Comparative Neuropharmacology and Pharmacokinetics of Methamphetamine and Its Thiophene Analog Methiopropamine in Rodents

Methiopropamine is a novel psychoactive substance (NPS) that is associated with several cases of clinical toxicity, yet little information is available regarding its neuropharmacological properties. Here, we employed in vitro and in vivo methods to compare the pharmacokinetics and neurobiological effects of methiopropamine and its structural analog methamphetamine. Methiopropamine was rapidly distributed to the blood and brain after injection in C57BL/6 mice, with a pharmacokinetic profile similar to that of methamphetamine. Methiopropamine induced psychomotor activity, but higher doses were needed (Emax 12.5 mg/kg; i.p.) compared to methamphetamine (Emax 3.75 mg/kg; i.p.). A steep increase in locomotor activity was seen after a modest increase in the methiopropamine dose from 10 to 12.5 mg/kg, suggesting that a small increase in dosage may engender unexpectedly strong effects and heighten the risk of unintended overdose in NPS users. In vitro studies revealed that methiopropamine mediates its effects through inhibition of norepinephrine and dopamine uptake into presynaptic nerve terminals (IC50 = 0.47 and 0.74 µM, respectively), while the plasmalemmal serotonin uptake and vesicular uptake are affected only at high concentrations (IC50 > 25 µM). In summary, methiopropamine closely resembles methamphetamine with regard to its pharmacokinetics, pharmacodynamic effects and mechanism of action, with a potency that is approximately five times lower than that of methamphetamine.

Comparative efficacy of haloperidol and placebo for treatment of delirium induced by biperiden and LPS in adult male rats based on their learning style and change in their short-term spatial memory

Background and Objectives: Delirium refers to acute loss of consciousness and is characterized by confused thinking and impaired orientation. It is a life-threatening, but reversible syndrome manifested by cognitive impairment, abnormal psychomotor activity and sleep disturbances. Due to high prevalence in hospitalized patients and high rate of morbidity and mortality, delirium significantly decreases the prognosis of hospitalized patients. Materials and Methods: This experimental animal study evaluated 54 adult male Wistar rats over 2 months of age that weighed 200 to 230 g. Of all, 24 rats received biperiden (40 mg/kg) while the remaining 24 received 50 µg/kg LPS. Induction of delirium was ensured using a Y-maze after 3 hours. The control group included 6 rats The efficacy of different doses of haloperidol for treatment of delirium was assessed 3 h after injection using the Y-maze . Data were compared using one-way ANOVA followed by Tukey’s post-hoc test via GraphPad Prism. Results: Haloperidol at 0.1, 0.2 and 0.5 mg/kg dosage significantly increased the percentage of spontaneous alternation and improved the memory, consciousness and learning compared with biperiden and LPS groups (P<0.01). No significant difference was noted between the haloperidol groups regarding efficacy (P>0.05). Conclusion: Delirium is characterized by attention deficit, impaired orientation, changes in memory, consciousness, perception and mood, and psychotic symptoms. Detection of the complete spectrum of delirium signs and symptoms in an animal that cannot talk (rat) is obviously difficult .using of Y-maze can facilitate this problem .

Topographic connectivity and cellular profiling reveal detailed input pathways and functionally distinct cell types in the subthalamic nucleus

SummaryThe subthalamic nucleus (STN) controls psychomotor activity and is an efficient therapeutic deep brain stimulation target in Parkinson’s disease patients. Despite evidence indicating position-dependent therapeutic effects and distinct functions within the STN, input circuit and cellular profile in the STN remain largely unclear. Using advanced neuroanatomical techniques, we constructed a comprehensive connectivity map of the indirect and hyperdirect pathways in both the mouse and human STN. Our detailed circuit- and cellular-level connectivity revealed a topographically graded organization with three convergent types of indirect and hyperdirect-pathways. Furthermore, we identified two functional types of glutamatergic STN neurons (parvalbumin, PV +/- neurons) segregated with a topographical distribution. Glutamatergic PV+ STN neurons contribute to burst firing. We confirmed synaptic connectivity from indirect and hyperdirect pathways to both PV+ and PV-. These data suggest a complex interplay of information integration within the basal ganglia underlying coordinated movement control and therapeutic effects.

