Synergistic effects of citicoline and silymarin nanomicelles in restraint stress-exposed mice.

This study evaluated the effects of citicoline and silymarin nanomicelles (SMnm) in repeated restraint stress (RRS). METHOD: Mice were exposed to RRS for four consecutive days, 2 hrs. daily. On day 5 of the study, SMnm (25 and 50 mg/kg, i.p.) and citicoline (25 and 75 mg/kg), and a combination of them (25 mg/kg, i.p.) were initiated. On day 18, anxiety-like behavior, behavioral despair, and exploratory behavior were evaluated. The prefrontal cortex (PFC) and the hippocampus were dissected measuring brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), and tumor necrosis factor-alpha (TNF-α) through Western Blot and ELISA, respectively. RESULTS: In RR-exposed mice, anxiety-like behavior in the elevated plus maze (EPM) was enhanced by reductions in open arm time (OAT%) P < 0.001, and open arm entry (OAE%) P < 0.001. In the forced swimming test (FST), the immobility increased P < 0.001 while the swimming and climbing reduced P < 0.001. In the open field test (OFT), general motor activity was raised P < 0.05. Further, body weights reduced P < 0.001, and tissue BDNF and pCREB expressions decreased P < 0.001 while TNF-α increased P < 0.001. Conversely, SMnm, citicoline and their combination could reduce anxiety-like behavior P < 0.001. The combination group reduced the depressive-like behaviors P < 0.001. Moreover, body weights were restored P < 0.001. Besides, BDNF and pCREB expressions increased while TNF-α reduced, P < 0.001. CONCLUSION: The combination synergistically improved emotion-like behaviors, alleviating the inflammation and upregulating the hippocampal BDNF-mediated CREB signaling pathway.

Additive anxiolytic-like effect of citicoline and ACPA in the non-acute restraint stress (NARS) and acute restraint stress (ARS) mice.

The cannabinoid system plays a key role in stress-related emotional symptoms such as anxiety. Citicoline is a supplemental substance with neuroprotective properties that alleviates anxiety-related behaviors. There is a relation between the actions of cannabinoids and cholinergic systems. So, we decided to evaluate the effects of intracerebroventricular (i.c.v.) infusion of cannabinoid CB1 receptor agents on citicoline-produced response to anxiety-like behaviors in the non-acute restraint stress (NARS) and acute restraint stress (ARS) mice. For i.c.v. microinjection of drugs, a guide cannula was inserted in the left lateral ventricle. ARS was induced by movement restraint for 4 h. Anxiety-related behaviors were assessed using an elevated plus maze (EPM). The results showed that induction of ARS for 4 h decreased the percentage of time spent in the open arms (%OAT) and the percentage of entries to the open arms (%OAE) without affecting locomotor activity, showing anxiogenic-like behaviors. i.c.v. infusion of ACPA (1 µg/mouse) induced an anxiolytic-like effect due to the enhancement of %OAT in the NARS and ARS mice. Nonetheless, i.c.v. microinjection of AM251 (1 µg/mouse) decreased %OAT in the NARS and ARS mice which suggested an anxiogenic-like response. Intraperitoneal (i.p.) administration of citicoline (80 mg/kg) induced an anxiolytic-like effect by the augmentation of %OAT in the ARS mice. Furthermore, when ACPA and citicoline were co-administrated, ACPA potentiated the anxiolytic-like effect induced by citicoline in the NARS and ARS mice. On the other hand, when AM251 and the citicoline were co-injected, AM251 reversed the anxiolytic-like response induced by the citicoline in the NARS and ARS mice. The results of this research exhibited an additive effect between citicoline and ACPA on the induction of anxiolytic-like response in the NARS and ARS mice. Our results indicated an interaction between citicoline and cannabinoid CB1 receptor drugs on the control of anxiety-like behaviors in the NARS and ARS mice.

Alcohol: Epigenome alteration and inter/transgenerational effect.

