepressant property, the tail suspension test (TST) and the forced swimming test (FST) in mice. Furthermore, the involvement of dopaminergic system in its antidepressant-like effect was investigated in the TST. Ursolic acid reduced the immobility time in the TST (0.01 and 0.1mg/kg, p.o.) and in the FST (10mg/kg, p.o.), similar to fluoxetine (10mg/kg, p.o.), imipramine (1mg/kg, p.o.) and bupropion (10mg/kg, p.o.). The effect of ursolic acid (0.1mg/kg, p.o.) in the TST was prevented by the pretreatment of mice with SCH23390 (0.05mg/kg, s.c., a dopamine D1 receptor antagonist) and sulpiride (50mg/kg, i.p., a dopamine D2 receptor antagonist). The administration of a sub-effective dose of ursolic acid (0.001mg/kg, p.o.) in combination with sub-effective doses of SKF38393 (0.1mg/kg, s.c., a dopamine D1 receptor agonist), apomorphine (0.5μg/kg, i.p., a preferential dopamine D2 receptor agonist) or bupropion (1mg/kg, i.p., a dual dopamine/noradrenaline reuptake inhibitor) reduced the immobility time in the TST as compared with either drug alone. Ursolic acid and dopaminergic agents alone or in combination did not cause significant alterations in the locomotor and exploratory activities. These results indicate that the antidepressant-like effect of ursolic acid in the TST is likely mediated by an interaction with the dopaminergic system, through the activation of dopamine D1 and D2 receptors.

Post-trial apomorphine at an autoreceptor dose level can eliminate apomorphine conditioning and sensitization: Support for the critical role of dopamine in re-consolidation

Re-exposure to conditioned drug stimuli triggers re-consolidation processes. In the present study post-trial apomorphine treatments were administered in order to interact with the re-consolidation of an apomorphine conditioned/sensitized locomotor response. A low (0.05mg/kg) and a high (2.0mg/kg) dose were used to inhibit or to enhance dopamine activity, respectively. Initially, groups received 5 daily apomorphine (2.0mg/kg)/vehicle treatments either paired or unpaired to open-field placement. The paired treatments generated a progressive locomotor response. Subsequently, all groups received a 5min non-drug test for conditioning and a conditioned locomotor response was observed in the paired group. The groups received another apomorphine (2.0mg/kg)/vehicle treatment as a re-induction treatment. At this stage the post-trial protocol was initiated. One set of paired, unpaired and vehicle groups were given a low dose of apomorphine (0.05mg/kg) post-trial; another set received a high dose of apomorphine (2.0mg/kg) post-trial. The remaining group set received vehicle post-trial. The low dose post-trial treatment eliminated the conditioned and sensitized locomotor response and the high dose post-trial treatment enhanced the conditioned and sensitized locomotor response. The efficacy of the post-trial apomorphine treatments to modify the conditioned and the sensitized response after a brief non-drug exposure to test cues supports the proposition that exteroceptive cues control conditioning and sensitization and that the interoceptive drug cues make little or no associational contribution to apomorphine conditioning and sensitization. In addition, the findings point to the importance of dopamine activation in both the acquisition and re-consolidation of conditioning processes.

