Spontaneous Locomotor Research Articles

Geometry of Wave Propagation on Active Deformable Surfaces.

Fundamental biological and biomimetic processes, from tissue morphogenesis to soft robotics, rely on the propagation of chemical and mechanical surface waves to signal and coordinate active force generation. The complex interplay between surface geometry and contraction wave dynamics remains poorly understood, but it will be essential for the future design of chemically driven soft robots and active materials. Here, we couple prototypical chemical wave and reaction-diffusion models to non-Euclidean shell mechanics to identify and characterize generic features of chemomechanical wave propagation on active deformable surfaces. Our theoretical framework is validated against recent data from contractile wave measurements on ascidian and starfish oocytes, producing good quantitative agreement in both cases. The theory is then applied to illustrate how geometry and preexisting discrete symmetries can be utilized to focus active elastic surface waves. We highlight the practical potential of chemomechanical coupling by demonstrating spontaneous wave-induced locomotion of elastic shells of various geometries. Altogether, our results show how geometry, elasticity, and chemical signaling can be harnessed to construct dynamically adaptable, autonomously moving mechanical surface waveguides.

Neuroprotective Effects of Spinosin on Recovery of Learning and Memory in a Mouse Model of Alzheimer's Disease.

Previous studies have shown that spinosin was implicated in the modulation of sedation and hypnosis, while its effects on learning and memory deficits were rarely reported. The aim of this study is to investigate the effects of spinosin on the improvement of cognitive impairment in model mice with Alzheimer’s disease (AD) induced by Aβ1–42 and determine the underlying mechanism. Spontaneous locomotion assessment and Morris water maze test were performed to investigate the impact of spinosin on behavioral activities, and the pathological changes were assayed by biochemical analyses and histological assay. After 7 days of intracerebroventricular (ICV) administration of spinosin (100 µg/kg/day), the cognitive impairment of mice induced by Aβ1–42 was significantly attenuated. Moreover, spinosin treatment effectively decreased the level of malondialdehyde (MDA) and Aβ1–42 accumulation in hippocampus. Aβ1–42 induced alterations in the expression of brain derived neurotrophic factor (BDNF) and B-cell lymphoma-2 (Bcl-2), as well as inflammatory response in brain were also reversed by spinosin treatment. These results indicated that the ameliorating effect of spinosin on cognitive impairment might be mediated through the regulation of oxidative stress, inflammatory process, apoptotic program and neurotrophic factor expression, suggesting that spinosin might be beneficial to treat learning and memory deficits in patients with AD via multi-targets.

Accumbens brain-derived neurotrophic factor (BDNF) transmission inhibits cocaine seeking.

Brain-derived neurotrophic factor (BDNF) regulates a variety of physiological processes, and several studies have explored the role of BDNF in addiction-related brain regions like the nucleus accumbens core (NAcore). We sought to understand the rapid effects of endogenous BDNF on cocaine seeking. Rats were trained to self-administer cocaine and extinguished. We then microinjected two inhibitors of BDNF stimulation of tropomyosin receptor kinase B (TrkB), the non-competitive receptor antagonist ANA-12 and TrkB/Fc, a fusion protein that binds BDNF and prevents TrkB stimulation. Blocking TrkB or inactivating BDNF in NAcore potentiated active lever pressing, showing that endogenous BDNF tone was present and supplying inhibitory tone on cue-induced reinstatement. To determine if exogenous BDNF also negatively regulated reinstatement, BDNF was microinjected into NAcore 15minutes before cue-induced reinstatement. BDNF decreased cocaine seeking through TrkB receptor binding, but had no effect on inactive lever pressing, spontaneous or cocaine-induced locomotion, or on reinstated sucrose seeking. BDNF-infusion potentiated within trial extinction when microinjected in the NAcore during cue- and context+cue induced reinstatement, and the inhibition of lever pressing lasted at least 3days post injection. Although decreased reinstatement endured for 3days when BDNF was administered prior to a reinstatement session, when microinjected before an extinction session or in the home cage, BDNF did not alter subsequent cued-reinstatement. Together, these data show that endogenous BDNF acts on TrKB to provide inhibitory tone on reinstated cocaine seeking, and this effect was recapitulated by exogenous BDNF.