While DNA serves as the fundamental genetic blueprint for an organism, it is not a static entity. Gene expression, the process by which genetic information is utilized to create functional products like proteins, can be modulated by a diverse range of environmental factors. Epigenetic mechanisms, including DNA methylation, histone modification, and microRNAs, play a pivotal role in mediating the intricate interplay between the environment and gene expression. Intriguingly, alterations in the epigenome have the potential to be inherited across generations. Alcohol use disorder (AUD) poses significant health issues worldwide. Alcohol has the capability to induce changes in the epigenome, which can be inherited by offspring, thus impacting them even in the absence of direct alcohol exposure. This review delves into the impact of alcohol on the epigenome, examining how its effects vary based on factors such as the age of exposure (adolescence or adulthood), the duration of exposure (chronic or acute), and the specific sample collected (brain, blood, or sperm). The literature underscores that alcohol exposure can elicit diverse effects on the epigenome during different life stages. Furthermore, compelling evidence from human and animal studies demonstrates that alcohol induces alterations in epigenome content, affecting both the brain and blood. Notably, rodent studies suggest that these epigenetic changes can result in lasting phenotype alterations that extend across at least two generations. In conclusion, the comprehensive literature analysis supports the notion that alcohol exposure induces lasting epigenetic alterations, influencing the behavior and health of future generations. This knowledge emphasizes the significance of addressing the potential transgenerational effects of alcohol and highlights the importance of preventive measures to minimize the adverse impact on offspring.

Synergistic antidepressant-like effect of citicoline and CB 1 agonist in male mice.

BACKGROUND: The endocannabinoid system plays a key role in the control of many emotional-correlated reactions such as stress, depressed mood, and anxiety. Moreover, citicoline has neuroprotective properties and indicates beneficial effects in the treatment of depressive problems. Acute restraint stress (ARS) is an experimental model used for the induction of rodent models of depression. OBJECTIVE: This research was designed to assess the effects of intracerebroventricular (i.c.v.) injection of cannabinoid CB1 receptor agents on citicoline-induced response to depression-like behaviors in the non-acute restraint stress (NARS) and ARS mice. METHODS: For i.c.v. microinjection, a guide cannula was implanted in the left lateral ventricle of male mice. The ARS model was carried out by movement restraint for 4 h. Depression-related behaviors were assessed by forced swimming test (FST), tail suspension test (TST), and splash test. RESULTS: The results exhibited that the ARS mice showed depressive-like responses. I.c.v. infusion of ACPA (1 µg/mouse) induced an antidepressant-like effect in the NARS and ARS mice by reduction of immobility time in the FST and TST as well as enhancement of grooming activity time in the splash test. On the other hand, i.c.v. microinjection of AM251 dose-dependently (0.5 and 1 µg/mouse) induced a depressant-like effect in the NARS mice. I.p. injection of citicoline (80 mg/kg) induced an antidepressant-like response in the NARS and ARS mice. Furthermore, ACPA (0.25 µg/mouse, i.c.v.) potentiated the antidepressant-like response induced by citicoline (20 mg/kg, i.p.) in the NARS and ARS mice. However, AM251 (0.25 µg/mouse, i.c.v.) reversed the antidepressant-like effect produced by the citicoline (80 mg/kg, i.p.) in the NARS and ARS mice. Interestingly, our results indicated a synergistic effect between citicoline and ACPA based on the induction of an antidepressant-like effect in the NARS and ARS mice. CONCLUSIONS: These results suggested an interaction between citicoline and cannabinoid CB1 receptors on the modulation of depression-like behaviors in the NARS and ARS mice.

Interaction between citalopram and omega-3 fatty acids on anxiety and depression behaviors and maintaining the stability of brain pyramidal neurons in mice.

