Modulation of Leucine Sensors to Mitigate Antipsychotics-Induced Metabolic Syndrome: A New Vista.

Second-generation antipsychotics (SGAs) are currently the mainstay in the pharmacotherapy of some psychiatric disorders, which have improved the quality of life of millions of patients globally. A broad spectrum of activity and diminished liabilities of extrapyramidal side effects have made SGAs better alternatives compared to first-generation antipsychotics. Nevertheless, they display a complex profile of activity by affecting an array of biological targets and, as a result, are associated with a constellation of metabolic abnormalities such as hyperglycemia, dyslipidemia, weight gain, and cardiovascular problems. The SGAs-induced metabolic syndrome's exact mechanism has remained nebulous, but some evidence points the finger at mTOR signaling. In this viewpoint, we propose potential strategies to prevent or alleviate the SGA-induced metabolic adverse effects by modulating the activity of the leucine sensors, Sestrins.

Peering into the Brain's Estrogen Receptors: PET Tracers for Visualization of Nuclear and Extranuclear Estrogen Receptors in Brain Disorders.

Estrogen receptors (ERs) play a multitude of roles in brain function and are implicated in various brain disorders. The use of positron emission tomography (PET) tracers for the visualization of ERs' intricate landscape has shown promise in oncology but remains limited in the context of brain disorders. Despite recent progress in the identification and development of more selective ligands for various ERs subtypes, further optimization is necessary to enable the reliable and efficient imaging of these receptors. In this perspective, we briefly touch upon the significance of estrogen signaling in the brain and raise the setbacks associated with the development of PET tracers for identification of specific ERs subtypes in the brain. We then propose avenues for developing efficient PET tracers to non-invasively study the dynamics of ERs in the brain, as well as neuropsychiatric diseases associated with their malfunction in a longitudinal manner. This perspective puts several potential candidates on the table and highlights the unmet needs and areas requiring further research to unlock the full potential of PET tracers for ERs imaging, ultimately aiding in deepening our understanding of ERs and forging new avenues for potential therapeutic strategies.

Sex and Estrous Cycle Are Not Mediators of S-Ketamine's Rapid-Antidepressant Behavioral Effects in a Genetic Rat Model of Depression.

BACKGROUND: Recent preclinical and clinical studies have shed light on the possible impact of sex and estrous/menstrual cycle on ketamine's antidepressant action but with incongruous results. The preclinical studies that have shown the effects of ovarian sex hormones have not done so in animal models of depression. Thus, the aim of the present study is to scrutinize the acute behavioral responses to a subanesthetic dose of S-ketamine in males vs females and in different estrous phases in free-cycling females in a well-powered translational approach. METHODS: We evaluated the behavioral sensitivity to 20 mg/kg S-ketamine (i.p.) in male and female Flinders Sensitive Line rats (FSLs) and their counterpart Flinders Resistant Line rats (FRLs) subjected to the open field and forced swim tests. Female rats were disaggregated into different estrous phases, and the behavioral outcomes were compared. RESULTS: Acute administration of S-ketamine had robust antidepressant-like effects in FSLs. Within our study power, we could not detect sex- or estrous cycle-specific different antidepressant-like responses to S-ketamine in FSLs. Fluctuations in the levels of ovarian sex hormones across different estrous cycles did not behaviorally affect S-ketamine's rapid-acting antidepressant mode of action. No sex-related or estrous cycle-related impact on behavioral despair was observed even among FRLs and saline-treated FSLs. CONCLUSIONS: We conclude that physiological oscillations of estrogen and progesterone levels neither amplify nor diminish the behavioral antidepressant-like effect of S-ketamine. In addition, fluctuations of ovarian sex hormones do not predispose female animals to exhibit enhanced or reduced depressive-like and anxiety-like behaviors.

Rethinking treatment-resistant depression to quasi-tenacious depression.

