Search

Interaction of cannabinoid receptor type 1 (CB1) and GABAergic neuronal activity is involved in drug abuse-related behavior. However, its role in drug-dependent Pavlovian conditioning is not well understood. In this study, we aimed to evaluate the effects of a CB1 agonist, JWH-210, on the development of conditioned place preference (CPP)-induced by methamphetamine (METH). Pretreatment with a synthetic cannabinoid, JWH-210 (CB1 agonist), increased METH-induced CPP score and METH-induced dopamine release in acute striatal slices. Interestingly, CB1 was expressed in glutamate decarboxylase 67 (GAD67) positive cells, and overexpression of CB1 increased GAD67 expression, while CB1 knockdown reduced GAD67 expression in vivo and in vitro. GAD67 is known as an enzyme involved in the synthesis of GABA. CB1 knockdown in the mice striatum increased METH-induced CPP. When GAD67 decreased in the mice striatum, mRNA level of CB1 did not change, suggesting that CB1 can regulate GAD67 expression. GAD67 knockdown in the mouse striatum augmented apomorphine (dopamine receptor D2 agonist)-induced climbing behavior and METH-induced CPP score. Moreover, in the human brain, mRNA level of GAD67 was found to be decreased in drug users. Therefore, we suggest that CB1 potentiates METH-induced CPP through inhibitory GABAergic regulation of dopaminergic neuronal activity.

The 20% ethanol extract of Polygala tenuifolia, Angelica tenuissima, and Dimocarpus longan (WIN-1001X) was derived from a modified version of Korean traditional herbal formula 'Chungsimyeolda-tang' which has been used for the treatment of cerebrovascular disorders. The Parkinson's disease presents with impaired motor functions and loss of dopaminergic neurons. However, the treatment for Parkinson's disease is not established until now. This study aims to elucidate the therapeutic advantages of WIN-1001X on animal models of Parkinson's disease. WIN-1001X administration successfully relieved the Parkinsonism symptoms in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease mice tested by rota-rod and pole tests. The loss of tyrosine hydroxylase activities in substantia nigra and striatum was also attenuated by administration of WIN-1001X. In mice with sub-chronical MPTP injections, autophagy-related proteins, such as LC3, beclin-1, mTOR, and p62, were measured using the immunoblot assay. The results were favorable to induction of autophagy after the WIN-1001X administration. WIN-1001X treatment on 6-hydroxydopamine-injected rats also exhibited protective effects against striatal neuronal damage and loss of dopaminergic cells. Such protection is expected to be due to the positive regulation of autophagy by administration of WIN-1001X with confirmation both in vivo and in vitro. In addition, an active compound, onjisaponin B was isolated and identified from WIN-1001X. Onjisaponin B also showed significant autophagosome-inducing effect in human neuroblastoma cell line. Our study suggests that relief of Parkinsonism symptoms and rescue of tyrosine hydroxylase activity in dopaminergic neurons are affected by autophagy enhancing effect of WIN-1001X which the onjisaponin B is one of the major components of activity., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Introduction: Female sexual arousal disorder (FSAD) can be caused by the change in vaginal structure due to the decline of estrogen and one of the main symptoms is vaginal dryness. FSAD is a prevalent problem afflicting women all over the world and thus the interest is growing on the matter, but related studies of monitoring FSAD using a non-invasive optical method barely have been carried out., Aim: This study aims to investigate the longitudinal changes in female sexual arousal response induced by apomorphine (APO) administration in the ovariectomized rat using near-infrared spectroscopy (NIRS) probe., Methods: To elicit sexual arousal, APO was administered subcutaneously to animals (n = 6) before and after ovariectomy, and the changes in oxyhemoglobin (OHb), deoxyhemoglobin (RHb), total hemoglobin (THb) concentration, and temperature on the vaginal wall after APO administration were monitored bi-weekly for 8 weeks. Furthermore, estradiol hormone, vaginal secretion, and body weight have been measured for comparison with the results from vaginal hemodynamics., Results: APO administration caused the increase of vaginal OHb and RHb concentration but a decrease in temperature. The amplitude of OHb, RHb, and THb increase induced by APO gradually decreased over 8 weeks after ovariectomy while the decrease in vaginal temperature became profound. The level of estradiol and vaginal secretions also decreased over 8 weeks after ovariectomy, but bodyweight showed an increasing trend., Conclusions: A comparison between the parameters measured from the NIRS probe and the others (estradiol level, amount of vaginal secretion, and body weight) proved that the NIRS has the potential as a monitoring tool to evaluate female sexual arousal response. Jeong H, Lee HS, Seong M, et al. Changes of Apomorphine-Induced Vaginal Hemodynamics in an Ovariectomized Rat Model Using Near-Infrared Spectroscopic Probe. J Sex Med 2021;18:1328-1336., (Copyright © 2021 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Schizophrenia modeling by disrupting prepulse inhibition (PPI) is one of the most frequently used psycho-pharmacological methods by administering pharmacological agents to stimulate disruption. However, since PPI is also a biological indicator of schizophrenia, it is possible to classify subjects based on their basal PPI values and group them as "low inhibition" and "high inhibition without taking any pharmacological agent. Therefore this study was conducted to show that rats can be divided into groups in terms of susceptibility to schizophrenia according to basal PPI values. It was also observed that these groups might give different responses to different pharmacological agents (apomorphine, amphetamine, MK-801, scopolamine, nicotine, caffeine). Male Sprague Dawley rats (250-350 g) were used in the study. To examine the effects of different pharmacological agents on the groups, apomorphine (0.5 mg/kg and 1 mg/kg), amphetamine (4 mg/kg), MK-801 (0.05 mg/kg and 0.15 mg/kg), scopolamine (0.4 mg/kg), nicotine (1 mg/kg) and caffeine (10 mg/kg and 30 mg/kg) were used. Amphetamine showed a disruptive effect on PPI in both low and high inhibitory groups, while apomorphine, MK-801, scopolamine, and nicotine showed PPI decrease only in the high inhibitory group. Besides, caffeine decreased PPI levels at two doses in the high inhibitory group; however, 10 mg/kg dose caffeine was increased only in the low inhibitory group. According to the data obtained from this study, rats can be grouped with baseline inhibition values by using PPI, and response differences of pharmacological agents to groups may vary., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Temperature passively affects biological processes involved in plant growth. Therefore, it is challenging to study the dedicated temperature signalling pathways that orchestrate thermomorphogenesis, a suite of elongation growth-based adaptations that enhance leaf-cooling capacity. We screened a chemical library for compounds that restored hypocotyl elongation in the pif4-2-deficient mutant background at warm temperature conditions in Arabidopsis thaliana to identify modulators of thermomorphogenesis. The small aromatic compound 'Heatin', containing 1-iminomethyl-2-naphthol as a pharmacophore, was selected as an enhancer of elongation growth. We show that ARABIDOPSIS ALDEHYDE OXIDASES redundantly contribute to Heatin-mediated hypocotyl elongation. Following a chemical proteomics approach, the members of the NITRILASE1-subfamily of auxin biosynthesis enzymes were identified among the molecular targets of Heatin. Our data reveal that nitrilases are involved in promotion of hypocotyl elongation in response to high temperature and Heatin-mediated hypocotyl elongation requires the NITRILASE1-subfamily members, NIT1 and NIT2. Heatin inhibits NIT1-subfamily enzymatic activity in vitro and the application of Heatin accordingly results in the accumulation of NIT1-subfamily substrate indole-3-acetonitrile in vivo. However, levels of the NIT1-subfamily product, bioactive auxin (indole-3-acetic acid), were also significantly increased. It is likely that the stimulation of hypocotyl elongation by Heatin might be independent of its observed interaction with NITRILASE1-subfamily members. However, nitrilases may contribute to the Heatin response by stimulating indole-3-acetic acid biosynthesis in an indirect way. Heatin and its functional analogues present novel chemical entities for studying auxin biology., (© 2021 The Authors. The Plant Journal published by Society for Experimental Biology and John Wiley & Sons Ltd.)