This research was done to examine the combination of citalopram, an antidepressant drug, and omega-3 in a mice model of depression. Mice received citalopram (1 and 2 mg/kg) or omega-3 (10 and 20 mg/kg) daily over 30 days. Then, they were exposed to acute and chronic restraint stress to assess the possible increasing effect of omega-3 on the antidepressant and anxiolytic effects of citalopram. Elevated plus-maze (EPM) and forced swimming test (FST) were used to assess anxiety and depression symptoms in non-restraint stress (NRS), acute restraint stress (ARS), and chronic restraint stress (CRS) mice. The results indicated that induction of acute and chronic restraint stress reduced %OAT (Open arm time) and %OAE (Open arm entrance) in the EPM test but enhanced immobility time in the FST, showing anxiogenic- and depressive-like effects. These stresses reduced the stability of pyramidal neurons in the prefrontal cortex (PFC) and hippocampus. Aone and combination administration with citalopram and omega-3 induced anxiolytic- and antidepressant-like effects in NRS, ARS, and CRS mice. This combination usage increased the stability of pyramidal neurons in the PFC and hippocampus. These results suggested an interaction between citalopram and omega-3 upon the induction of anxiolytic- and antidepressant-like effects as well as augmentation of the ratio of pyramidal live to dark neurons in the PFC and hippocampus of the ARS and CRS mice.

Synergistic effect between citalopram and muscimol upon induction of anxiolytic- and antidepressant-like effects in male mice: An isobologram analysis.

Background: There is evidence that both the GABAergic system and serotonin reuptake inhibitor (SSRI) such as citalopram are involved in the modulation of anxiety and depression processes. In this research, we examined the effects of GABAA receptor agents and citalopram on anxiety- and depression-related behaviors and their interaction in male mice. Methods: For intracerebroventricular (i.c.v.) infusion, a guide cannula was implanted in the left lateral ventricle. Anxiety and depression behaviors were evaluated using the elevated plus-maze (EPM) and forced swimming test (FST). Results: The results revealed that i.c.v. microinjection of muscimol (1 µg/mouse) enhanced % OAT (open arm time) and % OAE (open arm entries) in the EPM test and decreased immobility time in the FST without affecting locomotor activity, presenting anxiolytic- and antidepressant-like behaviors in the EPM and FST, respectively. On the other hand, i.c.v. microinjection of bicuculline (1 µg/mouse) reduced % OAT and % OAE without affecting locomotor activity and immobility time, presenting an anxiogenic-like effect. Moreover, i.p. administration of citalopram (8 mg/kg) increased %OAT and %OAE and reduced immobility time with no effect on locomotor activity, showing anxiolytic- and antidepressant-like responses in male mice. Furthermore, i.c.v. infusion of an ineffective dosage of muscimol potentiated the anxiolytic- and antidepressant-like responses induced by i.p. injection of citalopram in male mice. When citalopram and bicuculline were co-injected, a non-significant dose of bicuculline reversed the anxiolytic-like effect of citalopram in male mice. Also, the data revealed synergistic anxiolytic- and antidepressant-like behaviors between citalopram and muscimol in male mice. Conclusions: The results suggested an interaction between citalopram and GABAergic agents on the modulation of anxiety and depression behaviors in male mice.

Intracerebroventricular Cutibacterium acnes Generates Manifestations of Alzheimer's Disease-like Pathology in the Rat Hippocampus.

The infection hypothesis is a new causative explanation for Alzheimer's disease (AD). In recent decades, various species of bacterial pathogens have been distinguished in the autopsy of Alzheimer's patients; however, the mechanism of bacterial contribution to AD pathology is still unknown. To explore the hypothesis, Cutibacterium acnes (C. acnes) was selected, and effects of its intracerebroventricular (ICV) inoculation in rats was evaluated. The results revealed that C. acnes causes memory impairment, which might be a consequence of upregulated Amyloid ß (Aß) deposits in the hippocampus; Aß aggregates are co-localized with C. acnes colonies. The key point of our hypothesis is that the activation of the innate immune system by C. acnes through the TLR2/NF-κB/NLRP3 signaling pathway, eventually leads to increased neuroinflammation, which might be resulted from microgliosis and astrogliosis. Neuroinflammation increases oxidative stress and cell apoptosis. Overall, the obtained results of this study support our hypothesis that brain exposure to C. acnes prompted neuroinflammation with similar AD-like pathology.

Psychometric Characteristics of the Persian Version of the Opiate Dosage Adequacy Scale (ODAS).