With almost one-third of patients with major depression not adequately responsive to treatments, the management of treatment-resistant depression (TRD) has continued to be challenging. Recently, an essential step was taken to replace TRD with difficult-to-treat depression (DTD), pointing to some drawbacks associated with this terminology and identifying addressable barriers. In line with the DTD concept, we discuss why terming this population of patients as TRD could be semantically and clinically misleading. We then suggest replacing TRD with quasi-tenacious depression (QTD), a model and terminology that are derived from a potentially measurable outcome, the tenacity index (TI). QTD predicts that in theory remission is achievable by providing suitable treatments at hand. QTD states that every patient with major depression (even those who respond well) has some degree of tenacity that needs to be overcome by the use of proper treatment modalities. Ergo, in patients with a higher TI, due to the dearth of available armamentaria, one might suffice to achieve a partial resolution of symptoms balanced with an optimal quality of life. However, QTD calls for an incessant pursuit of novel treatments and the identification of contributing factors leading to high TI. On a track toward personalized psychiatry, and in harmony with DTD, QTD embraces all key barriers leading to a failure to treatment response and tries to provide a measurable entity for a better clinical decision while conveying a dynamic positive outlook of the disorder for both patients and health care providers.

Combined effects of quetiapine and opioids: A study of autopsy cases, drug users and sedation in rats.

Fatal opioid poisonings often involve methadone or morphine. This study aimed to elucidate if quetiapine, a widely used sedative antipsychotic medication, may increase the risk of fatal opioid poisoning by additive inhibitory effects on the central nervous system. We used data from 323 cases of fatal methadone or/and morphine poisonings autopsied from 2013 to 2020, a survey of 34 drug users, and performed blinded placebo-controlled studies in 75 Flinders Resistant Line rats receiving three cumulative intraperitoneal doses of vehicle, methadone (2.5, 10 and 15 mg/kg), morphine (3.75, 15 and 22.5 mg/kg), quetiapine (3, 10 and 30 mg/kg) or quetiapine combined with methadone or morphine. Quetiapine was detected in 20.4% of fatal opioid poisonings with a significantly increased frequency over time, primarily in low or therapeutic concentrations, and was not associated with methadone or morphine concentrations. Use of quetiapine, most commonly in low-to-moderate doses to obtain a sleep-inducing or tranquillizing effect, was reported by 67.6% of survey respondents. In the animal studies, a significant impairment of sedation score, performance on the rotarod and open field mobility was observed in all treatment groups compared with vehicle. However, the effect of quetiapine plus the opioid was not significantly different from that of the opioid alone. Thus, no additive sedative effects were observed in rats. Our results suggest that quetiapine is more often an innocent bystander than a contributor to fatal opioid poisoning. However, the combined effects on other parameters, including blood pressure, cardiac rhythm and respiratory rate, need investigation.

Synaptic Vesicle Glycoprotein 2A: Features and Functions.

In recent years, the field of neuroimaging dramatically moved forward by means of the expeditious development of specific radioligands of novel targets. Among these targets, the synaptic vesicle glycoprotein 2A (SV2A) is a transmembrane protein of synaptic vesicles, present in all synaptic terminals, irrespective of neurotransmitter content. It is involved in key functions of neurons, focused on the regulation of neurotransmitter release. The ubiquitous expression in gray matter regions of the brain is the basis of its candidacy as a marker of synaptic density. Following the development of molecules derived from the structure of the anti-epileptic drug levetiracetam, which selectively binds to SV2A, several radiolabeled markers have been synthetized to allow the study of SV2A distribution with positron emission tomography (PET). These radioligands permit the evaluation of in vivo changes of SV2A distribution held to be a potential measure of synaptic density in physiological and pathological conditions. The use of SV2A as a biomarker of synaptic density raises important questions. Despite numerous studies over the last decades, the biological function and the expressional properties of SV2A remain poorly understood. Some functions of SV2A were claimed, but have not been fully elucidated. While the expression of SV2A is ubiquitous, stronger associations between SV2A and Υ amino butyric acid (GABA)-ergic rather than glutamatergic synapses were observed in some brain structures. A further issue is the unclear interaction between SV2A and its tracers, which reflects a need to clarify what really is detected with neuroimaging tools. Here, we summarize the current knowledge of the SV2A protein and we discuss uncertain aspects of SV2A biology and physiology. As SV2A expression is ubiquitous, but likely more strongly related to a certain type of neurotransmission in particular circumstances, a more extensive knowledge of the protein would greatly facilitate the analysis and interpretation of neuroimaging results by allowing the evaluation not only of an increase or decrease of the protein level, but also of the type of neurotransmission involved.