Antidepressant-like effect of creatine in mice involves dopaminergic activation

Creatine has been shown to play a significant role in health and disease. However, studies concerning its effect on mood are scarce. This study investigated the effect of creatine (p.o.) in the tail suspension test, a predictive test of antidepressant activity. Creatine reduced the immobility time in the tail suspension test (0.1-1000 mg/kg, male and female mice), without affecting locomotor activity. Furthermore, the involvement of the dopaminergic system in creatine-induced antidepressant-like effect in male mice in the tail suspension test was investigated. The anti-immobility effect of creatine (1 mg/kg) was prevented by the pre-treatment of mice with haloperidol (0.2 mg/kg, intraperitoneal (i.p.) route, non-selective dopamine receptor antagonist), (R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390; 0.05 mg/kg, subcutaneous (s.c.) route, dopamine D₁ receptor antagonist) and sulpiride (50 mg/kg, i.p., dopamine D₂ receptor antagonist). Creatine (0.01 mg/kg, sub-effective dose) in combination with sub-effective doses of (1-phenyl-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine) hydrochloride (SKF38393; 0.1 mg/kg, s.c., dopamine D₁ receptor agonist), apomorphine (0.5 µg/kg, i.p., preferential dopamine D₂ receptor agonist) or bupropion (1 mg/kg, p.o., dopamine reuptake inhibitor with subtle activity on noradrenergic reuptake) reduced the immobility time in the tail suspension test as compared with either drug alone. These results indicate that the antidepressant-like effect of creatine is likely mediated by an activation of dopamine D₁ and D₂ receptors.

Apomorphine injections: Predictors of initial common adverse events and long term tolerability

BackgroundApomorphine injections effectively abort “off” episodes in Parkinson’s disease (PD). However, their use is limited by actual and perceived adverse events (AE). To our knowledge, no study has evaluated for predictors of these problems. ObjectivesTo assess predictors of initial common AE and long-term tolerability of apomorphine injections in PD. MethodsWe prospectively monitored for AE in 28 consecutive PD patients receiving initial apomorphine injections. Sequential visual analogue scale scores for nausea and in standing systolic blood pressure drops at baseline (mean of 2 assessments), 10, 20, and 40min post-injection were acquired. Assessed historic variables included patient demographics and clinical data, treatment histories, previous AE to other dopaminergic treatments and whether patients received the recommended three day pre-treatment dose of trimethobenzamide. We also correlated the L-dopa equivalent doses with apomorphine dose needed to turn “on”. ResultsNo patient demographic or previous history of dopaminergic AE predicted nausea, except for baseline pre-injection nausea that day at baseline. Three days of trimethobenzamide, as recommended, was actually associated with more nausea than a single dose or no dose, even though a lack of association after matched analysis was found. A younger patient age was associated with hypotension. L-dopa equivalent dose modestly correlated with final apomorphine dose to turn “on”. ConclusionA previous history of nausea and hypotension, and older age should not dissuade a trial of apomorphine if clinically justified. A three day pre-treatment dose of trimethobenzamide, as recommended in the United States, does not reduce nausea.

Studies of interferences of apomorphine and its metabolites or decomposition products with immunochemical screening tests for legal and illicit drugs after therapeutic doses of apomorphine.

This study deals with the question of whether apomorphine (CAS 314-19-2; e.g. in Ixense) and its metabolites or decomposition products interfere with the specificity of immunochemical screening tests (immunoassays) for legal and illicit drugs. It was the result of the investigations that after the therapeutic use of apomorphine no relevant false-positive screening findings were observed with the CEDIA (cloned enzyme donor immuno assay) and FPIA (fluorescence polarisation immuno assay) tests, which are commonly encountered in drug-screening programs, when using recommended cut-off values for urine.

Behavioural Effects of Thieno and Pyrazolo[2,1] benzothiazepine Derivatives in Mice

Behavioural studies were conducted in mice with a number of hetero[2,1]benzothiazepine derivatives, analogues of tianeptine. Previously published studies in mice have shown that some of these compounds were effective in the tetrabenazine and Porsolt tests. In the present study, four of the 15 compounds under study potentiated the actions of 5-hydroxytryptophan (5-HTP, 50 mg/kg i.p.), but no significant antagonism of the apomorphine (16 mg/kg s.c.)-induced hypothermia and potentiation of the amphetamine actions was found. Moreover, some of them inhibited the stereotyped behaviour and/or climbing behaviour of low doses of apomorphine and compound 2 was effective in the plus-maze test. These compounds also produced a slight inhibition of exploratory behaviour in the holeboard test. On the other hand, no significant muscle relaxant and anticonvulsant activities were observed at any dose employed. Together, these data suggest that some of the compounds under study combine the antidepressant effects with additional neuroleptic or anxiolytic activities in mice.