Introduction: The opiate dosage adequacy scale (ODAS) is one of the most common assessment tools in studies on substance use disorders, which evaluates the "adequacy" of opiate medication doses in individuals recruited in maintenance approaches. There is no investigation on the Persian version of this questionnaire in Iran. This research validated a Persian version of the ODAS. Methods: The Persian version of the ODAS was translated and revised based on the original scale presented by González-Saiz et al. The psychometric characteristics of the ODAS were assessed via direct interviews. Three trained interviewers questioned 250 patients treated in methadone maintenance clinics in Mazandaran Province (Northern Iran) for more than three months. Internal consistency and factor analysis were conducted using SPSS software, version 24. Results: The internal consistency of ODAS was satisfactory (Cronbach's α=0.81). Across all items, considerable inter-rater reliability was discovered (kappa values between 0.90 and 1). A four-component structure was produced by the factor analysis that accounted for 77.5% of the total variance. Cronbach's α coefficients of the four components of Heroin craving and overmedication, Consumption, objective opiate withdrawal symptoms, and subjective opiate withdrawal symptoms were 0.84, 0.91, 0.83, and 0.74, respectively. Conclusion: The reliability and validity of the Persian version of the ODAS were satisfactory in a sample of methadone maintenance subjects. Highlights: The opiate dosage adequacy scale (ODAS) is a clinical tool for measuring the adequacy of methadone dosesThe Persian version of ODAS has good validity, internal consistency, and inter-rater reliability;The Persian version of the ODAS, as a valid and reliable tool, can be used for the Iranian people under methadone maintenance. Plain Language Summary: In Iran, opioids are among the most common forms of illicit drugs. In opioid maintenance programs, the adequacy of methadone doses has an important effect on treatment outcomes. Clinicians typically assess the adequacy of doses based on the patient's response to the medication. Different tools are used in clinical studies to evaluate it. One of these tools is the ODAS, developed by González-Saiz et al. In the present study, we validated the Persian version of the ODAS for Iranian patients receiving methadone maintenance programs. The results confirmed the four-factor structure of the Persian ODAS and showed its good internal consistency and inter-rater reliability.

Paternal Aggression in Early-life Impairs the Spatial Memory and Passive Avoidance Learning in Adulthood of Male Rats: The Possible Role of DRD2.

Introduction: Negative early-life experiences (e.g. having an aggressive father) can leave long-lastingimpacts on the behavior. However, it is not clear if they influence learning and memory. Methods: In this study, we investigated the influences that the presence of an aggressive father had on the level of passive avoidance learning and spatial memory. We also studied the changes in the dopamine receptor D2 (DRD2) and peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) gene expression in the hippocampus. Then, we evaluated if a DRD2 antagonist (sulpiride, 0.125, 0.25, or 0.5 µg/rat) could modulate these changes. Results: We found that the subjects exposed to early-life stress made by aggressive fathers had impaired passive avoidance learning and spatial memory compared to subjects with normal fathers. Treatment with sulpiride improved passive avoidance learning and spatial memory in rats with aggressive fathers. The rats with aggressive fathers also had higher expression of the DRD2 gene in their hippocampus than those with normal fathers, while the PGC-1α gene expression was not different among groups. Treatment with sulpiride (0.125, 0.25, or 0.5 µg/rat) reduced the DRD2 gene expression in those with aggressive fathers to the normal level compared to those with normal fathers. Conclusion: These data suggest that having and living in a shared place with an aggressive father, even without any physical contact, can detrimentally affect passive avoidance learning and spatial memory which is accompanied by the increased expression of the DRD2 gene. Also, sulpiride as a dopaminergic antagonist could reverse this process. Highlights: Having and living with an aggressive father reduced learning and memory in offspring.Having and living with an aggressive father during early life increased DRD2 gene expression.Sulpiride improved learning and memory and also normalized DRD2 gene expression.A combination of genetic and environmental factors may modulate learning and memory. Plain Language Summary: In this study, we looked at how having an aggressive father, can affect behavior in the long term. We wanted to find out if this factor influences learning and memory. To do this, we investigated how the presence of an aggressive father affected passive avoidance learning and spatial memory in subjects. We also examined specific genes in the brain, called DRD2 and PGC-1α, which are known to be involved in learning and memory. Specifically, we wanted to see if the expression of these genes in the hippocampus (a region of the brain important for memory) was affected by having and presence of an aggressive father. To understand the role of the DRD2 gene further, we used a drug called sulpiride, which blocks the action of DRD2. We administered sulpiride to the subjects with aggressive fathers to see if it could reverse any negative effects on learning and memory. What we found was that subjects that had aggressive fathers had impaired passive avoidance learning and spatial memory compared to those with normal fathers. However, when we treated the subjects with sulpiride, their learning and memory improved. Additionally, we observed that rats with aggressive fathers had higher levels of the DRD2 gene in their hippocampus, while the PGC-1α gene expression was not different among the groups. The administration of sulpiride reduced the expression of the DRD2 gene in rats with aggressive fathers, bringing it back to normal levels similar to those with normal fathers. These findings suggest that having and living in the same environment as an aggressive father, even without direct physical contact, can negatively impact passive avoidance learning and spatial memory. This effect seems to be associated with increased expression of the DRD2 gene. However, using sulpiride as a dopaminergic antagonist can reverse this process and improve learning and memory in these subjects.