The intersection of astrocytes and the endocannabinoid system in the lateral habenula: on the fast-track to novel rapid-acting antidepressants.

Despite attaining significant advances toward better management of depressive disorders, we are still facing several setbacks. Developing rapid-acting antidepressants with sustained effects is an aspiration that requires thinking anew to explore possible novel targets. Recently, the lateral habenula (LHb), the brain's "anti-reward system", has been shown to go awry in depression in terms of various molecular and electrophysiological signatures. Some of the presumed contributors to such observed aberrations are astrocytes. These star-shaped cells of the brain can alter the firing pattern of the LHb, which keeps the activity of the midbrain's aminergic centers under tight control. Astrocytes are also integral parts of the tripartite synapses, and can therefore modulate synaptic plasticity and leave long-lasting changes in the brain. On the other hand, it was discovered that astrocytes express cannabinoid type 1 receptors (CB1R), which can also take part in long-term plasticity. Herein, we recount how the LHb of a depressed brain deviates from the "normal" one from a molecular perspective. We then try to touch upon the alterations of the endocannabinoid system in the LHb, and cast the idea that modulation of astroglial CB1R may help regulate habenular neuronal activity and synaptogenesis, thereby acting as a new pharmacological tool for regulation of mood and amelioration of depressive symptoms.

Tips and traps for behavioural animal experimentation.

Behavioural animal experimentation is an inseparable part of research trying to understand the biological underpinnings of human behaviour, diseases and disorders. Working with animals comes with great responsibility to achieve reliable and reproducible results of highest scientific quality. In a simple step-by-step fashion, we highlight some common issues that may occur along the path to conducting behavioural animal experimentations and posit some solutions and grounds to ensure the excellence of work done in this research area while aspiring to improve conditions for laboratory animals. It entails topics of study design, animal and experimenter welfare, experimental considerations and frequentist biostatistics. At the end, we direct to some guidelines and manuals that may prove valuable to researchers in this field. Our ten simple tips and traps are meant for students who are learning about important concepts for the first time; graduates whose statistics training all too often has neglected the concept of power in experimental design; and researches who would like a light-hearted refresher on these topics. With this perspective, we hope that you will avoid falling into traps and find answers to what you always wanted to know about conducting behavioural animal experimentation.

Looking into a Deluded Brain through a Neuroimaging Lens.

Delusions are irrational, tenacious, and incorrigible false beliefs that are the most common symptom of a range of brain disorders including schizophrenia, Alzheimer's, and Parkinson's disease. In the case of schizophrenia and other primary delusional disorders, their appearance is often how the disorder is first detected and can be sufficient for diagnosis. At this time, not much is known about the brain dysfunctions leading to delusions, and hindering our understanding is that the complexity of the nature of delusions, and their very unique relevance to the human experience has hampered elucidation of their underlying neurobiology using either patients or animal models. Advances in neuroimaging along with improved psychiatric and cognitive modeling offers us a new opportunity to look with more investigative power into the deluded brain. In this article, based on data obtained from neuroimaging studies, we have attempted to draw a picture of the neural networks involved when delusion is present and evaluate whether different manifestations of delusions engage different regions of the brain.

Validity and reliability of a Persian version of the Dissociative Experiences Scale II (DES-II) on Iranian patients diagnosed with schizophrenia and mood disorders.

