Use of neostigmine for the management of drug induced ileus in severe poisonings

Introduction

Effective whole bowel irrigation may be difficult in the presence of drug-induced ileus. Neostigmine, which inhibits the enzymatic degradation of acetylcholine, has been suggested to improve drug-induced ileus. We present two poisoning cases in which neostigmine was used to facilitate gut decontamination complicated by ileus.

Case Reports

A 47-year-old woman, after overdose with sodium valproate, venlafaxine, and ibuprofen, developed ileus that prevented whole bowel irrigation. Neostigmine, 2.5 mg intravenously followed by 1.25 mg three hours later, led to improved bowel transit and successful whole bowel irrigation. A 25-year-old man developed ileus after overdose with venlafaxine, dothiepin, and ethanol. Neostigmine administration led to improved intestinal motility and successful whole bowel irrigation.

Discussion

We demonstrate facilitated gut decontamination temporally associated with administration of neostigmine in two patients judged to have drug-induced ileus following overdose. No significant adverse events related to neostigmine were observed.     

Region-specific regulation of 5-HT1B receptors in the rat brain by chronic venlafaxine treatment

Rationale

Venlafaxine is a non-selective serotonin and noradrenaline reuptake inhibitor antidepressant drug for which clinical studies have suggested a high level efficacy and a possible early action onset compared to the classical antidepressants. Its therapeutic effects might be due, at least in part, to adaptive changes in serotonergic neurotransmission, through the activation of the different 5-HT receptor subtypes. 5-HT_1B receptors are located in the axon terminals of both serotonergic and non-serotonergic neurons, where they act as inhibitory autoreceptors or heteroreceptors, respectively. However, the information about the involvement of this subtype in the mechanism of action of antidepressants is limited and quite controversial.

Objectives

The aim of this study was to evaluate the effect of venlafaxine (10 mg kg^?1 day^?1, p.o.) after 21 days of treatment on the density of 5-HT_1B receptors and their functionality in rat brain.

Methods

Effects of chronic venlafaxine were evaluated at different levels of 5-HT_1B receptor by using receptor autoradiography, [³⁵S]GTPγS binding, and the regulation of body temperature induced by selective 5-HT_1B agonist.

Results

Our results show that venlafaxine induced an increase in sensitivity of 5-HT_1B receptors in hypothalamus both at G-protein level and the control of core temperature without affecting the receptor density.

Conclusions

These results demonstrate that adaptive changes on 5-HT_1B receptors induced by chronic administration of venlafaxine exhibit regional differences suggesting that the hypothalamus might be an important site of drug action.     

SERT and NET occupancy by venlafaxine and milnacipran in nonhuman primates: a PET study

Introduction

Serotonin and norepinephrine reuptake inhibitors (SNRIs) are antidepressants which have high affinity to both serotonin transporter (SERT) and norepinephrine transporter (NET). In studies in vitro, SNRIs have been reported to show a large variability in the affinity ratio between SERT and NET. For instance, the reported affinity ratio is about 30 for venlafaxine and 1.6 for milnacipran. In this study in nonhuman primates, we aimed to investigate the relationship between SERT and NET affinity by measuring the in vivo occupancy at both transporters of venlafaxine and milnacipran.

Methods

PET measurements with [¹¹C]MADAM and [¹⁸F]FMeNER-D₂ were performed in two female cynomolgus monkeys at baseline and after pretreatment with venlafaxine and milnacipran, respectively. Relationships between dose, plasma concentration, and transporter occupancy were evaluated by saturation analysis using a hyperbolic function. Binding affinity (Kd^plasma) was expressed by the dose or plasma concentration at which 50 % of the transporter was occupied.

Results

SERT and NET occupancy by venlafaxine and milnacipran increased in a dose and plasma concentration-dependent manner. The Kd^plasma ratio of SERT to NET was 1.9 for venlafaxine and 0.6 for milnacipran.