Does Morphine Exposure Before Gestation Change Anxiety-Like Behavior During Morphine Dependence in Male Wistar Rats?

Background: Anxiety is one of the comorbid disorders of opioid addiction, which leads to opioid abuse or persuades people to engage in opioid abuse. Evidence revealed that morphine exposure before conception changes the offspring's phenotype. The current study aimed to investigate the influence of morphine dependence and abstinence on anxiety-like behavior in morphine-exposed and drug-naïve offspring. Methods: Adult male and female rats were treated with morphine or vehicle for 21 days. Then, all rats were left without drug treatment for 10 days. A morphine-exposed female rat was mated with either a vehicle-exposed or morphine-abstinent male. According to parental morphine exposure, the offspring were categorized into four distinct groups: (1) control (both drug-naïve parents), (2) paternal morphine-exposed, (3) maternal morphine-exposed, and (4) biparental morphine-exposed. The anxiety-like behavior was measured in adult male offspring using open field and elevated plus-maze tests before morphine exposure (naïve), 21 days after morphine exposure (dependence), and ten days after the last morphine exposure (abstinence). Findings: The results indicated that anxiety-like behavior increased before morphine exposure in maternal and biparental morphine-exposed offspring (P<0.05). However, after morphine exposure, the anxiety level did not change among the groups. Ten days after the last morphine exposure, anxiety-like behavior increased only in biparental morphine-exposed offspring (P<0.05). Conclusion: The offspring of morphine-abstinent parents exhibited an anxious phenotype. Disruption of the HPA axis was seen in the progeny of maternal and biparental morphine-exposed rats. Indeed, morphine exposure for 21 days did not change anxiety-like behavior in these offspring which might be correlated to disruption of HPA axis in them.

Decoding hand kinetics and kinematics using somatosensory cortex activity in active and passive movement.

Area 2 of the primary somatosensory cortex (S1), encodes proprioceptive information of limbs. Several studies investigated the encoding of movement parameters in this area. However, the single-trial decoding of these parameters, which can provide additional knowledge about the amount of information available in sub-regions of this area about instantaneous limb movement, has not been well investigated. We decoded kinematic and kinetic parameters of active and passive hand movement during center-out task using conventional and state-based decoders. Our results show that this area can be used to accurately decode position, velocity, force, moment, and joint angles of hand. Kinematics had higher accuracies compared to kinetics and active trials were decoded more accurately than passive trials. Although the state-based decoder outperformed the conventional decoder in the active task, it was the opposite in the passive task. These results can be used in intracortical micro-stimulation procedures to provide proprioceptive feedback to BCI subjects.