Dissociative Experiences Scale (DES) is a valid self-reported tool to evaluate both non-pathological and pathological dissociative experiences. This study aims at evaluating the psychometric properties of a Persian version of the DES-II on both non-clinical samples and patients with schizophrenia and mood disorders. The back-translated DES-II was administered to 370 individuals being divided into three groups (270 healthy subjects, 50 patients with mood disorders, and 50 patients with schizophrenia) recruited from Shahid Beheshti Hospital of Kerman Medical University. The results showed a good reliability (Cronbach's alpha = 0.95), a very high item-total correlation, and a good internal consistency of 0.892 measured by split half. Moreover, the Persian version of the DES-II questionnaire demonstrated convergent validity of the scale. Analyses of the DES-II subscales revealed significant differences for amnesic experiences, absorption/imaginative involvement, and depersonalization/derealization among healthy individuals, and patients with mood disorders as well as schizophrenia. We also found significant differences among only schizophrenia group but not mood disorders group in comparison with healthy individuals (p value = .0001, and 0.70, respectively), and between patients with schizophrenia and patients with mood disorders (p value = .03) using DES-T. As a conclusion, the Persian version of the DES-II is an appropriate, reliable, and valid tool to screen dissociative experiences and discriminate subcomponents of dissociative disorders in the Iranian population.

Comparing Copper Serum Level and Cognitive Functioning in Patients With Schizophrenia and Healthy Controls.

INTRODUCTION: The altered serum profiles of several trace elements have been reported in Schizophrenia (SCZ). This study was designed to elucidate whether the serum levels of Copper (Cu) and Magnesium (Mg), the two essential trace elements which contribute to neurotransmitter transmission, are altered in patients with SCZ. We also investigated whether there is an interrelation between cognitive functioning and the serum levels of Cu and Mg. METHODS: Sixty patients with SCZ and 30 healthy controls participated in this study. The patient group was divided into the following: i) early patients (n=35, ≤5 years of illness initiation), and ii) chronic patients (n=25, ≥5 years of illness duration). The serum levels of Cu and Mg were measured by atomic absorption spectroscopy and ion-selective electrode potentiometry, respectively. To assess cognitive abilities, a Persian adaptation of the Brief Assessment of Cognition in Schizophrenia (BACS) was administered. RESULTS: The present research results revealed significantly higher Cu serum levels in both patient groups [early patients (M=94.6), chronic patients (M=97.5)], compared to the controls (M=71.0) (P<0.001); however, no significant difference was observed among the study groups for Mg [patients with the recent onset (M=2.0), chronic patients (M=2.0), and controls (M=1.9)] P=0.1. While the serum Cu profile of healthy individuals revealed a negative correlation with working memory (r=-0.42, P=0.02), and executive functioning (r=-0.40, P=0.03), no significant correlation was observed between Cu serum levels of patients and BACS cognitive domains. CONCLUSION: findings suggested that the high Cu serum concentration might impact the cognitive decline in healthy individuals; however, no significant correlation was observed in the Patients; i.e. most likely because cognition is severely impaired in SCZ. Additional studies examining trace elements in drug-naïve patients with SCZ are required.

When Thoughts Are in a Race: Area 10 and Bipolar Disorders.

Racing thought, when patients incessantly shift from one word or sentence to another while pending previous ones unfinished, is a symptom of (hypo)mania in bipolar disorders received less attention hitherto. Here, based on few evidence, we aim to unfold our hypothetical viewpoint that the frontopolar cortex that is believed to play a part in multitasking and management of competing goals might be dysfunctional in bipolar patients and may contribute in induction of flight of ideas. We then address new avenues for future research and try to encourage researchers to design more comprehensive studies to either accept or decline this proposed conjecture.

Bipolar disorder and the endocannabinoid system.