RETRACTED: Dopamine D3 receptor partial agonist LS-3-134 attenuates cocaine-motivated behaviors

The dopamine D3 receptor (D3R) is a pharmacotherapeutic target for drug dependence. We have successfully imaged human D3Rs using radiolabeled LS-3-134, an arylamide phenylpiperazine with moderate selectivity for the D3R over D2R and low efficacy at the D2 and D3R. In this study, we screened for effects of LS-3-134 as a potential anti-cocaine therapeutic. Male rats were pretreated with LS-3-134 (0, 1.0, 3.2, or 5.6 mg/kg, IP) 15 min prior to tests for its effects on spontaneous and cocaine-induced locomotion. We next investigated the effects of LS-3-134 (0, 1.0, 3.2, 5.6, or 10.0 mg/kg, IP) on operant responding on a multiple variable-interval (VI) 60-second schedule with alternating cocaine (0.375 mg/kg, IV) and sucrose (45 mg) reinforcer components. Additionally, we tested LS-3-134 (5.6 mg/kg, IP) effects on a progressive ratio (PR) schedule of cocaine reinforcement, on extinction of cocaine-seeking behavior, and on reinstatement of extinguished cocaine-seeking behavior by cocaine-associated light/tone cues. LS-3-134 did not alter spontaneous locomotion, but at 5.6 mg/kg, it reduced cocaine-induced locomotion, break points on the high-effort progressive ratio schedule of reinforcement, and responding during extinction and cue reinstatement. In contrast, LS-3-134 did not alter cocaine or sucrose reinforcement on the low-effort multiple VI 60-second schedule. The effects of LS-3-134 are similar to other dopamine D3 low efficacy partial agonists and antagonists in attenuating cocaine intake under high effort schedules of reinforcement and in attenuating cocaine-seeking behavior elicited by cocaine-associated cues. These findings are consistent with the anti-craving profile of other dopamine D3 drugs.

Muscle wasting in osteoarthritis model induced by anterior cruciate ligament transection.

This study aimed to investigate the molecular pathways involved in muscle wasting in an animal model of osteoarthritis (OA) induced by anterior cruciate ligament transection (ACLT) in rats. Reduction of protein syntheses, increased proteolysis and impaired muscle regeneration are important pathways related to muscle wasting, and myogenin, MyoD, myostatin and MuRF-1 are some of their markers. Female Wistar rats were allocated into two groups: OA (submitted to the ACLT) and SHAM (submitted to surgery without ACLT). Nociception, spontaneous exploratory locomotion and body weight of animals were evaluated weekly. Twelve weeks after the disease induction, animals were euthanized, and the right knee joints were collected. Gastrocnemius muscle of the right hind paw were dissected and weighed. Gastrocnemius was used for evaluation of muscle atrophy and expression of IL-1β, TNF-α, Pax7, myogenin, MyoD, myostatin and MuRF-1. Histopathology of the knee confirmed the development of the disease in animals of OA group. Gastrocnemius of OA animals showed a reduction of about 10% in area and an increased IL-1β expression compared to animals of SHAM group. Expression of myostatin was increased in OA group, while myogenin expression was decreased. TNF-α, Pax7, MuRF-1 and MyoD expression was similar in both OA and SHAM groups. Nociception was significantly elevated in OA animals in the last two weeks of experimental period. Spontaneous exploratory locomotion, body weight and weight of gastrocnemius showed no difference between OA and SHAM groups. Gastrocnemius atrophy in OA induced by ACLT involves elevated expression of IL-1β within the muscle, as well as increased expression of myostatin and decreased expression of myogenin. Therefore, muscle wasting may be linked to impaired muscle regeneration.

De novo tetrahydrobiopterin biosynthesis is impaired in the inflammed striatum of parkin(-/-) mice.