The emission of ultrasonic vocalizations (USVs) is thought to communicate the behavioral and emotional states elicited in rodents by social and non-social stimuli. On this basis, studies of psychopharmacology in rats are increasingly utilizing USVs as a behavioral marker to evaluate the effects of drugs on the emotional state. Conversely, very limited information is available as to whether psychoactive drugs influence USV emissions in mice. To provide new insights in this respect, we evaluated the emission of USVs in C57BL/6J mice subjected to repeated treatment with the dopaminergic psychostimulant of abuse amphetamine. Mice were first allowed to perform social contacts in dyads, and 2 days later they received amphetamine (1-4 mg/kg, i.p.) in a test cage (× 5 administrations) on alternate days. Seven days after treatment discontinuation, mice were re-exposed to the test cage to evaluate whether the presentation of drug-paired environmental cues elicited calling behavior, and thereafter received an amphetamine challenge. An additional group of animals received the dopamine receptor agonist apomorphine (1-4 mg/kg, i.p.), to further clarify the role of dopamine transmission in calling behavior of mice. C57BL/6J mice emitted USVs during social contacts, but did not significantly vocalize after amphetamine administration, in response to amphetamine-paired environmental cues, and after apomorphine administration. These results indicate that C57BL/6J mice may respond differently to social and pharmacological stimuli in terms of USV emissions, and may lay the foundation for future studies aimed at clarifying whether USVs may be a useful behavioral marker in studies of psychopharmacology in mice., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: We previously reported that the combination of the dopamine (DA) receptor agonist apomorphine and the 5-hydroxytryptamine (5-HT 2 ) receptor agonist m-chlorophenylpiperazine (m-CPP) in rats potently and selectively facilitates the ejaculatory response through activation of D 2 -like and 5-HT 2C receptors, respectively., Aim: The aim of this study was to clarify the target level of the proejaculatory effects induced by combination of these agonists., Methods: For in vivo behavioral studies, apomorphine and m-CPP were given intracerebroventricularly and intrathecally alone or in combination with either drug administered systemically. Male rats were acclimated to observational cages bedded in paper towels, and the occurrence of ex copula ejaculation was assessed by evaluating the presence and weight of ejaculatory plugs dropped from the tip of the penis to the paper towels or adhered to the tip of the penis at 30 min after drug administration. For in vitro contraction studies, seminal vesicles isolated from rats were suspended in an organ bath to test contractile responses to drug combinations, and the effects of the combined drugs on the contractile response of noradrenaline were also tested., Main Outcome Measures: The presence and weight of ejaculatory plugs produced by drug-induced ejaculation and the contractile responses of the seminal vesicle were evaluated., Results: Intrathecal m-CPP (10 μg), but not intracerebroventricular m-CPP, evoked the synergistic effects on ejaculation when used in combination with systemically administered apomorphine (0.1 mg/kg, subcutaneous). Moreover, the synergy between m-CPP and apomorphine was completely abolished by the intrathecal 5-HT 2C receptor antagonist SB242084 (10 μg). Intrathecal or intracerebroventricular apomorphine (1-10 μg) evoked proejaculatory effects in combination with systemically administered m-CPP (0.3 mg/kg, intraperitoneal). The selective peripherally acting D 2 -like receptor agonist carmoxirole did not evoke ejaculation when used in combination with m-CPP. Furthermore, isolated rat seminal vesicles were completely insensitive to the combination of apomorphine and m-CPP., Conclusion: These results indicated that the synergistic effects of the drugs on ejaculation were induced at the central level but not at peripheral sites. Our findings also suggested that the 5-HT 2C receptor mediated the stimulation of the spinal ejaculatory pattern generator and was synergistically potentiated by the spinal DA receptor and that activation of the supraspinal DA receptor was also involved in mediating these synergistic effects. Yoshizumi M, Yonezawa A, Kimura Y, et al. Central Mechanisms of Apomorphine and m-Chlorophenylpiperazine on Synergistic Action for Ejaculation in Rats. J Sex Med 2021;18:231-239., (Copyright © 2020 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Parkinson's disease (PD) is a disorder characterized by a progressive loss of the dopaminergic neurons in the substantia nigra and a depletion of the neurotransmitter dopamine in the striatum. Our published results indicate that fasciculation and elongation protein zeta-1 (FEZ1) plays a role in the astrocyte-mediated protection of dopamine neurons and regulation of the neuronal microenvironment during the progression of PD. In this study, we examined the effects of engrafted type-2 astrocytes (T2As) with high expression of FEZ1 on the improvement of the symptoms and functional reconstruction of PD rats. T2As were stereotactically transplanted into the striatum of rats with PD induced by 6-hydroxydopamine (6-OHDA). An examination of apomorphine (APO)-induced rotations was performed to evaluate dopamine neuron damage and motor functions. Remarkably, the grafted cells survived in the lesion environment for six weeks or longer after implantation. In addition, the transplantation of T2As decrease the average velocity and the duration time of the APO-induced rotations, and increase the actuation time, as measured in the rotation behavioural tests. In the substantia nigra, the transplantation of T2As reduced the PD-induced GFAP, TH and FEZ1 downregulation. The grafted cells exclusively migrated to other regions near the injection site in the striatum and differentiated into GFAP + astrocytes or TH + neurons. Furthermore, by detecting monoamine neurotransmitters through high-performance liquid chromatography, we found that the nigrostriatal pathway had been repaired to some extent. Taken together, these results suggest that engrafted T2As with high expression of FEZ1 improved the symptoms and functional reconstruction of PD rats, providing a theoretical basis for FEZ1 as a potential target and engraftment of T2As as a therapeutic strategy in the treatment of PD.

Introduction: The randomized, double-blind phase (DBP) of the TOLEDO study confirmed the efficacy of apomorphine infusion (APO) in reducing OFF time in PD patients with persistent motor fluctuations despite optimized oral/transdermal therapy. Here we report safety and efficacy results including the 52-week open-label phase (OLP)., Methods: All patients completing the 12-week DBP (including those switching early to open-label treatment) were offered OLP entry. The primary objective was the evaluation of long-term safety of APO., Results: Eighty-four patients entered the OLP (40 previously on APO, 44 on placebo) and 59 patients (70.2%) completed the study. The safety profile of APO was consistent with experience from extensive clinical use. Common treatment-related adverse events (AEs) were mild or moderate infusion site nodules, somnolence and nausea. Fourteen (16.7%) patients discontinued the OLP due to AEs, those involving >1 patient were infusion site reactions (n = 4) and fatigue (n = 2); hemolytic anemia occurred in one case. Reduction in daily OFF time and improvement in ON time without troublesome dyskinesia were sustained for up to 64 weeks. Pooled data for week 64 (n = 55) showed a mean (SD) change from DBP baseline in daily OFF time of -3.66 (2.72) hours and in ON time without troublesome dyskinesia of 3.31 (3.12) hours. Mean (±SD) daily levodopa-equivalent dose decreased from DBP baseline to week 64 by 543 mg (±674) and levodopa dose by 273 mg (±515)., Conclusions: The safety and efficacy of APO infusion were demonstrated with long-term use for persistent motor fluctuations, allowing substantial reductions in oral PD medication., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Blueberries (BB) are rich in antioxidant polyphenols, and their intake could prevent Parkinson's disease (PD). Here we assessed whether rats chronically fed dried raw BB develop resistance to dopaminergic denervation and motor disorders caused by unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA), a dopaminergic neurotoxin acting mainly by inducing oxidative stress. Male rats were fed either with LabDiet® alone or supplemented with 3% lyophilized raw BB for 2 weeks before and 3 weeks after injecting 6-OHDA (day 0) or vehicle (mock lesion) into the right striatum. The cylinder test was performed on days -14, -7, -1, +7, +14, and +21; the percentage of ipsilateral forepaw (IF) use asymmetry was determined by counting the wall contacts made with either forepaw or with both. Apomorphine (0.25 mg/kg, s.c.)-induced rotation was performed on days -1, +7, +14, and +21. Full contralateral rotations were counted in 3-min periods, every 15 min, up to 90 min. Striatal slices were immunostained for tyrosine hydroxylase (TH) and the ionized calcium-binding protein-1 adapter (Iba1) [immunoreactive area or microglia count in right striatum expressed as % of the left striatum]. Antioxidants in BB methanolic extracts neutralized the free radical 2,2-diphenyl-1-picrylhydrazyl in a concentration-dependent manner. Anthocyanins have been reported as the most abundant polyphenols in BB. Using the pH differential method, the total anthocyanin content (malvidin-3-glucoside equivalents) in raw BB averaged 21.04 mg/g dry weight. The range of anthocyanin intake by rats throughout the study varied from 37.7 to 72.2 mg/kg body weight. The time and food type factors, as well as their interaction were significant according to two-way RM-ANOVA in both the apomorphine-induced rotations and the cylinder test. Compared with LabDiet® alone, chronic supplementation with 3% dried raw BB decreased apomorphine-induced rotations on days +14 and +21 (p < 0.001) and produced a 46% reduction in total rotations post-surgery (p < 0.05), but only caused a partial, non-significant, decrease of IF asymmetry. BB supplementation reduced TH loss in the striatum (p < 0.05) but did not attenuate the increase of Iba1 + microglia. The consumption of 3% dried raw blueberries attenuates dopaminergic denervation and partially reverses motor disorders in the 6-OHDA-induced PD model in rats. The phytochemicals of raw blueberries that contribute to the observed neuroprotective effect are yet to be identified., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Dopamine (DA) and serotonin (5-HT) receptors are prime targets for the development of antipsychotics. The specific role of each receptor subtype to the pharmacological effects of antipsychotic drugs remains unclear. Understanding the relationship between antipsychotic drugs and their binding affinities at DA and 5-HT receptor subtypes is very important for antipsychotic drug discovery and could lead to new drugs with enhanced efficacies. We have previously disclosed SYA16263 (5) as an interesting compound with moderate radioligand binding affinity at the D 2 & D 3 receptors (Ki = 124 nM & 86 nM respectively) and high binding affinities towards D 4 and 5-HT 1A receptors (Ki = 3.5 nM & 1.1 nM respectively). Furthermore, we have demonstrated SYA16263 (5) is functionally selective and produces antipsychotic-like behavior but without inducing catalepsy in rats. Based on its pharmacological profile, we selected SYA16263 (5) to study its structure-affinity relationship with a view to obtaining new analogs that display receptor subtype selectivity. In this study, we present the synthesis of structurally modified SYA16263 (5) analogs and their receptor binding affinities at the DA and 5-HT receptor subtypes associated with antipsychotic action. Furthermore, we have identified compound 21 with no significant binding affinity at the D 2 receptor subtype but with moderate binding affinity at the D 3 and D 4 receptors subtypes. However, because 21 is able to demonstrate antipsychotic-like activity in a preliminary test, using the reversal of apomorphine-induced climbing behavior experiment in mice with SYA16263 and haloperidol as positive controls, we question the essential need of the D 2 receptor subtype in reversing apomorphine-induced climbing behavior., (Published by Elsevier Ltd.)