OBJECTIVE: Bipolar disorder (BD) is a debilitating, lifelong neuropsychiatric illness characterised by unsteady mood states which vacillate from (hypo)mania to depression. Despite the availability of pharmaceutical agents which can be effective in ameliorating the acute affective symptoms and prevent episodic relapse, BD is inadequately treated in a subset of patients. The endocannabinoid system (ECS) is known to exert neuromodulatory effects on other neurotransmitter systems critical in governing emotions. Several studies ranging from clinical to molecular, as well as anecdotal evidence, have placed a spotlight on the potential role of the ECS in the pathophysiology of BD. In this perspective, we present advantages and disadvantages of cannabis use in the management of illness course of BD and provide mechanistic insights into how this system might contribute to the pathophysiology of BD. RESULTS: We highlight the putative role of selective cannabinoid receptor 2 (CB2) agonists in BD and briefly discuss findings which provide a rationale for targeting the ECS to assuage the symptoms of BD. Further, data encourage basic and clinical studies to determine how cannabis and cannabinoids (CBs) can affect mood and to investigate emerging CB-based options as probable treatment approaches. CONCLUSION: The probable role of the ECS has been almost neglected in BD; however, from data available which suggest a role of ECS in mood control, it is justified to support conducting comprehensive studies to determine whether ECS manipulation could positively affect BD. Based on the limited available data, we suggest that activation of CB2 may stabilise mood in this disorder.

Role of anxiety and depression in association with migraine and myofascial pain temporomandibular disorder.

BACKGROUND: Previous studies have demonstrated a strong association between primary headaches (HAs) and temporomandibular disorders (TMDs), specifically the myofascial pain subtype of TMD (MP TMD). The role of anxiety and depression in presentation and maintenance of MP TMD and migraine is previously demonstrated. Therefore, the objective of the current study was to evaluate the modification effect of anxiety and depression on the possible association of MP TMD and migraine. METHODS: In this retrospective case-control study, individuals between 15 and 45 years old who were diagnosed with migraine HA according to the international classification of headache disorder-II (ICHD-II) were selected as case subjects (n = 65). Non-HA control subjects were matched by sex and age (n = 63). Research diagnostic criteria (RDC/TMD) (Axis I) was used to diagnose patients with MP TMD; other subtypes of RDC/TMD Axis I were excluded from the study. Subjects' anxiety and depression were screened using Persian version of Hospital Anxiety and Depression Scale-14. Chi-square and Mantel-Haenszel tests were used to analyze the data. P < 0.05 was considered statistically significant. RESULTS: A significant association was found between migraine and MP TMD so that subjects with MP TMD had a five times chance of developing HA (P < 0.001). Further analysis using stratification method revealed that anxiety and depression have a modification effect in the association of MP TMD and HA and MP TMD patients with anxiety or depression had more chance of developing migraine HA (P = 0.003). CONCLUSION: Association between HA and TMD was observed in this study. Besides, we depicted that anxiety and depression interact in this association so that patients who did not have anxiety or depression did not demonstrate an association between TMD and HA. We suggest further studies to confirm the modifying effects of anxiety and depression.

A road to bring Brij52 back to attention: Shear stress sensitive Brij52 niosomal carriers for targeted drug delivery to obstructed blood vessels.

Thrombosis is a shared perpetrating event in the pathophysiology of several cardiovascular disorders such as ischemic stroke, venous thromboembolism, atherosclerosis, and myocardial infarction. Despite holding a wide range of ammunition in our arsenal to ameliorate such conditions, we are still facing with many stumbling blocks in the satisfactory pharmacotherapy of cardiovascular diseases among which the risk of hemorrhage and life threatening drug interactions can be highlighted. Our hypothesis focuses on mimicking the nature of platelet activation, to design a novel targeted delivery system based on the alterations of a physical parameter, the hemodynamic shear stress, to aim at the offending thrombi in an attempt to offer a noninvasive, rapid, and monitoring-free method that not only can prolong the circulation time of the cargo, but also deliver it locally and reduce both the undesirable adverse effects and drug interactions. Brij52 is our chosen candidate due to its unique non-spherical morphology after forming a niosomal vesicle. We surmised that thanks to its non-spherical shape, diverse shear rates may generate different shear stresses to its equators and axes which might result in the breakdown or at least distortion of niosomal structure under elevated shear stress. The vesicles have to be synthesized in the size of platelets or in the nano-sized scale. In order to prolong the time vesicles are circulating in the blood, PEGylation may help and to make such carriers highly selective to be only activated during pathophysiological clot formation, attachment of domain A1 von Willebrand factor can be of benefit to lead this proposed delivery system to the site of thrombus formation where shear rate exceeds those of 1000 s-1. There is now an emerging fast growing universal research on shear activated carriers, and the present theory is an endeavor to reach a successful treatment strategy to combat cardiovascular diseases based on the hypothesis that a non-spherical nano-carrier such as Brij 52 niosomal vesicle can be of paramount benefit to deliver current antithrombotic agents in a targeted and controlled manner in the presence of elevated shear stress of the obstructed blood vessels. With more radical advanced drug delivery systems being developed and new strategies being pursued, there will be more options in our arsenal to represent a promising avenue for achieving preventive, well-tolerated, and intelligent drug carriers to circumvent the drawbacks of antithrombotic pharmacotherapy.