Parkinson's disease (PD), the second-most prevalent neurodegenerative disease, is primarily characterized by neurodegeneration in the substantia nigra pars compacta, resulting in motor impairment. Loss-of-function mutations in parkin are the major cause of the early onset familial form of the disease. Although rodents deficient in parkin (parkin(-/-) ) have some dopaminergic system dysfunction associated with central oxidative stress and energy metabolism deficiencies, these animals only display nigrostriatal pathway degeneration under inflammatory conditions. This study investigated the impact of the inflammatory stimulus induced by lypopolisaccharide (LPS) on tetrahydrobiopterin (BH4) synthesizing enzymes (de novo and salvage pathways), since this cofactor is essential for dopamine synthesis. The mitochondrial content and architecture was investigated in the striatum of LPS-exposed parkin(-/-) mice. As expected, the LPS (0.33 mg/kg; i.p.) challenge compromised spontaneous locomotion and social interaction with juvenile parkin(-/-) and WT mice. Moreover, the genotype impacted the kinetics of the investigation of the juvenile. The inflammatory scenario did not induce apparent changes in mitochondrial ultrastructure; however, it increased the quantity of mitochondria, which were of smaller size, and provoked the perinuclear distribution of the organelle. Furthermore, the BH4 de novo biosynthetic pathway failed to be up-regulated in the LPS challenge, a well-known stimulus for its activation. The LPS treatment increased sepiapterin reductase (SPR) expression, suggesting compensation by the salvage pathway. This might indicate that dopamine synthesis is compromised in parkin(-/-) mice under inflammatory conditions. Finally, this scenario impaired the striatal expression of the transcription factor BDNF, possibly favoring cell death.

Investigation of TRPV1 loss-of-function phenotypes in TRPV1 Leu206Stop mice generated by N-ethyl-N-nitrosourea mutagenesis

N-ethyl-N-nitrosourea (ENU) random mutagenesis was used to generate a mouse model for the analysis of the transient receptor potential vanilloid 1 (TRPV1) cation channel. A transversion from T→A in exon 4 led to a Leu206Stop mutation generating a loss-of-function mutant. The TRPV1 agonist capsaicin was used to analyze functional and nociceptive parameters in vitro and in vivo in TRPV1 Leu206Stop mice and congenic C3HeB/FeJ controls. Capsaicin-induced [Ca2+]i changes in small diameter DRG neurons were significantly diminished in TRPV1 Leu206Stop mice and administration of capsaicin induced neither hypothermia nor nocifensive behaviour in vivo. TRPV1 Leu206Stop mice were tested in the spinal nerve ligation of mononeuropathic pain and developed mechanical hypersensitivity two weeks after nerve injury. In the open field test, a significant increase in spontaneous locomotion was detected in TRPV1 Leu206Stop mice as compared to wildtype controls. TRPV1 knockout mice have been reported to carry a similar phenotype regarding capsaicin-evoked responses in vitro and in vivo. However, in contrast to TRPV1 Leu206Stop mice, TRPV1 knockout mice did not differ in spontaneous locomotion as compared to congenic C57BL/6 mice, suggesting subtle ENU-dependent or independent strain differences between TRPV1 Leu206Stop mice and their wildtype controls. In summary, these data revealed a target-related (i.e. capsaicin-evoked) phenotype of TRPV1 Leu206Stop mice closely resembling that of published TRPV1 knockout mice. However, since ENU-mutant mice are congenic with the mouse strain initially used in random mutagenesis, direct phenotypic comparison with the respective wildtype controls is possible, and the time-consuming backcrossing in lines with targeted mutations is avoided.

Lateral habenular norepinephrine contributes to states of arousal and anxiety in male rats

Recent research has identified the lateral habenula (LHb) as a brain region playing an important role in the production of stressful and anxiogenic states. Additionally, norepinephrine (NE) has long been known to be involved in arousal, stress and anxiety, and NE projections to the LHb have been identified emanating from the locus coeruleus (LC). The current research was devised to test the hypothesis that NE release within the LHb contributes to the occurrence of anxiogenic behaviors. Male rats were implanted with bilateral guide cannula aimed at the LHb and subsequently treated with intracranial (IC) infusions of the selective α2 adrenergic autoreceptor agonist, dexmedetomidine (DEX) (0, 0.5, 1.0 μg/side), prior to assessment of ambulatory and anxiogenic behavior in tests of spontaneous locomotion, open field behavior, and acoustic startle-response. Results demonstrated that DEX administration significantly reduced the overall locomotor behavior of subjects at both doses indicating that infusion of even small doses of this α2 agonist into the LHb can have profound effects on the subjects’ general levels of alertness and activity. DEX was also found to attenuate anxiety as evidenced by a reduction in the magnitude of a startle-response to an acoustic 110 dB stimulus. Taken together, these results identify a role for NE release within the LHb in both arousal and anxiety.