Rationale: Schizophrenia is a devastating mental disease that affects nearly 1% of the population worldwide. It is well documented that the dopaminergic (DAergic) system is compromised in schizophrenia. It is of note that the mixed dopamine (DA) D 1 /D 2 receptor agonist apomorphine induces schizophrenia-like symptoms in rodents, including disruption of memory abilities. Neuroactive steroids, comprising dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEAS), were shown to affect brain DAergic system and to be involved in schizophrenia. BNN27 is a novel DHEA derivative, which is devoid of steroidogenic activity. It has recently been reported that BNN27 counteracted schizophrenia-like behavioural deficits produced by glutamate hypofunction in rats., Objectives: The aim of the present study was to investigate the ability of BNN27 to attenuate non-spatial, spatial recognition and discrete memory deficits induced by apomorphine in rats., Methods: To this end, the object recognition task (ORT), the object location task (OLT) and the step-through passive avoidance test (STPAT) were used., Results: BNN27 (3 and 6 mg/kg, i.p.) attenuated apomorphine (0.5 mg/kg, i.p.)-induced non-spatial, spatial recognition and discrete memory deficits. Interestingly, the effects of compounds on memory cannot be ascribed to changes in locomotor activity., Conclusions: Our findings suggest that BNN27 is effective to DA dysfunction caused by apomorphine, attenuating cognitive impairments induced by this D1/D2 receptor agonist in rats. Additionally, our findings illustrate a functional interaction between BNN27 and the DAergic system that may be of relevance for schizophrenia-like behavioural symptoms.

Background: Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motor neurons resulting in muscle atrophy. In contrast to the lower motor neurons, the role of upper (cortical) neurons in ALS is yet unclear. Maturation of locomotor networks is supported by dopaminergic (DA) projections from substantia nigra to the spinal cord and striatum., Objective: To examine the contribution of DA mediation in the striatum-cortex networks in ALS progression., Methods: We studied electroencephalogram (EEG) from striatal putamen (Pt) and primary motor cortex (M1) in ΔFUS(1-359)-transgenic (Tg) mice, a model of ALS. EEG from M1 and Pt were recorded in freely moving young (2-month-old) and older (5-month-old) Tg and non-transgenic (nTg) mice. EEG spectra were analyzed for 30 min before and for 60 min after systemic injection of a DA mimetic, apomorphine (APO), and saline., Results: In young Tg versus nTg mice, baseline EEG spectra in M1 were comparable, whereas in Pt, beta activity in Tg mice was enhanced. In older Tg versus nTg mice, beta dominated in EEG from both M1 and Pt, whereas theta and delta 2 activities were reduced. In younger Tg versus nTg mice, APO increased theta and decreased beta 2 predominantly in M1. In older mice, APO effects in these frequency bands were inversed and accompanied by enhanced delta 2 and attenuated alpha in Tg versus nTg mice., Conclusion: We suggest that revealed EEG modifications in ΔFUS(1-359)-transgenic mice are associated with early alterations in the striatum-cortex interrelations and DA transmission followed by adaptive intracerebral transformations.

In the suited rat-models, we focused on the stable pentadecapeptide BPC 157, L-NAME, NOS-inhibitor, and L-arginine, NOS-substrate, relation, the effect on schizophrenia-like symptoms. Medication (mg/kg intraperitoneally) was L-NAME (5), L-arginine (100), BPC 157 (0.01), given alone and/or together, at 5 min before the challenge for the acutely disturbed motor activity (dopamine-indirect/direct agonists (amphetamine (3.0), apomorphine (2.5)), NMDA-receptor non-competitive antagonist (MK-801 (0.2)), or catalepsy, (dopamine-receptor antagonist haloperidol (2.0)). Alternatively, BPC 157 10 μg/kg was given immediately after L-NAME 40 mg/kg intraperitoneally. To induce or prevent sensitization, we used chronic methamphetamine administration, alternating 3 days during the first 3 weeks, and challenge after next 4 weeks, and described medication (L-NAME, L-arginine, BPC 157) at 5 min before the methamphetamine at the second and third week. Given alone, BPC 157 or L-arginine counteracted the amphetamine-, apomorphine-, and MK-801-induced effect, haloperidol-induced catalepsy and chronic methamphetamine-induced sensitization. L-NAME did not affect the apomorphine-, and MK-801-induced effects, haloperidol-induced catalepsy and chronic methamphetamine-induced sensitization, but counteracted the acute amphetamine-induced effect. In combinations (L-NAME + L-arginine), as NO-specific counteraction, L-NAME counteracts L-arginine-induced counteractions in the apomorphine-, MK-801-, haloperidol- and methamphetamine-rats, but not in amphetamine-rats. Unlike L-arginine, BPC 157 maintains its counteracting effect in the presence of the NOS-blockade (L-NAME + BPC 157) or NO-system-over-stimulation (L-arginine + BPC 157). Illustrating the BPC 157-L-arginine relationships, BPC 157 restored the antagonization (L-NAME + L-arginine + BPC 157) when it had been abolished by the co-administration of L-NAME with L-arginine (L-NAME + L-arginine). Finally, BPC 157 directly inhibits the L-NAME high dose-induced catalepsy. Further studies would determine precise BPC 157/dopamine/glutamate/NO-system relationships and clinical application., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Caffeine and taurine, which possess neuro-modulatory activity happen to be consumed together as part of the constituents of energy drinks, could have beneficial effects and prevent neuronal deterioration in Parkinson's disease (PD)., Objective: This study aimed to investigate behavioral and neurochemical effects of these two agents in an animal model of PD at two time points to evaluate possible neuro-protective or neuro-modulatory effects., Methods: Stereotaxic injection of 6-hydroxydopamine (6-OHDA) in rat striatum was used to model PD-like behavior in animals. Motor behavior was assessed by a characteristic rotation behavior response to the apomorphine challenge and dopamine levels in the striatum were quantified using HPLC-ED., Results: A reduction in apomorphine induced rotations following administration of caffeine and/or taurine as compared to the untreated lesioned group (controls) was shown. Significant decreases in dopamine levels were also seen in the ipsilateral side of 6-OHDA group, this effect was not significantly reversed in caffeine and taurine treated groups. Treatments partially restored the content of DA levels in the lesioned striatum., Conclusions: Current results demonstrated beneficial effects for the combination of caffeine and taurine in PD animal model, suggesting that consumption of both agents could be a new added therapeutic target for Parkinson's disease prevention and treatment.