Conclusions

In this nonhuman primate PET study, the affinity in vivo for SERT and NET, respectively, was shown to be at a similar level for venlafaxine and milnacipran. Both drugs were found to produce balanced inhibition of SERT and NET binding. This observation is not consistent with previous in vitro binding data and illustrates the need to characterize antidepressants at in vivo condition.     

Tretinoin overdose: A first case report

Introduction

Tretinoin (Vesanoid) is an all-trans-retinoic acid, and is related to retinol (Vitamin A). To date, there have been several case reports on overdose with its isomer isotretinoin, but none involving overdose of tretinoin. We report the first known case of a patient who ingested a massive overdose of tretinoin.

Case Report

A 31-year-old man ingested 1000 mg of tretinoin (100 pills of Vesanoid 10 mg) in a suicide attempt. He developed nonbloody diarrhea, but otherwise had no complaints. Clinical examination was normal. The patient was treated with activated charcoal and was hydrated. The patient’s blood results did not show any deterioration on the third consecutive day. He was discharged well on the third day, but was subsequently lost to follow-up.

Discussion

Although there has been no reported experience with acute tretinoin overdose in humans, our patient took a dose approximately 3 times the recommended maximum tolerated daily dose in patients with myelodysplastic syndrome or solid tumors (195 mg/m² per day). Overdose with other retinoids such as isotretinoin have been associated with only minor symptoms that resolved quickly. Our patient had diarrhea, which also resolved quickly with symptomatic treatment and hydration.

Conclusion

We believe this to be the first case report of an acute oral overdose of tretinoin. The patient developed diarrhea, but was otherwise asymptomatic.     

Methadone Toxicity and Possible Induction and Enhanced Elimination in a Premature Neonate

Introduction

Reports describing methadone overdose in adult and pediatric patient populations are not uncommon. Reports in the preterm neonate patient population, however, are infrequent even though the utilization of methadone in that population continues to increase. Significant age-related pharmacokinetic differences complicate the management of methadone overdose in neonates, and literature involving methadone toxicokinetics and toxicodynamics in pediatric and neonate populations is largely limited.

Case Report

The clinical course and pharmacologic data of a massive methadone overdose in a 20-day-old male neonate is described, and a contemporary review of developmental pharmacology is presented.

Discussion

As clinicians continue to use methadone in neonates, they should be aware of the many significant peculiarities regarding its toxicology and pharmacology in that patient population.     

Acute Oral Potassium Overdose: The Role of Hemodialysis

Introduction

Hyperkalemia is a common condition, particularly in the setting of renal dysfunction. Hyperkalemia due to intentional oral potassium overdose is not commonly reported.

Case Report

We present a case of acute intentional potassium overdose in a patient with normal renal function resulting in significant hyperkalemia, with a maximum serum potassium concentration of 11 mEq/L. Despite an initial course complicated by various unstable cardiac rhythms, including ventricular tachycardia, ventricular fibrillation, and pulseless electrical activity, the patient was discharged from the hospital neurologically intact. Treatment for hyperkalemia included hemodialysis.

Discussion

The role of dialysis in potassium overdose is poorly defined.

Conclusion

Based on this case and a review of the medical literature, we recommend hemodialysis for cases of potassium overdose with hemodynamic instability and significantly elevated serum potassium concentrations that do not respond promptly to medical therapy. Hemodialysis should also be considered in cases with underlying renal dysfunction.     

The role of Akt/FoxO3a in the protective effect of venlafaxine against corticosterone-induced cell death in PC12 cells

Rationale

Antidepressants could exert neuroprotective effects against various insults and the antidepressant-like effect may result from its neuroprotective effects. The phosphatidylinositol-3-kinase/protein kinase B/Forkhead box O3 (PI3K/Akt/FoxO3a) pathway is a key signaling pathway in mediating cell survival. However, no information is available regarding the interaction of FoxO3a and antidepressants.

Objectives

PC12 cells treated with corticosterone were used as a model to study the protective effect of venlafaxine and underlying mechanisms.