Mutations in the Drosophila homolog of human PLA2G6 give rise to age-dependent loss of psychomotor activity and neurodegeneration

Infantile neuroaxonal dystrophy (INAD) is a fatal neurodegenerative disorder that typically begins within the first few years of life and leads to progressive impairment of movement and cognition. Several years ago, it was shown that >80% of patients with INAD have mutations in the phospholipase gene, PLA2G6. Interestingly, mutations in PLA2G6 are also causative in two other related neurodegenerative diseases, atypical neuroaxonal dystrophy and Dystonia-parkinsonism. While all three disorders give rise to similar defects in movement and cognition, some defects are unique to a specific disorder. At present, the cellular mechanisms underlying PLA2G6-associated neuropathology are poorly understood and there is no cure or treatment that can delay disease progression. Here, we show that loss of iPLA2-VIA, the Drosophila homolog of PLA2G6, gives rise to age-dependent defects in climbing and spontaneous locomotion. Moreover, using a newly developed assay, we show that iPLA2-VIA mutants also display impairments in fine-tune motor movements, motor coordination and psychomotor learning, which are distinct features of PLA2G6-associated disease in humans. Finally, we show that iPLA2-VIA mutants exhibit increased sensitivity to oxidative stress, progressive neurodegeneration and a severely reduced lifespan. Altogether, these data demonstrate that Drosophila iPLA2-VIA mutants provide a useful model to study human PLA2G6-associated neurodegeneration.

Neuroprotective Effects of Filgrastim in Rotenone-Induced Parkinson's Disease in Rats: Insights into its Anti-Inflammatory, Neurotrophic, and Antiapoptotic Effects.

All current treatments of Parkinson's disease (PD) focus on enhancing the dopaminergic effects and providing symptomatic relief; however, they cannot delay the disease progression. Filgrastim, a recombinant methionyl granulocyte colony-stimulating factor, demonstrated neuroprotection in many neurodegenerative and neurological diseases. This study aimed to assess the neuroprotective effects of filgrastim in rotenone-induced rat model of PD and investigate the potential underlying mechanisms of filgrastim actions. The effects of two doses of filgrastim (20 and 40μg/kg) on spontaneous locomotion, catalepsy, body weight, histology, and striatal dopamine (DA) content, as well as tyrosine hydroxylase (TH) and α-synuclein expression, were evaluated. Then, the effective dose was further tested for its potential anti-inflammatory, neurotrophic, and antiapoptotic effects. Filgrastim (40μg/kg) prevented rotenone-induced motor deficits, weight reduction, striatal DA depletion, and histological damage. Besides, it significantly inhibited rotenone-induced decrease in TH expression and increase in α-synuclein immunoreactivity in the midbrains and striata of the rats. These effects were associated with reduction of rotenone-induced neuroinflammation, apoptosis, and brain-derived neurotrophic factor depletion. Collectively, these results suggest that filgrastim might be a good candidate for management of PD.

A multi‐ingredient athletic supplement disproportionately enhances hind leg musculature, jumping performance, and spontaneous locomotion in crickets (Acheta domesticus)

AbstractNutrition is a key component of life‐history theory with profound impacts on fitness traits. We examined lifetime impacts of a multi‐ingredient athletic supplement (MAS) on physical performance, anatomical morphology, survivorship, and general life‐history features in the house cricket, Acheta domesticus (L.) (Orthoptera: Gryllidae). The MAS was formulated using 13 nutraceutical supplements that are commonly used by human athletes specifically to improve athletic performance. Cricket doses were based on human doses adjusted for body size and metabolic rate. Markers of athletic performance included: jumping distance, spontaneous locomotor activity, and morphology of the hind legs (femurs). Supplemented adult crickets jumped ca. 25% further and expressed elevated spontaneous locomotion relative to controls. The MAS disproportionately increased hind leg femur length and width. Life‐history endpoints included survivorship, juvenile growth rate, maturation age, and mature body size. Supplemented crickets showed faster juvenile growth and earlier maturation, but no change in final adult size. A 20% increase in mean survivorship (extending into older ages) was also documented. Crickets represent an excellent new model for assessing athletic diets and associated performance criteria. Finally, as experimental animals were untrained, we argue that our supplement may represent a novel ‘exercise mimetic’ that impacts both performance and survivorship.