A synergistic analgesic effect of morphine in combination with the CB1 receptor agonist, ACPA, in normal, hypothyroid, and hyperthyroid male rats.

Both cannabinoid and opioid receptors are involved in pain behavior. The administration of morphine and cannabis in rats has been shown to decrease thyroid weight and thyroid­stimulating hormone (TSH) levels. We hypothesized that the third ventricle, due to its adjacency to the hypothalamus, is involved in the modulation of hypothalamic­pituitary­thyroid axis activity and descending pain pathways. The present study examined the effect of intra­third ventricle administration of morphine and cannabis agents on the modulation of pain behavior in normal, hypothyroid (increased serum TSH), and hyperthyroid (decreased serum TSH) rats using the tail­flick test. The results indicated that intra­third ventricle injection of AM251 (CB1 receptor antagonist) caused hyperalgesia, while intra­third ventricle administration of ACPA (CB1 receptor agonist) and morphine produced analgesia in normal, hypothyroid, and hyperthyroid rats. A non­effective dose of morphine (0.5 µg/rat) did not attenuate hyperalgesia induced by an effective dose of AM251. Co­injection of ACPA and morphine into the third ventricle induced anti­nociceptive effect in normal, hypothyroid, and hyperthyroid rats. An isobolographic analysis demonstrated a synergistic effect between ACPA and morphine in the production of the anti­nociceptive effect. Consequently, the third ventricle may modulate pain behavior induced by cannabinoid and opioid receptors via descending pain pathways in normal, hypothyroid, and hyperthyroid rats.

The effect of nicotine on antidepressant and anxiolytic responses induced by citalopram and citicoline in mice.

The effect of nicotine on both anxiety and depression has been broadly studied. Moreover, citalopram and citicoline play a role in the modulation of anxiety and depression. This study was designed to examine the effects of nicotine on the antidepressant and anxiolytic responses induced by citalopram and citicoline in mice. Anxiety­ and depression­related behaviors were assessed with the elevated plus maze and forced swim test, respectively. The results showed that subcutaneous administration of nicotine decreased open­arm time (OAT) and open­arm entries (OAE) but increased immobility time, suggesting anxiogenic­like and depressive­like effects. Intraperitoneal administration of citalopram increased OAT but decreased immobility time, indicating that citalopram induced anxiolytic­like and antidepressant­like responses. Additionally, an injection of citicoline increased OAE but decreased immobility time, revealing anxiolytic­like and antidepressant­like effects. Interestingly, the subthreshold dose of nicotine potentiated the citalopram and citicoline effects on OAT and immobility time, which revealed anxiolytic­like and antidepressant­like behaviors. Locomotor activity was not significantly changed by any doses of the drugs. In conclusion, these findings suggest that interactions between nicotine and citalopram or citicoline occur upon induction of anxiolytic and antidepressant responses in mice.

Additive effect of histamine and muscimol upon induction of antinociceptive and antidepressant effects in mice.

We investigated the effects of histamine and GABAA receptor agents on pain and depression-like behaviors and their interaction using a tail-flick test and the forced swimming test (FST) in male mice. Our data revealed that intraperitoneal administration of muscimol (0.12 and 0.25 mg/kg) increased the percentage of maximum possible effect (%MPE) and area under the curve (AUC) of %MPE, indicating an antinociceptive response. Intraperitoneal injection of bicuculline (0.5 and 1 mg/kg) decreased %MPE and AUC of %MPE, suggesting hyperalgesia. Moreover, muscimol by reducing the immobility time of the FST elicited an antidepressant-like response but bicuculline by enhancing the immobility time of the FST caused a depressant-like response. Intracerebroventricular (i.c.v.) microinjection of histamine (5 µg/mouse) enhanced %MPE and AUC of %MPE. i.c.v. infusion of histamine (2.5 and 5 µg/mouse) decreased immobility time in the FST. Co-administration of different doses of histamine along with a sub-threshold dose of muscimol potentiated antinociceptive and antidepressant-like responses produced by histamine. Cotreatment of different doses of histamine plus a noneffective dose of bicuculline reversed antinociception and antidepressant-like effects elicited by histamine. Cotreatment of histamine, muscimol, and bicuculline reversed antinociceptive and antidepressant-like behaviors induced by the drugs. The results demonstrated additive antinociceptive and antidepressant-like effects between histamine and muscimol in mice. In conclusion, our results indicated an interaction between the histaminergic and GABAergic systems in the modulation of pain and depression-like behaviors.