Contribution of CB1Rs in anxiety-related behaviors but not locomotor deficits induced by methamphetamine.

Several lines of evidence have indicated that Methamphetamine (METH) exposure leads to neurodegenerative changes in the dopaminergic neurons and subsequently may predispose users to motor deficit. On the other hand, there is a reciprocal regulation between the endocannabinoid and the dopaminergic systems. Previous studies also showed that the endocannabinoids are involved in the signaling mechanisms of various brain regions related to motor and cognitive functions. The cerebellum seems as a rational target to investigate the action of cannabinoids on motor coordination because of the high concentration of the cannabinoid receptor in the molecular layer of it and other regions involved in motor activity. The behavioral effects of systemic CBR agonist (3mg/kg/day WIN55,212-2) and antagonist (10mg/kg SR141716A) treatment on METH-induced motor deficits in rats were assessed using open field, rota-rod, and grip tests. Our results show that motor coordination and muscle strength significantly decreased in the animals received METH (5mg/kg, daily×3days) as compared to the saline groups. Pretreatment with neither WIN55,212-2 nor SR141716A had no effects on impairments induced by METH. Meanwhile, motor activity and anxiety-related behaviors significantly increased in the animals that received METH and pretreatment with SR141716A significantly attenuated anxiety-related behaviors induced by METH. In sum, our findings show that anxiety-related behaviors induced by METH can be affected by CB1R manipulation and provide evidence that antagonism of CB1R at high dose cannot reverse the deteriorative METH-induced locomotion changes.

A Brain on a Roller Coaster: Can the Dopamine Reward System Act as a Protagonist to Subdue the Ups and Downs of Bipolar Disorder?

One of the most interesting but tenebrous parts of the bipolar disorder (BD) story is the switch between (hypo)mania and depression, which can give bipolar patients a thrilling, but somewhat perilous, 'ride'. Numerous studies have pointed out that there are some recognizable differences (either state-dependent or state-independent) in several brain regions of people with BD, including components of the brain's reward system. Understanding the underpinning mechanisms of high and low mood statuses in BD has potential, not only for the development of highly specific and selective pharmaceutical agents, but also for better treatment approaches and psychological interventions to manage BD and, thus, give patients a safer ride. Herein, we review evidence that supports involvement of the reward system in the pathophysiology of mood swings, with the main focus on the mesocorticolimbic dopaminergic neural circuitry. Principally using findings from neuroimaging studies, we aim to signpost readers as to how mood alterations may affect different areas of the reward system and how antipsychotic drugs can influence the activity of these brain areas. Finally, we critically evaluate the hypothesis that the mesocorticolimbic dopamine reward system may act as a functional rheostat for different mood states.

Modulation of sphingosine-1-phosphate receptor ameliorates harmaline-induced essential tremor in rat.