Linalool-rich essential oils from the Amazon display antidepressant-type effect in rodents

Ethnopharmacological relevanceThe essential oils of the leaves of Aniba rosaeodora (pau-rosa), Aniba parviflora (macacaporanga) and Aeollanthus suaveolens (catinga-de-mulata), rich in linalool, are used in the traditional medicine of the Brazilian Amazon for its effects on the central nervous system, such as sedative, anticonvulsant and antidepressant, among other therapeutic properties. Aim of the studyTo analyze the chemical composition of these oils and to evaluate their neurobehavioral effects in rodents, based on different and established behavioral tests. Material and methodsThe oils were distilled and analyzed by GC and GC-MS. Male Wistar rats received intraperitoneal doses of the oils of pau-rosa (3.5 and 35mg/kg), macacaporanga (8.5 and 85mg/kg) and catinga-de-mulata (7.5 and 75mg/kg), in addition to a linalool standard (30mg/kg). The neurobehavioral effects were evaluated using the tests: Open Field (spontaneous locomotion activity), Elevated Plus Maze (anxiolytic- type activity), Splash and Forced Swimming (antidepressive-type activity) and the Inhibitory Avoidance (memory retention). ResultsThe three oils (highest dose) and standard linalool presented significant antidepressant activity in rodents. Linalool was identified as the major constituent of the oils (pau-rosa, 88.6%, macacaporanga, 45%, catinga-de-mulata, 49.3%). The standard linalool used was 97.0%. ConclusionThe pau-rosa, macacaporanga, and catinga-de-mulata oils presented antidepressant activity due to the presence of linalool, which, by the final synergistic action of other constituents found in oils, may have contributed to the increase or reduction of this behavioral effect in the treated animals. A relevant fact is that there was no compromise of spontaneous locomotion and the memory retention in the rodents.

Effects of a 5-HT1B Receptor Agonist on Locomotion and Reinstatement of Cocaine-Conditioned Place Preference after Abstinence from Repeated Injections in Mice.

5-HT1B receptors (5-HT1BRs) modulate behavioral effects of cocaine. Here we examined the effects of the 5-HT1BR agonist 5-propoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-pyrrolo[3,2-b]pyridine (CP94253) on spontaneous and cocaine-induced locomotion and on cocaine-primed reinstatement of conditioned place preference (CPP) in male mice given daily repeated injections of either saline or cocaine (15 mg/kg, IP) for 20 days. In the locomotor activity experiment, testing occurred both 1 and 20 days after the final injection. In the CPP experiment, mice underwent conditioning procedures while receiving the last of their daily injections, which were given either during or ≥2 h after CPP procedures. The CPP procedural timeline consisted of baseline preference testing (days 12–13 of the chronic regimen), conditioning (days 14–19, 2 daily 30-min sessions separated by 5 h), CPP test (day 21), extinction (days 22–34; no injections), CPP extinction test (day 35), and reinstatement test (day 36). Mice that had not extinguished received additional extinction sessions prior to reinstatement testing on day 42. On test days, mice were pretreated with either saline or CP94253 (10 mg/kg, IP). Testing began 30 min later, immediately after mice were primed with either saline or cocaine (5 mg/kg for locomotion; 15 mg/kg for reinstatement). We found that CP94253 increased spontaneous locomotion in mice receiving repeated injections of either saline or cocaine when tested 1 day after the last injection, but had no effect on spontaneous locomotion after 20 days abstinence from repeated injections. Surprisingly, cocaine-induced locomotion was sensitized regardless of whether the mice had received repeated saline or cocaine. CP94253 attenuated expression of the sensitized locomotion after 20 days abstinence. A control experiment in noninjected, drug-naïve mice showed that CP94253 had no effect on spontaneous or cocaine-induced locomotion. Mice reinstated cocaine-CPP when given a cocaine prime, and CP94253 pretreatment attenuated cocaine reinstatement.The findings suggest that stress from repeated saline injections and/or co-housing with cocaine-injected mice may cross-sensitize with cocaine effects on locomotion and that CP94253 attenuates these effects, as well as reinstatement of cocaine-CPP. This study supports the idea that 5-HT1BR agonists may be useful anti-cocaine medications.