The role of lateral habenula NMDA receptors in tramadol-induced conditioning.

The role of the lateral habenula (LHb) as a hub for receiving and relaying signals from the limbic system to serotonergic, dopaminergic, and norepinephrinergic regions in the brainstem makes this area a critical region in the control of reward and addiction. Behavioral evidence reveals the vital role of the LHb in negative symptoms during withdrawal. In this investigation, we study the role of the LHb N-Methyl D-Aspartate receptor (NMDAR) in the modulation of tramadol reward. Male adult Wistar rats were used in this study. The effect of intra-LHb micro-injection of NMDAR agonist (NMDA, 0.1, 0.5, 2 µg/rat) and antagonist (D-AP5, 0.1, 0.5, 1 µg/rat) was evaluated in conditioned place preference (CPP) paradigm. The obtained results showed that intra-LHb administration of NMDA induced place aversion dose-dependently, while blockade of NMDAR in the LHb using D-AP5 micro-injection led to an increased preference score in the CPP task. Co-administration of NMDA (0.5 µg/rat) with tramadol (4 mg/kg) reduced preference score, while co-administration of D-AP5 (0.5 µg/rat) with a non-effective dose of tramadol (1 mg/kg) potentiate the rewarding effect of tramadol. LHb receives inputs from the limbic system and projects to the monoaminergic nuclei in the brainstem. It has been declared that NMDAR is expressed in LHb, and as obtained data revealed, these receptors could modulate the rewarding effect of tramadol. Therefore, NMDA receptors in the LHb might be a new target for modulating tramadol abuse.

Effect of citicoline and transcranial direct current stimulation on depressive-like behaviors in mice & quot.

Recent investigations revealed the positive role of transcranial direct current stimulation (tDCS) in the treatment of depressive-like behavior & quot. Citicoline is a dietary supplement. It acts as a neuroprotective factor for the treatment of neurological disorders. The aim of this research was to evaluate a possible interaction between tDCS and citicoline on the modulation of depressive-like behavior s & quot in male mice. For tDCS, an electrode was surgically implanted in the left prefrontal of the brain of male mice & quot. Acute restraint stress was induced by movement restraint for 4 h. Locomotor activity and depressive-like behaviors & quot were examined by open field test (OFT), forced swimming test (FST), and tail suspension test (TST). The results indicated that the intraperitoneal (i.p.) administration of citicoline, left prefrontal anodal tDCS, and co-treatment of citicoline and tDCS had no significant effect on locomotor activity. I.p. injection of citicoline (30 mg/kg) decreased immobility time in the FST and TST, showing an antidepressant-like effect & quot. Moreover, the application of left prefrontal anodal tDCS (0.2 mA) for 20 min induced antidepressant-like effect & quot by reducing immobility time in the FST and TST. Co-administration of citicoline (7 and 15 mg/kg) along with tDCS (0.1 mA) decreased immobility time in the FST and TST, indicating an antidepressant-like effect & quot. Therefore, it can be concluded that administration of citicoline in combination with tDCS enhanced the efficacy of tDCS for remedy of depressive-like behaviors & quot.

Modulation of social and depression behaviors in cholestatic and drug-dependent mice: possible role of opioid receptors.