Methods

Methyl thiazolyl tetrazolium (MTT) assay, Hoechst staining, and the observation of FoxO3a subcellular location were used to study the protective effect of venlafaxine against cell damage caused by corticosterone. Pretreatments with various pathway inhibitors were used to investigate the possible pathways involved in the protection of venlafaxine. The phosphorylation of Akt and FoxO3a was analyzed by Western blot.

Results

Corticosterone decreased the phosphorylation of Akt and FoxO3a and led to the nuclear localization of FoxO3a and the apoptosis of PC12 cells. Venlafaxine concentration-dependently protected PC12 cells against corticosterone. The protective effect of venlafaxine was reversed by LY294002 and wortmannin, two PI3K inhibitors, and Akt inhibitor VIII, whereas mitogen-activated protein kinase kinase (MAPK kinase) inhibitor PD98059 and the p38 MAPK inhibitor PD160316 had no effect. Western blot analyses showed that venlafaxine induced the phosphorylation of Akt and FoxO3a by the PI3K/Akt pathway and reversed the reduction of the phosphorylated Akt and FoxO3a, and the nuclear translocation of Foxo3a induced by corticosterone.

Conclusions

Venlafaxine protects PC12 cells against corticosterone-induced cell death by modulating the activity of the PI3K/Akt/FoxO3a pathway.     

Prolonged Use of Intravenous Lipid Emulsion in a Severe Tricyclic Antidepressant Overdose

Introduction

Intravenous lipid emulsion (ILE) resuscitation is now frequently being used for severe overdoses due to lipophilic drugs. However, the optimal dose, duration, and safety are still unclear.

Case Report

A patient with refractory cardiovascular collapse following an amitriptyline overdose was treated with ILE with initial improvement. Instability recurred after ILE discontinuation and lipid therapy was restarted, but high-dose treatment was complicated by severe lipemia. A low-dose infusion was instead used, and the patient did not experience further toxicity despite amitriptyline levels in the toxic range for 21 days. He survived to discharge without long-term sequelae.

Discussion

A low-dose infusion of ILE was well tolerated and may have successfully prevented recurrent toxicity in a case of severe tricyclic antidepressant overdose.     

The modulation of venlafaxine on cortical activation of language area in healthy subjects with fMRI study

Rationale

Previous studies have shown that selective serotonin reuptake inhibitors, activators of the cortex, apparently improved language functional recovery after brain damage rather than simply affective disorders.

Objective

Our aim was to determine whether venlafaxine (an agonist of both norepinephrine and 5-hydroxytryptamine) could modulate language cortex function.

Methods

A double-blind, crossover, randomized design was used to compare two 7-day treatment sessions with either venlafaxine (75?mg per day) or placebo. A functional magnetic resonance imaging experiment and two language function tests were performed on eight healthy males (mean age, 28.25?±?3.15?years) at the end of each session, i.e., study entry, after venlafaxine, and after placebo (days 0, 7, and 18). Hyperactivation (venlafaxine minus placebo >0) or hypoactivation (placebo minus venlafaxine >0) by venlaxafine was assessed on the basis of the activation–baseline contrast.

Results

The naming score (P?P?相似文献   

Pramipexole Overdose Associated with Visual Hallucinations,Agitation and Myoclonus

Introduction

Pramipexole is a dopamine D₂ receptor agonist used to treat idiopathic Parkinson’s disease and primary restless legs syndrome. There is limited information on pramipexole overdose.