The current study sought to characterize the pro-survival effects of erythropoietin (EPO) in a toxicant model of Parkinson's disease (PD). EPO treatment induced time-dependent elevations of antioxidant glutathione peroxidase (GPx) and anti-apoptotic factors (pAkt and pBad/Bad) within the striatum and substantia nigra pars compacta (SNc). Intriguingly, our results indicated a region- and lesion size- dependence of pro-survival effects of EPO. Indeed, intra-striatal (but not intra-nigral) infusion of EPO was effective at preventing dopaminergic terminal degeneration and sSNc neuronal loss induced by two different doses of 6-OHDA. These neuroprotective consequences were paralleled by a diminution of microglial morphological changes, along with enhanced motor functioning seen through a reduction in apomorphine-induced rotational behaviour. Finally, in the context of the 6-OHDA lesion, EPO again induced anti-apoptotic (Bcl-2) and antioxidant (GPx) factors within the striatum. Taken together, these results raise the possibility of EPO's potential use as an adjuvant therapy in the treatment of PD, or at least, suggest possible brain-region specific targets for the protective effects of EPO., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

A novel approach for treatment of enterovirus infections was characterized. Application of treatment course of consecutive alternating administration (CAA) of triple combination of enterovirus replication inhibitors in experimental infections (20 MLD50) with coxsackievirus B3 (CVB3) strains in newborn mice is presented. It was established that in infection with cardiotropic Woodruff strain the combination of pleconaril, МDL-860 and oxoglaucine (PMO) subjected to the CAA scheme, a significant protective effect was observed. Monotherapeutic courses as well as simultaneously daily applied PMO were without effect. Analogous data were observed at experimental infection with the neurotriopic Nancy strain of CVB3. Following IC50 values of virus samples taken every day from target organs of infected animals during the whole period of study, a drug-resistance was established in monotherapy with compounds-partners in the PMO combination. At courses by the treatment scheme CAA of PMO development of drug-resistance was not established, but an increased susceptibility to the effect of the inhibitor-components in the combination was proven. Toxicity of PMO applied via the CAA scheme and in the monotherapeutic courses in both healthy and CVB3 infected animals was recorded. All data obtained prove the potential of the CAA treatment scheme for development of effective chemotherapy of enterovirus infections., (© The Author(s) 2020. Published by Oxford University Press on behalf of FEMS.)

Dopaminergic medication for Parkinson's disease is associated with troubling dystonia and dyskinesia and, in rodents, dopaminergic agonists likewise induce a variety of orofacial motor responses, certain of which are mimicked by serotonin2C (5-HT 2C ) receptor agonists. However, the neural substrates underlying these communalities and their interrelationship remain unclear. In Sprague-Dawley rats, the dopaminergic agonist, apomorphine (0.03-0.3 mg/kg) and the preferential D2/3 receptor agonist quinpirole (0.2-0.5 mg/kg), induced purposeless oral movements (chewing, jaw tremor, tongue darting). The 5-HT 2C receptor antagonist 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxyl]-5-pyridyl]carbamoyl]-6-trifluoromethylindone (SB 243213) (1 mg/kg) reduced the oral responses elicited by specific doses of both agonists (0.1 mg/kg apomorphine; 0.5 mg/kg quinpirole). After having confirmed that the oral bouts induced by quinpirole 0.5 mg/kg were blocked by another 5-HT 2C antagonist (6-chloro-5-methyl-1-[6-(2-methylpiridin-3-yloxy)pyridine-3-yl carbamoyl] indoline (SB 242084), 1 mg/kg), we mapped the changes in neuronal activity in numerous sub-territories of the basal ganglia using c-Fos expression. We found a marked increase of c-Fos expression in the subthalamic nucleus (STN) in combining quinpirole (0.5 mg/kg) with either SB 243213 or SB 242084. In a parallel set of electrophysiological experiments, the same combination of SB 243213/quinpirole produced an irregular pattern of discharge and an increase in the firing rate of STN neurons. Finally, it was shown that upon the electrical stimulation of the anterior cingulate cortex, quinpirole (0.5 mg/kg) increased the response of substantia nigra pars reticulata neurons corresponding to activation of the "hyperdirect" (cortico-subthalamonigral) pathway. This effect of quinpirole was abolished by the two 5-HT 2C antagonists. Collectively, these results suggest that induction of orofacial motor responses by D2/3 receptor stimulation involves 5-HT 2C receptor-mediated activation of the STN by recruitment of the hyperdirect (cortico-subthalamonigral) pathway.

Sublingual apomorphine could be an option in patients with erectile dysfunction who cannot take phosphodiesterase type 5 inhibitors (e.g., using nitrates). We have completed a systematic review to evaluate the effects of sublingual apomorphine comparing with placebo for treating erectile dysfunction. The evidence searching process finished on 9 January 2019. We included nine randomized controlled trials (RCTs). Treatment length varied from 4 to 8 weeks and doses ranged from 2 to 6 mg. The percent of successful sexual intercourse attempts per ingested dose of apomorphine was evaluated in eight studies. All the studies found that apomorphine was better than placebo (6-27% more successful intercourse attempts than with placebo), but differences were not statistically significant in one study done in patients previously treated with radical prostatectomy. Regarding erectile function scores, three studies reported higher improvement on the erectile function scores for apomorphine. Differences with placebo were not clinically relevant in another two studies, one in which only diabetic patients were included and one in which only patients with radical prostatectomy were involved. Discontinuation of treatment due to adverse events was higher for apomorphine, particularly for higher doses. Available evidence suggests that sublingual apomorphine is more effective than placebo, except for patients previously treated with radical prostatectomy, and is generally well tolerated at doses of 2 or 3 mg. Nowadays, sublingual apomorphine is the only licensed oral drug for erectile dysfunction not absolutely contraindicated with nitrates use, and more RCTs should be performed to evaluate its effects and safety for treating ED.

Ketamine, a non-competitive NMDA receptor antagonist, has been reported to mimic the cognitive symptoms of schizophrenia in animals. It has been reported to produce learning and memory deficits in rodents. However, there have limited number of reports that investigated the specific components of memory process that are affected with ketamine. In the present study, we investigated the effects of ketamine [8 and 20 mg/kg, intraperitoneally, (i.p.)] on storage and retrieval of information in rats using an object recognition test. We examined also whether a low dose range of the D1/D2 dopamine receptor agonist apomorphine (0.05 and 0.1 mg/kg, i.p.) would counteract the effects of ketamine. The results show that ketamine dose-dependently impaired storage of information while it did not affect rats' retrieval abilities. Administration of apomorphine reversed the ketamine-induced performance deficits in the ORT. The current findings show a differential modulation of post-training memory components (storage and retrieval of information) by ketamine and suggest a functional interaction between dopamine and NMDA receptors in the control of memory storage which may be of relevance to cognitive deficits a core feature of schizophrenia., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The neurodegenerative Alzheimer's disease (AD) affects more than 30 million people worldwide. There is thus far no cure or prevention for AD. Aggregation of hyperphosphorylated tau in the brain correlates with the cognitive decline of patients of AD and other neurodegenerative tauopathies. Intracerebral injection of tau aggregates isolated from tauopathy brains causes similar pathology in the recipient mice, demonstrating the pathogenic role of abnormally phosphorylated tau. Compounds controlling the aggregation of hyperphosphorylated tau therefore are probable modulators for the disease. Here we report the use of recombinant hyperphosphorylated tau (p-tau) to identify potential tauopathy therapeutics and risk factors. Hyperphosphorylation renders tau prone to aggregate and to impair cell viability. Taking advantage of these two characters of p-tau, we performed a screen of a 1280-compound library, and tested a selective group of prescription drugs in p-tau aggregation and cytotoxicity assays. R-(-)-apomorphine and raloxifene were found to be p-tau aggregation inhibitors that protected p-tau-treated cells. In contrast, a subset of benzodiazepines exacerbated p-tau cytotoxicity apparently via enhancing p-tau aggregation. R-(-)apomorphine and raloxifene have been shown to improve cognition in animals or in humans, whereas benzodiazepines were linked to increased risks of dementia. Our results demonstrate the feasibility and potential of using hyperphosphorylated tau-based assays for AD drug discovery and risk factor identification.