Acute Regression in Down Syndrome

Background: Acute regression has been reported in some individuals with Down syndrome (DS), typically occurring between the teenage years and mid to late 20s. Characterized by sudden, and often unexplained, reductions in language skills, functional living skills and reduced psychomotor activity, some individuals have been incorrectly diagnosed with Alzheimer’s disease (AD). Methods: This paper compares five individuals with DS who previously experienced acute regression with a matched group of 15 unaffected individuals with DS using a set of AD biomarkers. Results: While the sample was too small to conduct statistical analyses, findings suggest there are possible meaningful differences between the groups on proteomics biomarkers (e.g., NfL, total tau). Hippocampal, caudate and putamen volumes were slightly larger in the regression group, the opposite of what was hypothesized. A slightly lower amyloid load was found on the PET scans for the regression group, but no differences were noted on tau PET. Conclusions: Some proteomics biomarker findings suggest that individuals with DS who experience acute regression may be at increased risk for AD at an earlier age in comparison to unaffected adults with DS. However, due to the age of the group (mean 38 years), it may be too early to observe meaningful group differences on image-based biomarkers.

CORRECTION OF LEARNING DISORDERS BY OPTIMIZING THE DEVELOPMENT OF SPATIAL AND TEMPORAL ORIENTATION

Learning to read, write and calculate are proving to be some of the most significant cognitive processes in early education. The objective of this systematic review is to explore the associations between the psychomotor component and the academic achievement in writing, reading, and mathematics. An organized and methodical research of electronic databases was completed in order to determine significant studies. Twenty eligible articles were strictly evaluated, with extracted and summarized keywords. The two components of the psychomotor activity that influence reading were primarily the orientation ability and the fine motor skill, which is the one responsible for the correct spelling of “mirror-writing”. Differences in motor function were observed after intervention programmes. The results of all researchers have shown that there is a link between dysgraphia, dyslexia and the orientation ability or visual perception. Meanwhile, the role of cognitive and motor skills that underpinned mathematical performance was highlighted, and children who had a high capacity for spatial and visual orientation benefited from a better understanding and perception of geometric figures. However, the importance of students'''' spatial reasoning in relation to mathematics was identified, but only in terms of geometry. Poor quality of spatial notions has been found to be one of the causes of delay in the acquisition of reading, writing and mathematical calculation. The role of fine motor skills in the writing process was also noted, being of real importance in times when the child manipulates the writing tool and puts a word or a sentence on the page.

Implementasi Model Problem Based Instruction terhadap Penguasaan Materi Hukum Newton dan Kecakapan Berpikir Kritis Siswa

This study aims to determine the difference in the achievement of students' average scores between the implementation of the problem based instruction (PBI) model and conventional learning on student activities, mastery of Newton's Law material, and students' critical thinking skills. This research method is a true experiment using a randomized control-group pre-test-post-test design, where the experimental class and the control class are given pre-test and post-test. The results of this study indicate, a) in the psychomotor aspect, the percentage of the good category for the experimental class is on average higher than the control class, while in the affective aspect there is no significant difference; b) there is a significant difference in the mastery of Newton's Law material between students taught through the implementation of the PBI model with an average change in value of 56.59 compared to conventional learning of 46.14; c) there is a significant difference in critical thinking skills between students taught through the implementation of the PBI model with an average change in score of 55.85 compared to conventional learning of 45.62. The conclusion, that the implementation of PBI the average score of psychomotor activity, mastery of Newton's Law material, and students' critical thinking skills are significantly different compared to conventional learning. Keywords: Critical Thinking Skills, Newton's Law Material, Problem Based Instruction Model, Conventional Learning

Role of Lateral Hypothalamus in Acupuncture Inhibition of Cocaine Psychomotor Activity

Acupuncture modulates the mesolimbic dopamine (DA) system; an area implicated in drug abuse. However, the mechanism by which peripheral sensory afferents, during acupuncture stimulation, modulate this system needs further investigation. The lateral hypothalamus (LH) has been implicated in reward processing and addictive behaviors. To investigate the role of the LH in mediating acupuncture effects, we evaluated the role of LH and spinohypothalamic neurons on cocaine-induced psychomotor activity and NAc DA release. Systemic injection of cocaine increased locomotor activity and 50 kHz ultrasonic vocalizations (USVs), which were attenuated by mechanical stimulation of needles inserted into HT7 but neither ST36 nor LI5. The acupuncture effects were blocked by chemical lesions of the LH or mimicked by activation of LH neurons. Single-unit extracellular recordings showed excitation of LH and spinohypothalamic neurons following acupuncture. Our results suggest that acupuncture recruits the LH to suppress the mesolimbic DA system and psychomotor responses following cocaine injection.