Case Report

A 59-year-old male ingested 3 mg pramipexole, 2250 mg venlafaxine, 360 mg mirtazapine, with suicidal intent. He presented alert, had normal vital observations and normal pupillary reflexes. He was mildly agitated, reported visual hallucinations and was given 5 mg diazepam. He had a mildly elevated lactate of 1.7 mmol/L, but otherwise normal laboratory investigations. Overnight, he remained agitated with visual hallucinations and developed myoclonus while awake. He had increasing difficulty passing urine on a background of mild chronic urinary retention. On review, 14 h post-ingestion, he was hypervigilant, jittery and mildly agitated. He had pressured speech and difficulty focusing on questioning. He had a heart rate of 110 bpm, but had an otherwise normal examination, with no clonus or extrapyramidal effects. He was unable to mobilize due to dizziness and ataxia. Over the next few hours, he improved, the visual hallucinations and agitation resolved and he mobilized independently. Pramipexole was measured with liquid chromatography mass spectrometry. The initial plasma pramipexole concentration was 34.2 ng/mL (therapeutic range 0.2 to 7 ng/mL), 9 h post-overdose. Concentration time data fitted a one-compartment model with an estimated elimination half-life of 18 h.

Discussion

Pramipexole overdose with hallucination, agitation, and myoclonus is consistent with adverse effects reported with therapeutic toxicity, but mirtazapine and venlafaxine may have contributed. Pramipexole concentrations exceeded the therapeutic range for over 24 h. With the increasing use of pramipexole in restless legs syndrome, adult overdoses may become more common.

     

Kappa opioid mediation of cannabinoid effects of the potent hallucinogen, salvinorin A, in rodents

Rationale

Salvinorin A, the primary psychoactive derivative of the hallucinogenic herb Salvia divinorum, is a potent and highly selective kappa-opioid receptor (KOR) agonist. Several recent studies, however, have suggested endocannabinoid system mediation of some of its effects.

Objectives

This study represents a systematic examination of this hypothesis.

Methods

Salvinorin A was isolated from S. divinorum and was evaluated in a battery of in vitro and in vivo procedures designed to detect cannabinoid activity, including CB₁ receptor radioligand and [³⁵S]GTPγS binding, calcium flux assay, in vivo cannabinoid screening tests, and drug discrimination.

Results

Salvinorin A did not bind to nor activate CB₁ receptors. In vivo salvinorin A produced pronounced hypolocomotion and antinociception (and to a lesser extent, hypothermia). These effects were blocked by the selective KOR antagonist, JDTic, but not by the CB₁ receptor antagonist rimonabant. Interestingly, however, rimonabant attenuated KOR activation stimulated by U69,593 in a [³⁵S]GTPγS assay. Salvinorin A did not substitute for Δ⁹-tetrahydrocannabinol (THC) in mice trained to discriminate THC.

Conclusions

These findings suggest that similarities in the pharmacological effects of salvinorin A and those of cannabinoids are mediated by its activation of KOR rather than by any direct action of salvinorin A on the endocannabinoid system. Further, the results suggest that rimonabant reversal of salvinorin A effects in previous studies may be explained in part by rimonabant attenuation of KOR activation.     

Engineered Andrographolide Nanoparticles Mitigate Paracetamol Hepatotoxicity in Mice

Purpose

Paracetamol (acetaminophen, APAP) overdose is often fatal due to progressive and irreversible hepatic necrosis. The aim of this work was to design Andrographolide (AG) loaded nanoparticles to prevent similar hepatic necrosis.

Methods

Functionalized AG-loaded PLGA nanoparticles carrying different densities of heparin were prepared following a facile emulsion solvent evaporation technique. Nanoparticle morphology, loading and release kinetics were studied. Hepatic localization of the nanoparticles was investigated in both normal and APAP damaged conditions using FITC fluorescent probe. Different serum parameters and liver histopathology were further examined as indicators of hepatic condition before and after treatment.

Result

A collection of heparin functionalized AG-loaded PLGA nanoparticles were designed. Low amount of heparin on the particle surface could rapidly localize the nanoparticles up to the liver. The new functionalized AG nanoparticles affect efficient hepatoprotection in experimental mouse APAP overdose conditions. AG nanoparticle hepatoprotection was due to the rapid regeneration of antioxidant capacity and hepatic GSH store.

Conclusions

Engineered nanoparticles loaded with AG provided a fast protection in APAP induced acute liver failure.     