Introduction: The efficacy and safety of apomorphine sublingual film (APL-130277; APL) for the on-demand treatment of "OFF" episodes associated with Parkinson's disease (PD) was demonstrated in a double-blind trial. Herein we describe the ability of patients to receive effective and tolerable APL dose titration during the open-label titration phase., Methods: Adult patients with levodopa-responsive PD and "OFF" episodes were enrolled. In practically defined "OFF," patients were observed for a FULL "ON" after their usual morning carbidopa/levodopa (CD/LD) dose and then after titration with APL following each increasing dose (10-35 mg). Antiemetic medication was administered for 3 days before initiation of titration and was continued throughout titration. Motor responses were evaluated predose and postdose using Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III score. Safety outcomes were evaluated., Results: Among 141 patients who enrolled in the study and received APL during open-label titration, 109 (77.3%) achieved a FULL "ON" (66.1% at 10-20 mg) and 10 did not. Patients who successfully completed APL dose titration tended to be younger, had a longer mean time since PD diagnosis, and had lower levodopa requirements than those who discontinued during titration for any reason. Change in MDS-UPDRS Part III scores from predose to 30 min postdose after titration with the effective dose of APL (n = 109) was similar across all dose groups. In a post hoc analysis, the magnitude of motor response with APL was ~2-fold higher than with CD/LD 15 min postdose, and the observed peak response occurred earlier with APL than with the trend seen for CD/LD (45 vs 90 min, respectively). Overall, the most common (≥10%) treatment-emergent adverse events (TEAEs) during APL dose titration were nausea (20.6%), yawning (12.1%), dizziness (11.3%), and somnolence (11.3%). Twelve patients discontinued due to TEAEs during APL dose titration, most commonly (≥2%) because of dizziness (2.8%), nausea (2.1%), and somnolence (2.1%)., Conclusion: Among eligible patients with PD and "OFF" episodes who had their APL dose successfully titrated to an effective and tolerable level, most were able to do so within the first 3 titrated doses but some required further dose escalations. The use of APL can provide benefit for the treatment of "OFF" episodes., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Earlier, we have shown the efficacy of racemic (±) CIQ, a positive allosteric modulator of GluN2C/2D receptor against MK-801 induced impairment of prepulse inhibition as well as working memory. The present study investigated the antipsychotic-like profile of different CIQ (±, +, -) isomers against schizophrenia-like symptoms in series of behavioural animal models like apomorphine climbing, social isolation behaviour and NMDA receptor antagonist MK-801 induced cognitive deficits. Further, we also tested CIQ (±, +, -) isomers in neurodevelopmental model against MK-801induced deficits using open field test, Y-maze test and novel object recognition test. CIQ (±, +, -) isomers decreased climbing behaviour, increased social interaction and improved the MK-801 induced deficits in working memory in Y-maze. Further, CIQ (±, +) but not CIQ (-) improved the recognition memory in novel object recognition test as well as reduced hyperlocomotion and stereotyped behaviour. We conclude that CIQ (±, +) but not CIQ (-) exhibit the significant antipsychotic-like profile.

Apomorphine is a derivative of morphine that is used for the treatment of Parkinson's disease because of its effects on the hypothalamus. Therapeutic effects of apomorphine have also been reported for various neurological diseases and cancers. However, the molecular mechanisms of the antitumor effects of apomorphine are not clear, especially with respect to choriocarcinoma. This is the first study to elucidate the anticancer effects of apomorphine on choriocarcinoma. We found that apomorphine suppressed the viability, proliferation, ATP production, and spheroid formation of JEG3 and JAR choriocarcinoma cells. Moreover, apomorphine activated the intrinsic apoptosis pathway by activating caspases and inhibited the production of anti-apoptotic proteins in choriocarcinoma cells. Further, apomorphine caused depolarization of mitochondria, calcium overload, energy deprivation, and endoplasmic reticulum stress in JEG3 and JAR cells. We confirmed synergistic effects of apomorphine with paclitaxel, a traditional chemotherapeutic agent, and propose that apomorphine could be a potential therapeutic agent in choriocarcinoma and an important candidate for drug repositioning that could help overcome resistance to conventional chemotherapy.

Drug abuse and impaired adaptation to stress are inter-related. Drug abuse is more potentiated upon exposure to stress and an impairment to cope with stress may lead to depression. On the other hand, use of addictive compounds increase the vulnerability to depression by inhibiting the adaptation to stress. Present study investigates relationship between behavioral tolerance to repeated restraint stress and apomorphine-induced sensitization. Apomorphine was injected either before or after the restraint stress episode, to monitor drug-induced behavioral sensitization and place preference. Apomorphine-induced sensitization and place preference were enhanced if the drug is experiencing during restraint stress. Conversely, apomorphine-induced sensitization and place preference were attenuated if the drug is experiencing after restraint stress. It shows that apomorphine, if experienced during restraint stress, produces greater sensitization Conversely, sensitization effects of apomorphine are blocked in animals receiving apomorphine after the termination of restraint stress. The results tend to show that drug of abuse may be effective for the treatment but not prevention of stress-induced depression.

Apomorphine, a therapeutic agent for neurological diseases, is structurally similar to dopamine, and thereby holds potential in cancer therapy. However, there are no reports regarding its anti-cancer effects on human epithelial ovarian cancers (EOCs); therefore, we aimed to elucidate the mechanism underlying its action after drug repositioning. Apomorphine inhibited the proliferation of ES2 and OV90 EOC cells by inducing caspase activation and mitochondrion-associated apoptosis; it also promoted endoplasmic reticulum stress and mitochondrial dysfunction through mitochondrial membrane potential depolarization and mitochondrial calcium overload. Moreover, following apomorphine treatment, we noted the loss of respiratory chain activity by reduction of oxidative phosphorylation and energy-production shift in EOC cells. Further, we verified the anti-angiogenic capacity of apomorphine using fli:eGFP transgenic zebrafish. As a preclinical assessment, we demonstrated the synergistic anti-cancer effects of apomorphine and paclitaxel combination., Competing Interests: Declaration of competing interest The authors have declared no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Parkinson's disease is a neurodegenerative disorder, and no treatment has been yet established to prevent disease progression. Coenzyme Q10, an antioxidant, has been considered a promising neuroprotective agent; however, conventional oral administration provides limited efficacy due to its very low bioavailability. In this study, we hypothesised that continuous, intrastriatal administration of a low dose of Coenzyme Q10 could effectively prevent dopaminergic neuron degeneration. To this end, a Parkinson's disease rat model induced by 6-hydroxydopamine was established, and the treatment was applied a week before the full establishment of this disease model. Behavioural tests showed a dramatically decreased number of asymmetric rotations in the intrastriatal Coenzyme Q10 group compared with the no treatment group. Rats with intrastriatal Coenzyme Q10 exposure also exhibited a larger number of dopaminergic neurons, higher expression of neurogenetic and angiogenetic factors, and less inflammation, and the effects were more prominent than those of orally administered Coenzyme Q10, although the dose of intrastriatal Coenzyme Q10 was 17,000-times lower than that of orally-administered Coenzyme Q10. Therefore, continuous, intrastriatal delivery of Coenzyme Q10, especially when combined with implantable devices for convection-enhanced delivery or deep brain stimulation, can be an effective strategy to prevent neurodegeneration in Parkinson's disease.

Linalool (LIN) is a monoterpene, responsible for the aroma of essential oils in some species. It presents a sedative and anxiolytic potential, enhancing GABAergic currents and behaving as a benzodiazepine-type of drug. The objectives of the present work were to study the neuroprotective effects of LIN on a model of Parkinson's disease. For that, male Wistar rats were divided into the following groups: sham-operated (SO), 6-OHDA-lesioned, and 6-OHDA-lesioned and treated with LIN (25, 50, and 100 mg/kg, p.o.) for 2 weeks. Afterwards, the animals were subjected to behavioral tests (apomorphine-induced rotations, open field, and forced swimming tests). Then, the animals were euthanized, and the striatum, hippocampus, and prefrontal cortex were processed for neurochemistry (nitrite and lipoperoxidation measurements) and immunohistochemistry (TH and DAT) assays. The results were analyzed by ANOVA and Tukey's test for multiple comparisons and considered significant at p < 0.05. LIN significantly improved the behavioral alterations of the 6-OHDA-lesioned group, as evaluated by the apomorphine-induced rotations, open field, and forced swimming tests. In addition, LIN partially reversed the decreased DA, DOPAC, and HVA contents observed in the 6-OHDA-lesioned striatum. The untreated 6-OHDA group presented increased nitrite contents and lipoperoxidation in all the brain areas studied, and these changes were completely reversed after LIN treatments. Finally, LIN significantly prevented the reduction in TH and DAT expressions demonstrated in the right 6-OHDA-lesioned striatum. All these data strongly suggest that LIN presents a neuroprotective action in hemiparkinsonian rats, probably related to the drug anti-inflammatory and antioxidant activities.