HIV-1 Tat Protein Promotes Neuroendocrine Dysfunction Concurrent with the Potentiation of Oxycodone’s Psychomotor Effects in Female Mice

Human immunodeficiency virus (HIV) is associated with neuroendocrine dysfunction which may contribute to co-morbid stress-sensitive disorders. The hypothalamic-pituitary-adrenal (HPA) or -gonadal (HPG) axes are perturbed in up to 50% of HIV patients. The mechanisms are not known, but we have found the HIV-1 trans-activator of transcription (Tat) protein to recapitulate the clinical phenotype in male mice. We hypothesized that HPA and/or HPG dysregulation contributes to Tat-mediated interactions with oxycodone, an opioid often prescribed to HIV patients, in females. Female mice that conditionally-expressed the Tat1–86 protein [Tat(+) mice] or their counterparts that did not [Tat(−) control mice] were exposed to forced swim stress (or not) and behaviorally-assessed for motor and anxiety-like behavior. Some mice had glucocorticoid receptors (GR) or corticotropin-releasing factor receptors (CRF-R) pharmacologically inhibited. Some mice were ovariectomized (OVX). As seen previously in males, Tat elevated basal corticosterone levels and potentiated oxycodone’s psychomotor activity in females. Unlike males, females did not demonstrate adrenal insufficiency and oxycodone potentiation was not regulated by GRs or CRF-Rs. Rather OVX attenuated Tat/oxycodone interactions. Either Tat or oxycodone increased anxiety-like behavior and their combination increased hypothalamic allopregnanolone. OVX increased basal hypothalamic allopregnanolone and obviated Tat or oxycodone-mediated fluctuations. Together, these data provide further evidence for Tat-mediated dysregulation of the HPA axis and reveal the importance of HPG axis regulation in females. HPA/HPG disruption may contribute vulnerability to affective and substance use disorders.

Early loss of Scribble affects cortical development, interhemispheric connectivity and psychomotor activity

Neurodevelopmental disorders arise from combined defects in processes including cell proliferation, differentiation, migration and commissure formation. The evolutionarily conserved tumor-suppressor protein Scribble (Scrib) serves as a nexus to transduce signals for the establishment of apicobasal and planar cell polarity during these processes. Human SCRIB gene mutations are associated with neural tube defects and this gene is located in the minimal critical region deleted in the rare Verheij syndrome. In this study, we generated brain-specific conditional cKO mouse mutants and assessed the impact of the Scrib deletion on brain morphogenesis and behavior. We showed that embryonic deletion of Scrib in the telencephalon leads to cortical thickness reduction (microcephaly) and partial corpus callosum and hippocampal commissure agenesis. We correlated these phenotypes with a disruption in various developmental mechanisms of corticogenesis including neurogenesis, neuronal migration and axonal connectivity. Finally, we show that Scrib cKO mice have psychomotor deficits such as locomotor activity impairment and memory alterations. Altogether, our results show that Scrib is essential for early brain development due to its role in several developmental cellular mechanisms that could underlie some of the deficits observed in complex neurodevelopmental pathologies.

Treatment-resistant schizophrenia characterised by dopamine supersensitivity psychosis and efficacy of asenapine

Dopamine supersensitivity psychosis (DSP) frequently arises with long-term antipsychotic treatment and accounts for a significant proportion of treatment-resistant schizophrenia. The mechanism underlying DSP is thought to be a compensatory increase in dopamine receptor density in the striatum caused by long-term antipsychotic treatment. Previous animal studies have reported that antipsychotics increase serotonin 5-HT2A receptor density in the striatum and that 5-HT2A receptor blockers suppress dopamine-sensitive psychomotor activity, which may be linked to the pathophysiology of DSP. In this paper, we describe a patient who was hospitalised with treatment-resistant schizophrenia. Following treatment with high-dose antipsychotic polypharmacy for 10 weeks, the patient experienced worsening of psychotic and extrapyramidal symptoms. The patient was then started on second-generation antipsychotic asenapine while other antipsychotics were tapered off, resulting in improvement of these symptoms. Retrospectively, we presumed that the high-dose antipsychotic polypharmacy caused DSP, which was effectively treated by the potent 5-HT2A receptor antagonism of asenapine.