Milnacipran enhances the control of impulsive action by activating D1-like receptors in the infralimbic cortex

Rationale

Elevated impulsivity is often observed in patients with depression. We recently found that milnacipran, an antidepressant and a serotonin/noradrenaline reuptake inhibitor, could enhance impulse control in rats. However, the neural mechanisms underlying the effects of milnacipran on impulsive action remain unclear. Milnacipran increases not only extracellular serotonin and noradrenaline but also dopamine specifically in the medial prefrontal cortex, which is one of the brain regions responsible for impulsive action.

Objectives

Our goal was to identify whether D₁- and/or D₂-like receptors in the infralimbic cortex (IL), the ventral portion of the medial prefrontal cortex, mediates the milnacipran-enhanced impulse control in a three-choice serial reaction time task.

Methods

The rats were bilaterally injected with SCH23390, a selective D₁-like receptor antagonist (0.3 or 3 ng/side) or eticlopride, a selective D₂-like receptor antagonist (0.3 or 1 μg/side) into the IL after acute intraperitoneal administration of milnacipran (10 mg/kg).

Results

Intra-IL SCH23390 injections reversed the milnacipran-enhanced impulse control, whereas injections of eticlopride into the IL failed to block the effects of milnacipran on impulsive action.

Conclusions

This is the first report that demonstrates a critical role for D₁-like receptors of the IL in milnacipran-enhanced control of impulsive action.     

A report of two deaths from massive ibuprofen ingestion

Introduction

Ibuprofen is a commonly used non-steroidal anti-inflammatory drug. While the vast majority of exposures to the drug do not result in significant morbidity, we are reporting 2 fatalities that resulted from massive ibuprofen ingestion.

Case 1

A 17-year-old girl presented to the emergency department (ED) following an ibuprofen overdose; she was unresponsive with a metabolic acidosis and hypothermic. Her serum ibuprofen concentration was 352 μg/mL: the therapeutic range is 10–50 μg/mL. Despite intensive supportive care and continuous veno-venous hemofiltration, she expired.

Case 2

A 49-year-old man presents to the ED with a history of divalproex sodium and ibuprofen ingestion. He was unresponsive, hypotensive, and had a significant metabolic acidosis. His serum ibuprofen concentration was 260 μg/mL and serum valproate concentration was 560 μg/mL: the therapeutic range is 50–100 μg/mL. In spite of supportive care and hemodialysis, he expired.

Discussion

We will describe 2 cases of ibuprofen overdose characterized by cardiovascular collapse, acidosis, and hypothermia despite the use of vasopressors and renal replacement therapy. Although rarely reported, massive ibuprofen overdose may result in refractory multisystem organ failure and death.     

Impact of age on serum concentrations of venlafaxine and escitalopram in different CYP2D6 and CYP2C19 genotype subgroups

Purpose

The aim of the present study was to investigate the effect of age on venlafaxine and escitalopram serum concentrations in various cytochrome P450 (CYP) 2D6 and CYP2C19 genotype subgroups.

Methods

Serum concentration measurements from CYP-genotyped patients treated with venlafaxine (n?=?255) or escitalopram (n?=?541) were collected retrospectively from a therapeutic drug monitoring database. Patients were divided into three CYP2D6 (venlafaxine) or CYP2C19 (escitalopram) phenotype subgroups according to inherited genotype, i.e., poor metabolizers (PMs), heterozygous extensive metabolizers (HEMs), and extensive metabolizers (EMs), and subsequently distributed into three age groups, i.e., <40 (control), 40–65, and >65 years. The effect of age on dose-adjusted serum concentrations (i.e., nmol/L/mg/day) of venlafaxine and escitalopram in each of the phenotype subgroups was evaluated by separate multivariate mixed model analyses.

Results

In CYP2D6 PMs, the mean dose-adjusted serum concentration of venlafaxine was 8-fold higher in patients >65 years compared with those <40 years (p?<?0.001). In comparison, the respective age-related differences in mean dose-adjusted serum concentrations of venlafaxine were much less pronounced in CYP2D6 HEMs and EMs (<2-fold differences between age groups). A similar genotype-related effect of age was not observed for escitalopram (<1.5-fold age differences in all CYP2C19 subgroups).