Effects of Electroacupuncture on Metabolic Changes in Motor Cortex and Striatum of 6-Hydroxydopamine-Induced Parkinsonian Rats.

To explore the possible underlying mechanism by investigating the effect of electroacupuncture (EA) treatment on the primary motor cortex and striatum in a unilateral 6-hydroxydopamine (6-OHDA) induced rat Parkinson's disease (PD) model. Male Sprague-Dawley rats were randomly divided into sham group (n=16), model group (n=14), and EA group (n=14). EA stimulation at Dazhui (GV 14) and Baihui (GV20) was applied to PD rats in the EA group for 4 weeks. Behavioral tests were conducted to evaluate the effectiveness of EA treatment. Metabolites were detected by 7.0 T proton nuclear magnetic resonance. Following 4 weeks of EA treatment in PD model rats, the abnormal behavioral impairment induced by 6-OHDA was alleviated. In monitoring changes in metabolic activity, ratios of myoinositol/creatine (Cr) and N-acetyl aspartate (NAA)/Cr in the primary motor cortex were significantly lower at the injected side than the non-injected side in PD rats (P=0.024 and 0.020). The ratios of glutamate + glutamine (Glx)/Cr and NAA/Cr in the striatum were higher and lower, respectively, at the injected side than the non-injected side (P=0.046 and 0.008). EA treatment restored the balance of metabolic activity in the primary motor cortex and striatum. In addition, the taurine/Cr ratio and Glx/Cr ratio were elevated in the striatum of PD model rats compared to sham-lesioned rats (P=0.026 and 0.000). EA treatment alleviated the excessive glutamatergic transmission by down-regulating the striatal Glx/Cr ratio (P=0.001). The Glx/Cr ratio was negatively correlated with floor plane spontaneous locomotion in PD rats (P=0.027 and P=0.0007). EA treatment is able to normalize the metabolic balance in the primary motor cortex and striatum of PD rats, which may contribute to its therapeutic effect on motor deficits. The striatal Glx/Cr ratio may serve as a potential indicator of PD and a therapeutic target of EA treatment.

Pharmacological characterisation of S 47445, a novel positive allosteric modulator of AMPA receptors.

S 47445 is a novel positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors (AMPA-PAM). S 47445 enhanced glutamate’s action at AMPA receptors on human and rat receptors and was inactive at NMDA and kainate receptors. Potentiation did not differ among the different AMPA receptors subtypes (GluA1/2/4 flip and flop variants) (EC50 between 2.5–5.4 μM), except a higher EC50 value for GluA4 flop (0.7 μM) and a greater amount of potentiation on GluA1 flop. A low concentration of S 47445 (0.1 μM) decreased receptor response decay time of GluA1flop/GluA2flip AMPA receptors and increased the sensitivity to glutamate. Furthermore, S 47445 (0.1 and 0.3 μM) in presence of repetitive glutamate pulses induced a progressive potentiation of the glutamate-evoked currents from the second pulse of glutamate confirming a rapid-enhancing effect of S 47445 at low concentrations. The potentiating effect of S 47445 (1 μM) was concentration-dependently reversed by the selective AMPA receptor antagonist GYKI52466 demonstrating the selective modulatory effect of S 47445 on AMPA receptors. Using an AMPA-kainate chimera approach, it was confirmed that S 47445 binds to the common binding pocket of AMPA-PAMs. S 47445 did not demonstrate neurotoxic effect against glutamate-mediated excitotoxicity in vitro, in contrast significantly protected rat cortical neurons at 10 μM. S 47445 was shown to improve both episodic and spatial working memory in adult rodents at 0.3 mg/kg, as measured in the natural forgetting condition of object recognition and T-maze tasks. Finally, no deleterious effect on spontaneous locomotion and general behavior was observed up to 1000 mg/kg of S 47445 given acutely in rodents, neither occurrence of convulsion or tremors. Collectively, these results indicate that S 47445 is a potent and selective AMPA-PAM presenting procognitive and potential neuroprotective properties. This drug is currently evaluated in clinical phase 2 studies in Alzheimer’s disease and in Major Depressive Disorder.