An extensive literature has validated the critical importance of a brief post-trial consolidation period for the incorporation of an experience into memory. Importantly, during this active consolidation state the memory formation is vulnerable to modification. While the subsequent stabilization of the memory makes it relatively resistant to modification, conditioned drug cues that re-activate the cue drug state association can initiate a re-consolidation process and during this re-consolidation the drug-cue association again becomes briefly unstable and sensitive to modification by post-trial treatments. Although most post-trial treatments shown to interact with memory consolidation processes have been used with instrumental learning protocols, this review is focused on recent findings that indicate that psycho-stimulant drug responses induced by apomorphine and morphine during the post-trial consolidation/re-consolidation state can become incorporated into the memory process. As a consequence, these post-trial drug treatment effects can be expressed in a subsequent non-drug test as behavioral responses comparable to the drug induced responses. In fact, apomorphine and morphine when administered post-trial can induce sensitization/conditioned effects that mirror the effects generated when these same drugs are administered in the presence of contextual cues. In addition, it has been shown that apomorphine given at stimulant/inhibitory dopaminergic dose levels post-trial during re-consolidation of a conditioned drug behavior can intensify/reverse the drug conditioning previously induced by apomorphine, morphine or haloperidol. The apparent efficacy of a post-trial drug state induced by a psycho-stimulant drug during consolidation/re-consolidation to become incorporated into contextual memory points up an alternative way, in addition to Pavlovian conditioning, by which psycho-stimulant drug effects can become embedded into an engram activated by contextual cues. These findings further suggest that drug treatments can be used to counter-condition the re-consolidated conditioned addictive drug response to substantially reduce the salience and motivational significance the conditioned association induced by the addictive drug., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Experimental evidence shows that the phenylpyrazole pesticide fipronil exerts neurotoxic effects at central level in rodents, and in particular on nigrostriatal dopaminergic neurons, whose degeneration is well known to cause motor and non-motor deficits in animals and in humans. In order to characterize better the central neurotoxic effect of fipronil, we injected fipronil (15 and 25 μg) dissolved in dimethyl sulfoxide (DMSO) unilaterally into the substantia nigra of male rats. Male rats injected with DMSO unilaterally into the substantia nigra were used as controls. Control and fipronil-treated rats were then tested in different motor (i.e., open field arena, rotarod, tail flick) and non motor tests (novel object recognition, social interaction) 15 days after injection. A systemic challenge dose of the dopamine-agonist apomorphine was also used to study the presence of a rotational behavior. Sixteen days after fipronil or DMSO injection into the substantia nigra, rats were sacrificed, and either striatal dopamine content or substantia nigra tyrosine hydroxylase (TH) immunoreactivity were measured. The results confirm that the unilateral injection of fipronil into the substantia nigra caused the degeneration of nigrostriatal dopaminergic neurons, which leads to a decrease around 50 % in striatal dopamine content and substantia nigra TH imunoreactivity. This occurred together with changes in motor activity and coordination, and in nociception but not in recognition memory and in social interaction, as revealed by the results of the behavioral experiments performed in fipronil-treated rats compared to vehicle-treated rats 15 days after treatment, as found with other compounds that destroy nigrostriatal dopaminergic neurons., Competing Interests: Declaration of Competing Interest The authors have nothing to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Parkinson's disease is a neurodegenerative disease characterized by a loss of dopaminergic substantia nigra neurons and depletion of dopamine. To date, current therapeutic approaches focus on managing motor symptoms and trying to slow neurodegeneration, with minimal capacity to promote neurorecovery. mGluR5 plays a key role in neuroplasticity, and altered mGluR5 signaling contributes to synucleinopathy and dyskinesia in patients with Parkinson's disease. Here, we tested whether the mGluR5-negative allosteric modulator, (2-chloro-4-[2[2,5-dimethyl-1-[4-(trifluoromethoxy) phenyl] imidazol-4-yl] ethynyl] pyridine (CTEP), would be effective in improving motor deficits and promoting neural recovery in a 6-hydroxydopamine (6-OHDA) mouse model. Lesions were induced by 6-ODHA striatal infusion, and 30 days later treatment with CTEP (2 mg/kg) or vehicle commenced for either 1 or 12 weeks. Animals were subjected to behavioral, pathological, and molecular analyses. We also assessed how long the effects of CTEP persisted, and finally, using rapamycin, determined the role of the mTOR pathway. CTEP treatment induced a duration-dependent improvement in apomorphine-induced rotation and performance on rotarod in lesioned mice. Moreover, CTEP promoted a recovery of striatal tyrosine hydroxylase-positive fibers and normalized FosB levels in lesioned mice. The beneficial effects of CTEP were paralleled by an activation of mammalian target of rapamycin (mTOR) pathway and elevated brain-derived neurotrophic factor levels in the striatum of lesioned mice. The mTOR inhibitor, rapamycin (sirolimus), abolished CTEP-induced neurorecovery and rescue of motor deficits. Our findings indicate that mTOR pathway is a useful target to promote recovery and that mGluR5 allosteric regulators may potentially be repurposed to selectively target this pathway to enhance neuroplasticity in patients with Parkinson's disease.

Objective: To determine the success rate and complications associated with inducing emesis in dogs that have ingested foreign material., Design: Retrospective case series, 2010-2014., Setting: Private practice and referral center., Animals: Sixty-one client-owned dogs that had emesis induced for the treatment of ingestion of foreign material., Interventions: None., Measurements and Main Results: Emesis was successfully induced in 59 of 61 (97%) dogs administered an emetic. Of those 59 dogs, 46 (78%) produced the foreign body. There were no complications reported in any of the dogs in which emesis was successfully induced. Dogs in which emesis was successfully induced were likely to produce the foreign body (P = 0.01)., Conclusion: Based on the results of this study, emesis appears to be a safe and effective means for the removal of certain gastric foreign bodies in dogs., (© Veterinary Emergency and Critical Care Society 2020.)

The development of sensitization is one of the hallmarks of addictive drugs. Consistent with this relationship many studies have demonstrated that the highly addictive opioid agonist morphine induces sensitization effects. In this study, we administered morphine (10 mg/kg) (MOR) to induce sensitization. In that sensitization is considered to involve associative processes and that dopamine activity is an important contributor to learning and memory processes, we administered a dopamine inhibitory treatment using apomorphine (0.05 mg/kg) (APO) during memory consolidation following a morphine sensitization treatment protocol. Seemingly, a decrease in dopamine activity during consolidation would impair the salience of the association of the morphine response with the contextual cues during consolidation and interfere with the development of morphine sensitization. In two separate experiments, MOR or vehicle (VEH) were administered pre-trial and either VEH or APO were administered post-trial over 5 and 10 days of treatment, respectively. In both the 5 and 10 drug treatment sessions post-trial experiments, MOR groups given VEH immediately post-trial exhibited strong sensitization effects. These sensitization effects were substantially attenuated in the MOR groups given APO immediately post-trial but not in the MOR groups given APO after a 15 min. post-trial delay. In subsequent conditioning and sensitization challenge tests, the MOR groups that had been given APO immediately post-trial exhibited diminished sensitization and conditioned responses relative to MOR groups that had received VEH or APO delayed post-trial. This MOR-APO interaction effect was unique in that it occurred post-trial so that it was only expressed in a pre-trial test in which only MOR was administered. Seemingly, the inhibitory dopamine effect of APO was incorporated into memory during the post-trial consolidation process suggesting that drug/drug interactions can occur during consolidation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Cognitive flexibility, shown to be impaired in patients presenting with compulsions, is dependent on balanced dopaminergic and serotonergic interaction. Towards the development of a zebrafish (Danio rerio) screening test for anti-compulsive drug action, we manipulated social reward appraisal under different contexts by means of dopaminergic (apomorphine) and serotonergic (escitalopram) intervention. Seven groups of zebrafish (n = 6 per group) were exposed for 24 days (1 h per day) to either control (normal tank water), apomorphine (50 or 100 μg/L), escitalopram (500 or 1000 μg/L) or a combination (A100/E500 or A100/E1000 μg/L). Contextual reward appraisal was assessed over three phases i.e. Phase 1 (contingency association), Phase 2 (dissociative testing), and Phase 3 (re-associative testing). We demonstrate that 1) sight of social conspecifics is an inadequate motivational reinforcer under circumstances of motivational conflict, 2) dopaminergic and serotonergic intervention lessens the importance of an aversive stimulus, increasing the motivational valence of social reward, 3) while serotoninergic intervention maintains reward directed behavior, high-dose dopaminergic intervention bolsters cue-directed responses and 4) high-dose escitalopram reversed apomorphine-induced behavioral inflexibility. The results reported here are supportive of current dopamine-serotonin opponency theories and confirm the zebrafish as a potentially useful species in which to investigate compulsive-like behaviors., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Paracetamol (PAR) is an over-the-counter medicine used as analgesic or antipyretic by 40-50% of the pregnant women in different countries. Epidemiologic studies have been associating maternal use of PAR with neurodevelopmental disruption and special attention has been given to its potential to increase the odds for neurodevelopmental disorders, such as attention-deficit hyperactive disorder and autism spectrum disorder. Population-based research do not allow the establishment of causal relationships because variable control is weak. We aimed to evaluate the potential of PAR to induce developmental neurotoxicity in rats. Pregnant Wistar rats were gavaged with PAR (350 mg/kg/day) or water from gestational day 6 until delivery. General toxicity endpoints included dams' body weight and food intake as well as pups' body weight until weaning. Behavioral evaluation occurred at post-natal days 10 (nest seeking test), 27 (behavioral stereotypy), 28 (three chamber sociability test and open field) and 29 (hot plate and elevated plus-maze). Moreover, lipid hidroperoxide (LOOH), reduced glutathione (GSH) and brain derived neurotrophic factor (BDNF) levels were quantified in prefrontal cortex and hippocampus of 22-days-old rats. Gestational exposure to PAR impaired nest seeking behavior, augmented apomorphine-induced behavioral stereotypy and decreased rostral grooming in the elevated plus maze. Exposed female pups presented elevated vertical exploration in the open field test. No alterations were observed in LOOH, GSH or BDNF levels in the prefrontal cortex or hippocampus. Exposure regimen did not affect general toxicity parameters or pups' behavior in the hot plate and sociability tests. These data suggest PAR as a developmental neurotoxicant. Observed alterations may be relevant for neurodevelopmental disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019. Published by Elsevier Inc.)