Objectives: Social behavior, a set of motivating activities critical for survival, is disturbed in cholestasis conditions and many substance abusers as well as psychiatric disorders. The documented loss of social interest in cholestatic patients may be associated with depressive symptoms. Interestingly, the endogenous opioid system is involved in the modulation of depression. Methods in this research: , we assessed the effect of cholestasis and drug dependence on social and depression behaviors using the Three-Chamber Paradigm Test, Forced Swim Test (FST), and Tail Suspension Test (TST) as well as Open Field Test (OFT) in male NMRI mice. Results: The results indicated that alone administration of morphine and tramadol, as well as co-administration of them, increased social motivation and novelty but decreased depression in bile duct ligated mice. Whereas, alone administration of naloxone (a µ-opioid receptor antagonist) and co-administration of it along with morphine and tramadol decreased social motivation and novelty while enhanced depression in the sham-operated and bile duct ligated mice. These administrations of drugs did not change locomotor activity compared to the control group. Conclusion: In conclusion, it appears that (i) both cholestasis and drug dependence impaired social motivation behavior, as well as induced depression-like behavior in the bile duct, ligated mice, (ii) alone administration of morphine and tramadol as well as co-treatment of them may protect against cholestasis and drug dependence induced abnormal behaviors, (iii) µ-opioid receptors play an important role in modulation of social motivation and depression behaviors in mice.

The Interaction Effect of Sleep Deprivation and Treadmill Exercise in Various Durations on Spatial Memory with Respect to the Oxidative Status of Rats.

Sleep deprivation (SD) has deleterious effects on cognitive functions including learning and memory. However, some studies have shown that SD can improve cognitive functions. Interestingly, treadmill exercise has both impairment and improvement effects on memory function. In this study, we aimed to investigate the effect of SD for 4 (short-term) and 24 (long-term) hours, and two protocols of treadmill exercise (mild short-term and moderate long-term) on spatial memory performance, and oxidative and antioxidant markers in the serum of rats. Morris Water Maze apparatus was used to assess spatial memory performance. Also, SD was done using gentle handling method. In addition, the serum level of catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) was measured. The results showed that 24 h SD (but not 4 h) had negative effect on spatial memory performance, decreased SOD, CAT, and GSH-Px level, and increased MDA level. Long-term moderate (but not short-term mild) treadmill exercise had also negative effect on spatial memory performance, decreased SOD, CAT, and GSH-Px level, and increased MDA level. Interestingly, both protocols of treadmill exercise reversed spatial memory impairment and oxidative stress induced by 24 h SD. In conclusion, it seems that SD and treadmill exercise interact with each other, and moderate long-term exercise can reverse the negative effects of long-term SD on memory and oxidative status; although, it disrupted memory function and increased oxidative stress by itself.

Dopamine as a Potential Target for Learning and Memory: Contributing to Related Neurological Disorders.

It is well established that learning and memory are complex processes. They involve and recruit different brain modulatory neurotransmitter systems. Considerable evidence points to the involvement of dopamine (DA) in learning and memory. Manifestations of the synaptic spatial localization of the effect of DA have gained a great deal of interest. Despite the molecular cloning of the five DA receptor subtypes, the underlying signaling of the DA receptors in spatial learning and memory is less compelling. Fluctuations in the DA level in the brain are associated with many diseases that comprise deficits in learning and memory, including Parkinson's disease, Huntington's disease, schizophrenia, and Alzheimer's disease. This review aims to briefly summarize existing information regarding the memory performance modified by DA. The signaling of the DA system, particularly examining the origin of DA-modulated memory, is also discussed. Then, several kinds of memories in which DA plays a critical role, including reward signaling, working memory, and long-term plasticity, as well as memory consolidation, are also described. Finally, memory impairment in some DA-related neurological disorders is also examined.

Inter/Transgenerational Effects of Drugs of Abuse: A Scoping Review.

Drug addiction is a chronic relapsing disorder that makes it a global problem. Genetics and environmental factors are the two most important factors that make someone vulnerable to drug addiction. Investigations in the past decade highlighted the role of epigenetics in the inter/transgenerational inheritance of drug addiction. A growing body of evidence showed that parental (paternal, maternal, and biparental) drug exposure before conception changes the phenotype of the offspring, which is correlated with neurochemical and neurostructural changes in the brain. The current paper reviews the effects of parental (maternal, paternal, and biparental) exposure to drugs of abuse (opioids, cocaine, nicotine, alcohol, and cannabis) before gestation in animal models.