Psychostimulant Effect of the Synthetic Cannabinoid JWH-018 and AKB48: Behavioral, Neurochemical, and Dopamine Transporter Scan Imaging Studies in Mice.

JWH-018 and AKB48 are two synthetic cannabinoids (SCBs) belonging to different structural classes and illegally marketed as incense, herbal preparations, or chemical supply for theirs psychoactive cannabis-like effects. Clinical reports from emergency room reported psychomotor agitation as one of the most frequent effects in people assuming SCBs. This study aimed to investigate the psychostimulant properties of JWH-018 and AKB48 in male CD-1 mice and to compare their behavioral and biochemical effects with those caused by cocaine and amphetamine. In vivo studies showed that JWH-018 and AKB48, as cocaine and amphetamine, facilitated spontaneous locomotion in mice. These effects were prevented by CB1 receptor blockade and dopamine (DA) D1/5 and D2/3 receptors inhibition. SPECT-CT studies on dopamine transporter (DAT) revealed that, as cocaine and amphetamine, JWH-018 and AKB48 decreased the [123I]-FP-CIT binding in the mouse striatum. Conversely, in vitro competition binding studies revealed that, unlike cocaine and amphetamine, JWH-018 and AKB48 did not bind to mouse or human DAT. Moreover, microdialysis studies showed that the systemic administration of JWH-018, AKB48, cocaine, and amphetamine stimulated DA release in the nucleus accumbens (NAc) shell of freely moving mice. Finally, unlike amphetamine and cocaine, JWH-018 and AKB48 did not induce any changes on spontaneous [3H]-DA efflux from murine striatal synaptosomes. The present results suggest that SCBs facilitate striatal DA release possibly with different mechanisms than cocaine and amphetamine. Furthermore, they demonstrate, for the first time, that JWH-018 and AKB48 induce a psychostimulant effect in mice possibly by increasing NAc DA release. These data, according to clinical reports, outline the potential psychostimulant action of SCBs highlighting their possible danger to human health.

The effect of electroacupuncture on proteomic changes in the motor cortex of 6-OHDA Parkinsonian rats

Electroacupuncture (EA) has been reported to alleviate motor deficits in Parkinson’s disease (PD) patients, and PD animal models. However, the mechanisms by which EA improves motor function have not been investigated. We have employed a 6-hydroxydopamine (6-OHDA) unilateral injection induced PD model to investigate whether EA alters protein expression in the motor cortex. We found that 4weeks of EA treatment significantly improved spontaneous floor plane locomotion and rotarod performance. High-throughput proteomic analysis in the motor cortex was employed. The expression of 54 proteins were altered in the unlesioned motor cortex, and 102 protein expressions were altered in the lesioned motor cortex of 6-OHDA rats compared to sham rats. Compared to non-treatment PD control, EA treatment reversed 6 proteins in unlesioned and 19 proteins in lesioned motor cortex. The present study demonstrated that PD induces proteomic changes in the motor cortex, some of which are rescued by EA treatment. These targeted proteins were mainly involved in increasing autophagy, mRNA processing and ATP binding and maintaining the balance of neurotransmitters.