Parkinson's disease (PD) is well known as a neurodegenerative disorder with progressive loss of dopaminergic (DA) neurons. Nei-like 1 (NEIL1) is one of four mammalian DNA glycosylases involved in the progression of various diseases, including neuroinflammation. However, it is still unknown if the expression changes of NEIL1 could contribute to PD progression. In the present study, we established mouse model with PD using 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to explore the effects of NEIL1 on PD development. Here, we found that NEIL1 deletion significantly promoted the motor dysfunction in the wild type mice treated with 6-OHDA. Furthermore, DA neuronal loss was further accelerated by NEIL1 deletion in 6-OHDA-injected mice, as evidenced by the significantly reduced expression of tyrosine hydroxylase (TH) and dopamine transporter (DAT). Furthermore, in PD mice induced by MPTP, remarkably reduced expression of NEIL1 was observed in nigra and striatum of mice. A strong positive correlation was detected in the expression of NEIL1 and the survival rate of DA neurons. Also, NEIL1 ablation further elevated the DA neuronal loss in MPTP-treated mice, accompanied with higher glial activation, as evidenced by the obvious up-regulation of glial fibrillary acidic protein (GFAP) and Ionized calcium-Binding Adapter molecule 1 (Iba1). Moreover, MPTP-triggered inflammation was highly aggravated by the loss of NEIL1 through inducing the expression of pro-inflammatory cytokines and chemokines. In contrast, promoting NEIL1 expression effectively reversedPD progression induced by MPTP in mice. Together, these results demonstrated that NEIL1 insufficiency might be a contributing factor for the progression of PD, which therefore could be considered as a novel candidate to develop effective treatments against PD progression., (Copyright © 2019. Published by Elsevier Inc.)

The effect of C60 fullerene aqueous colloid solution (C60FAS) on the intensity of long‑lasting (persisting for one hour) rotational movements in non‑anesthetized rats was investigated. For this purpose, an experimental hemiparkinsonic animal model was used in the study. Rotational movements in hemiparkinsonic animals were initiated by the intraperitoneal administration of the dopamine receptor agonist apomorphine. It was shown that a preliminary injection of C60FAS (a substance with powerful antioxidant properties) in hemiparkinsonic rats induced distinct changes in animal motor behavior. It was revealed that fullerene‑pretreated animals, in comparison with non‑pretreated or vehicle‑pretreated rats, rotated for 1 h at an approximately identical speed until the end of the experiment, whereas the rotation speed of control rats gradually decreased to 20-30% of the initial value. One can assume that the observed changes in the movement dynamics of the hemiparkinsonic rats after C60FAS pretreatment presumably can be induced by the influence of C60FAS on the dopaminergic system, although the isolated potentiation of the action of apomorphine C60FAS cannot be excluded. Nevertheless, earlier data on the action of C60FAS on muscle dynamics has suggested that C60FAS can activate a protective action of the antioxidant system in response to long‑lasting muscular activity and that the antioxidant system in turn may directly decrease fatigue‑relate d changes during long‑lasting muscular activity.

Background: Parkinson's disease (PD) is a common neurodegenerative disorder that is characterized by motor symptoms related to the deficiency in dopamine levels, and cognitive symptoms that are similar in nature to those manifested during Alzheimer's disease. Levosimendan, on the other hand, is a calcium sensitizer and phosphodiesterase inhibitor that was shown to possess neuroprotective, memoryenhancing, and anti-apoptotic properties., Objective: In the current study, the possible protective effect of levosimendan was investigated in two animal models of Parkinson's disease., Methods: Both intracerebral injection 6-hydroxydopamine (6-OHDA) and the direct injection of lipopolysaccharide (LPS) into the substantia nigra were used as models to induce Parkinson's-like behavior. Levosimendan (12 μg/kg intraperitoneally once weekly) was started 7 days before or 2 days after lesioning of the animals. At day 14 post-lesioning, animals were subjected to apomorphine challenge, which was correlated with dopamine levels in the striatum and tyrosine hydroxylase (TH)-positive nigral cells., Results: Results showed that levosimendan restored the number of rotations in the apomorphine challenge test, the levels of dopamine in the striatum, and the TH-positive nigral cells when administered 7 days before, but not two days after 6-OHDA lesioning. In the LPS model of PD, the number of rotations in the apomorphine challenge test, the levels of dopamine in the striatum, and the TH-positive nigral cells were restored when levosimendan was administered 7 days before as well as two days after lesioning., Conclusion: Levosimendan seems to provide a promising agent with potential clinical value for PD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Long-term antipsychotic treatment in patients with schizophrenia can induce supersensitivity psychosis and tardive dyskinesia which is thought to be caused by dopamine D 2 receptor sensitization. We evaluated the effects of brexpiprazole on D 2 receptor sensitivity after subchronic treatment in rats. We also evaluated whether brexpiprazole could suppress enhanced response to D 2 receptors in rats subchronically dosed with another atypical antipsychotic., Methods: The maximum D 2 receptor density (B max ) and apomorphine (a D 2 receptor agonist)-induced stereotypy were measured in rats orally dosed with vehicle, haloperidol (1 mg/kg), or brexpiprazole (4 or 30 mg/kg for B max , 6 or 30 mg/kg for stereotypy) for 21 days. Then, effects of oral administrations of brexpiprazole (3 mg/kg), aripiprazole (10 mg/kg), and olanzapine (3 mg/kg) against increases in apomorphine-induced hyperlocomotion and (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI: a 5-HT 2A receptor agonist)-induced head twitches were evaluated in rats subcutaneously treated with risperidone (1.5 mg/kg/d) via minipumps for 21 days., Results: Haloperidol and brexpiprazole (30 mg/kg: approximately tenfold ED 50 of anti-apomorphine-induced stereotypy) but not brexpiprazole (4 or 6 mg/kg) significantly increased the B max and apomorphine-induced stereotypy. Brexpiprazole (3 mg/kg) and olanzapine (3 mg/kg) significantly suppressed both increases in apomorphine-induced hyperlocomotion and also DOI-induced head twitches in rats subchronically treated with risperidone, but aripiprazole (10 mg/kg) significantly suppressed only apomorphine-induced hyperlocomotion., Conclusion: Brexpiprazole has a low risk of D 2 receptor sensitization after a repeated administration and suppresses the rebound phenomena related to D 2 and 5-HT 2A receptors after a repeated administration of risperidone., (© 2019 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of NeuropsychoPharmacology.)