Essential tremor (ET) is one of the most common movement disorders with unknown etiology. Despite lack of effective clinical treatments, some potential therapeutic factors and modulation of some neurotransmitters have been utilized to ameliorate motor symptoms in the animal models of tremor. In the current study, male Wistar rats (n=10 in each group) weighing 40-60g were divided into vehicle control groups (saline or DMSO), saline/DMSO+harmaline (30mg/kg, i.p.)+fingolimod (FTY720) (1mg/kg, i.p, 1h before harmaline injection) groups. Open field, rotarod, wire grip and foot print tests were used to evaluate motor function. The results demonstrated that administration of FTY720 can improve harmaline-induced tremor in rats. Moreover, FTY720 ameliorated gait disturbance. The results showed that FTY720 can recover step width, left and right step length; however, FTY720 failed to recover mobility duration. FTY720 also improved falling time and time spent in wire grip and rotarod, respectively. The current study provides the first evidence for the effectiveness of FTY720 on motor function in the harmaline model of ET. Furthermore, neuroprotective effects of FTY720 demonstrated in this study offer sphingosine-1-phosphate receptor (S1PR) modulators as a potential neuroprotective candidate against substance-induced tremor and a possible strategy for the treatment of patients with tremor.

Nitric oxide pathway presumably does not contribute to antianxiety and memory retrieval effects of losartan.

Nitric oxide (NO) and angiotensin (AT) receptors have demonstrated well-established interactions in various physiological phenomena. AT1 receptors can play a part in stress-induced activation of the hypothalamic-pituitary-adrenal axis; also, angiotensinergic neurotransmission plays a pivotal role in stress-evoked physiological responses. On the basis of the stress-modulating characteristics of NO, AT1, and AT2 receptors, the present study evaluated the roles of NO and AT1 receptors in the attenuation of stress-induced anxiety-like behaviors after administration of losartan, an AT1 antagonist. Male Wistar rats were exposed to the communication stress box, using a novel method to induce physical or emotional stress, and losartan (10 mg/kg), losartan+L-NG-nitroargininemethyl ester (L-NAME), L-NAME (1, 10, and 100 mg/kg), and normal saline-treated groups were compared. Losartan had reduced behavioral changes induced by both types of stressor and enhanced memory retrieval. Anxiety-like behaviors were significantly attenuated by administration of losartan, to a greater extent in the emotional rather than physical stress group. None of the injected dosages of L-NAME reversed the antianxiety and memory retrieval effects of losartan. Our results indicate that losartan probably improves memory retrieval and lessens anxiety-like behaviors through mechanisms other than the NO pathway.

Attenuation Effect of Cannabinoid Type 1 Receptor Activation on Methamphetamine-Induced Neurodegeneration and Locomotion Impairments among Male Rats.

BACKGROUND: A number of neuroimaging studies on human addicts have revealed that abuse of Methamphetamine (METH) can induce neurodegenerative changes in various brain regions like the cerebral cortex and cerebellum. Although the underlying mechanisms of METH-induced neurotoxicity have been studied, the cellular and molecular mechanisms of METH-induced neurotoxicity remain to be clarified. Previous studies implicated that cannabinoid type 1 receptors (CB1Rs) exert neuroprotective effects on several models of cerebral toxicity, but their role in METH-induced neurotoxicity has been rarely investigated. Moreover, the cerebellum was considered as a potential target to evaluate the effects of cannabinoids on locomotion activity as the CB1Rs are most widely distributed in the molecular layer of cerebellum. Therefore, the present study was carried out to evaluate whether neurodegeneration induced in the cerebellum tissue implicated in locomotion deficit induced by METH. METHODS: In the current study, open field test was used to examine locomotor activity. Using hematoxylin and eosin (H&E) staining, morphology of the cerebellar vermis was investigated after repeated exposure to METH. Then, the effects of CB1Rs antagonist [SR17141A, 10 mg/kg, intraperitoneally (IP)] and CB1Rs agonist [WIN55, 212-2 (WIN), 3 mg/kg] against METH-induced neurodegeneration and locomotor deficit were assessed. FINDINGS: The results of the present study demonstrated that repeated exposure to METH increased cerebellar degeneration level as compared to the saline and dimethyl sulfoxide (DMSO) groups. In addition, METH-treated rats showed hyperactivity as compared to the saline and DMSO groups. Pretreatment with WIN significantly attenuated neurodegeneration and hyperactivity induced by METH. CONCLUSION: The findings of this study provided evidence that CB1Rs may serve as a therapeutic strategy for attenuation of METH-induced locomotor deficits.