Assessing the ecotoxicity of potentially neurotoxic substances – Evaluation of a behavioural parameter in the embryogenesis of Danio rerio

The pollution of the aquatic environment is currently characterised by a large number of contaminants, especially by mixtures of micro-pollutants including neurotoxins. The ecotoxicological consequences of this burden are not yet assessable. Within the present study, a new test method was applied which evaluates behavioural changes in zebrafish (Danio rerio) embryos to quantify the neurotoxic effect of selected chemicals. Changes in the frequency of spontaneous tail movements – a parameter of locomotion – occurring during embryogenesis was assessed as parameter for neurotoxic effects. Embryos were exposed in 24-microwell plates to neurotoxic compounds. Behaviour was examined after 24 h of exposure by videotaping and quantifying spontaneous locomotion. Additionally, acute toxicity was determined after 48 h of exposure by utilising the fish embryo toxicity test. Abamectin, emamectin benzoate, chlorpyrifos-oxon and carbamazepine were analysed using both: the new and classic acute test methods. The results showed the neurotoxic effect of the substances. Furthermore, an increased sensitivity compared to acute toxicity data was shown. The aim of the present study, to illustrate the sensitivity and specificity of the established endpoint to reliably assess adverse, neurotoxic effects of compounds on the model organism Danio rerio and to apply a new test method was achieved. Therefore, the present study is a substantial contribution to an effect-based risk assessment of contaminants in aquatic ecosystems.

Adolescent social isolation affects schizophrenia-like behavior and astrocyte biomarkers in the PFC of adult rats

Social isolation is regarded as a cause of schizophrenia spectrum disorders. Animal models of schizophrenia are constructed by repeated early environment deprivation as an important paradigm to reveal its pathological mechanism. Male Sprague Dawley rats were assigned to either social-rearing (SR) or isolated-rearing (IR) groups during postnatal days (PNDs) 21–34. On PND 56, all rats underwent behavioral testing including locomotor activity, anxiety-related behaviors in an open field and prepulse inhibition (PPI). Then, the rats were sacrificed and prefrontal cortex (PFC) tissues were separated for high-throughput proteomics analysis and Western blot validation. Rats of the IR group showed increased spontaneous locomotion, increased anxiety-like behavior and disrupted PPI compared with rats of the SR group. Based on proteomics analysis, a total of 124 PFC proteins were found to be significantly differentially expressed between the SR group and the IR group, the most remarkable of which were glial fibrillary acidic protein (GFAP), Annexin A2 (ANXA2) and vimentin (VIM), three astrocyte biomarkers. Further Western blot measurement confirmed that the levels of GFAP, ANXA2 and VIM were increased significantly in IR rats. Adolescent social isolation induced schizophrenia-like behaviors and significantly different expression of 124 PFC proteins in adult rats, especially GFAP, ANXA2 and VIM, which suggests that astrocyte development might be involved in the neural mechanism of schizophrenia.

The Cathinones MDPV and α-PVP Elicit Different Behavioral and Molecular Effects Following Acute Exposure.

Since the mid-to-late 2000s, synthetic cathinones have gained popularity among drug users due to their psychostimulant effects greater than those produced by cocaine and amphetamine. Among them, 3,4-methylenedioxypyrovalerone (MDPV) and 1-phenyl-2-(pyrrolidin-1-yl)pentan-1-one (α-PVP) are ones of the most popular cathinones available in the clandestine market as "bath salts" or "fertilizers." Pre-clinical studies indicate that MDPV and α-PVP induced psychomotor stimulation, affected thermoregulation, and promoted reinforcing properties in rodents. However, a direct comparative analysis on the effects caused by MDPV and α-PVP on the behavior and neuronal activation in rodents is still lacking. Behavioral analyses revealed that both MDPV and α-PVP affect spontaneous and stimulated motor responses. In particular, MDPV showed a greater psychomotor effect than α-PVP in line with its higher potency in blocking the dopamine transporter (DAT). Notably, MDPV was found to be more effective than α-PVP in facilitating spontaneous locomotion and it displayed a biphasic effect in contrast to the monophasically stimulated locomotion induced by α-PVP. In addition to the behavioral results, we also found a different modulation of immediate early genes (IEGs) such as Arc/Arg3.1 and c-Fos in the frontal lobe, striatum, and hippocampus, indicating that these drugs do impact brain homeostasis with changes in neuronal activity that depend on the drug, the brain area analyzed, and the timing after the injection. These results provide the first discrimination between MDPV and α-PVP based on behavioral and molecular data that may contribute to explain, at least in part, their toxicity.