Background: This study was designed to evaluate whether overconsumption of NaCl, a well-known risk factor for hypertension, leads to erectile dysfunction in rodents., Methods: Male Wistar rats received regular chow (control group) or 4% NaCl chow for 24 weeks and were subjected to blood pressure measurement and apomorphine-induced erection. Moreover, cavernosal strips from both the control and 4% NaCl groups were evaluated in organ baths., Results: Animals subjected to 4% NaCl chow did not develop hypertension but presented a significant reduction in the total number of erections following apomorphine administration as compared with the control group. The addition of high KCl or phenylephrine resulted in similar contractile responses in the corpus cavernosal strips from both the control and 4% NaCl groups. However, electrical field stimulation-induced contraction was significantly enhanced in cavernosal strips from animals exposed to 4% NaCl. Incubation of Y-27632, but not of atropine and Nω-nitro-l-arginine methyl ester (L-NAME), entirely prevented the potentiation of the contractile responses evoked by electrical stimulation. The enhanced contractile responses evoked by electrical stimulation found in the high-salt group were also avoided in the absence of extracellular calcium. Concentration-response curves of CaCl2 revealed augmented contractility in response to extracellular calcium in cavernosal strips from the 4% NaCl-treated rats, compared with control samples., Conclusions: A high-salt diet alone rendered the animals less responsive to apomorphine-induced penile erection and enhanced neurally mediated contractile responses in the corpus cavernosum, a clear indication that overconsumption of sodium can lead to erectile dysfunction even without the development of hypertension., (© American Journal of Hypertension, Ltd 2019. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) catalyzes the cleavage of membrane NAPEs into bioactive fatty-acid ethanolamides (FAEs). Along with this precursor role, NAPEs might also serve autonomous signaling functions. Here, we report that injections of 6-hydroxydopamine (6-OHDA) into the mouse striatum cause a local increase in NAPE and FAE levels, which precedes neuronal cell death. NAPE, but not FAE, accumulation is enhanced in mice lacking NAPE-PLD, which display a substantial reduction in 6-OHDA-induced neurotoxicity, as shown by increased survival of substantia nigra dopamine neurons, integrity of striatal dopaminergic fibers, and striatal dopamine metabolite content. Reduced damage is accompanied by attenuation of the motor response evoked by apomorphine. Furthermore, NAPE-PLD silencing protects cathecolamine-producing SH-SY5Y cells from 6-OHDA-induced reactive oxygen species formation, caspase-3 activation and death. Mechanistic studies in mice suggest the existence of multiple molecular contributors to the neuroprotective effects of NAPE-PLD deletion, including suppression of Rac1 activity and attenuated transcription of several genes (Cadps, Casp9, Egln1, Kcnj6, Spen, and Uchl1) implicated in dopamine neuron survival and/or Parkinson's disease. The findings point to a previously unrecognized role for NAPE-PLD in the regulation of dopamine neuron function, which may be linked to the control of NAPE homeostasis in membranes.

Mitochondrial disease is a genetic disorder in which individuals suffer from energy insufficiency. The various clinical phenotypes of mitochondrial disease include Leigh syndrome (LS), myopathy encephalopathy lactic acidosis and stroke-like episodes (MELAS). Thus far, no curative treatment is available, and effective treatment options are eagerly awaited. We examined the cell protective effect of an existing commercially available chemical library on fibroblasts from four patients with LS and MELAS and identified apomorphine as a potential therapeutic drug for mitochondrial disease. We conducted a cell viability assay under oxidative stress induced by L-butionine (S, R)-sulfoximine (BSO), a glutathione synthesis inhibitor. Among the chemicals of library, 4 compounds (apomorphine, olanzapine, phenothiazine and ethopropazine) rescued cells from death induced by oxidative stress much more effectively than idebenone, which was used as a positive control. The EC 50 value showed that apomorphine was the most effective compound. Apomorphine also significantly improved all of the assessed oxygen consumption rate values by the extracellular flux analyzer for fibroblasts from LS patients with complex I deficiency. In addition, the elevation of the Growth Differentiation Factor-15 (GDF-15), a biomarker of mitochondrial disease, was significantly reduced by apomorphine. Among 441 apomorphine-responsive genes identified by the microarray, apomorphine induced the expression of genes that inhibit the mammalian target of rapamycin (mTOR) activity and inflammatory responses, suggesting that apomorphine induced cell survival via a new potential pathway. In conclusion, apomorphine rescued fibroblasts from cell death under oxidative stress and improved the mitochondrial respiratory activity and appears to be potentially useful for treating mitochondrial disease., (Copyright © 2019 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

Few behavioral tests allow measuring several characteristics and most require training, complex analyses, and/or are time-consuming. We present an apparatus based on rat exploratory behavior. Composed of three different environments, it allows the assessment of more than one behavioral characteristic in a short 3-min session. Factorial analyses have defined three behavioral dimensions, which we named Exploration, Impulsivity, and Self-protection. Behaviors composing the Exploration factor were increased by chlordiazepoxide and apomorphine and decreased by pentylenetetrazole. Behaviors composing the Impulsivity factor were increased by chlordiazepoxide, apomorphine, and both acute and chronic imipramine treatments. Behaviors composing the Self-protection factor were decreased by apomorphine. We submitted Wistar rats to the open-field test, the elevated-plus maze, and to the apparatus we are proposing. Measures related to exploratory behavior in all three tests were correlated. Measures composing the factors Impulsivity and Self-protection did not correlate with any measures from the two standard tests. Also, compared with existing impulsivity tests, the one we proposed did not require previous learning, training, or sophisticated analysis. Exploration measures from our test are as easy to obtain as the ones from other standard tests. Thus, we have proposed an apparatus that measured three different behavioral characteristics, was simple and fast, did not require subjects to be submitted to previous learning or training, was sensitive to drug treatments, and did not require sophisticated data analyses.

Evidence of changes in central noradrenergic activity has been reported in schizophrenic patients and studies indicate that activation of the α2-adrenoceptor improves memory and neuroprotection. In this study, a new imidazolidine derivative 3-(2-chloro-6-fluorobenzyl)-imidazolidine-2,4-dione, PT-31, a putative α2A-adrenoceptor agonist, was evaluated in mouse models predictive of efficacy in the treatment of positive and cognitive symptoms of schizophrenia, as well as its ability to promote cerebellar granule cell survival in vitro, in the presence or absence of glutamate (100 µmol/l). PT-31 prevented apomorphine-induced climbing and the ketamine-induced hyperlocomotion, without inducing catalepsy or motor impairment. PT-31 protected against the impairment of prepulse inhibition induced by apomorphine, (±)-DOI, and ketamine. The molecule did not affect mouse short nor long-term memory per se, but it protected against ketamine-induced memory impairment when administered at different stages of the memory process (acquisition, consolidation, and retrieval) in the novel object recognition task. When added to cultured cerebellar granule neurons, PT-31 was not toxic per se and protected neurons from glutamate-induced apoptosis. In conclusion, PT-31 displayed a preclinical pharmacology predictive of neuroprotective effects and efficacy in relieving schizophrenia symptoms, without inducing motor side effects, suggesting that it could represent a molecular scaffold for antipsychotic drug development.

Introduction: Apomorphine 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., Methods: Sixteen 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., Results: After 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., Conclusion: These 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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Galanin is a neuropeptide which mediates its effects via three G-protein coupled receptors (GAL 1-3 ). Administration of a GAL 3 antagonist reduces alcohol self-administration in animal models while allelic variation in the GAL 3 gene has been associated with an increased risk of alcohol use disorders in diverse human populations. Based on the association of GAL 3 with alcoholism, we sought to characterize drug-seeking behavior in GAL 3 -deficient mice for the first time. In the two-bottle free choice paradigm, GAL 3 -KO mice consistently showed a significantly increased preference for ethanol over water when compared to wildtype littermates. Furthermore, male GAL 3 -KO mice displayed significantly increased responding for ethanol under operant conditions. These differences in alcohol seeking behavior in GAL 3 -KO mice did not result from altered ethanol metabolism. In contrast to ethanol, GAL 3 -KO mice exhibited similar preference for saccharin and sucrose over water, and a similar preference for a high fat diet over a low fat diet as wildtype littermates. No differences in cognitive and locomotor behaviors were observed in GAL 3 -KO mice to account for increased alcohol seeking behavior. Overall, these findings suggest genetic ablation of GAL 3 in mice increases alcohol consumption., (© 2018 Society for the Study of Addiction.)