Conclusion

This study suggests that the effect of age on serum concentration of venlafaxine is dependent on CYP genotype, in contrast to escitalopram. Thus, to prevent potential side effects, it might be particularly relevant to consider CYP2D6 genotyping prior to initiation of venlafaxine treatment in older patients.     

Effect of Activated Charcoal on Apixaban Pharmacokinetics in Healthy Subjects

Background

Activated charcoal is commonly used to manage overdose or accidental ingestion of medicines. This study evaluated the effect of activated charcoal on apixaban exposure in human subjects.

Methods

This was an open-label, three-treatment, three-period, randomized, crossover study of single-dose apixaban (20 mg) administered alone and with activated charcoal given at 2 or 6 h post-dose to healthy subjects. Blood samples for assay of plasma apixaban concentration were collected up to 72 h post-dose. Pharmacokinetic parameters, including peak plasma concentration (C _max), time to C _max (T _max), area under the concentration–time curve from time 0 to infinity (AUC_INF), and terminal half-life (T _½), were derived from apixaban plasma concentration–time data. A general linear mixed-effect model analysis of C _max and AUC_INF was performed to estimate the effect of activated charcoal on apixaban exposure.

Results

A total of 18 subjects were treated and completed the study. AUC_INF for apixaban without activated charcoal decreased by 50 and 28 %, respectively, when charcoal was administered at 2 and 6 h post-dose. Apixaban C _max and T _max were similar across treatments. The mean T _½ for apixaban alone (13.4 h) decreased to ~5 h when activated charcoal was administered at 2 or 6 h post-dose. Overall, apixaban was well tolerated in this healthy population, and most adverse events were consistent with the known profile of activated charcoal.

Conclusion

Administration of activated charcoal up to 6 h after apixaban reduced apixaban exposure and facilitated the elimination of apixaban. These results suggest that activated charcoal may be useful in the management of apixaban overdose or accidental ingestion.     

Cariprazine (RGH-188), a D3-preferring dopamine D3/D2 receptor partial agonist antipsychotic candidate demonstrates anti-abuse potential in rats

Rationale

Cariprazine (RGH-188) is a D₃-preferring dopamine D₃/D₂ receptor partial agonist antipsychotic candidate for the treatment of schizophrenia and bipolar mania. Substance abuse is a frequent comorbidity of both disorders and is associated with serious health issues. Based on preclinical efficacy, dopamine D₂ and D₃ receptor partial agonists and antagonists are assumed to have relapse-preventing potential in human cocaine addiction.

Objectives

We investigated the anti-abuse potential of cariprazine in cocaine self-administration paradigms. Aripiprazole and bifeprunox were used as comparators because of their pharmacological similarity to cariprazine.

Methods

The effects of compounds on cocaine's rewarding effect were investigated in a continuous self-administration regimen. The relapse-preventing potential of drugs was studied in rats with a history of cocaine self-administration after a period of complete abstinence in a relapse to cocaine-seeking paradigm.

Results

Cariprazine, as well as aripiprazole and bifeprunox, were able to reduce the rewarding effect of cocaine (minimum effective doses were 0.17, 1, and 0.1 mg/kg, respectively) and attenuated relapse to cocaine seeking with half maximal effective dose [ED₅₀] values of 0.2, 4.2, and 0.17 mg/kg, respectively.

Conclusions

These results may predict a relapse-preventing action for cariprazine in humans in addition to its already established antipsychotic and antimanic efficacy.     

Four-year experience with methotrexate exposures

Introduction

Unintentional methotrexate (MTX) acute oral overdose is rarely reported.

Methods

We conducted a retrospective chart review of all human exposure calls (> 150,000 charts) for MTX ingestions reported to our Poison Center during 2000–2003.

Results

Thirteen patients met the criteria. The average amount of MTX ingested was 13.03 mg (data from 7 cases), and the average patient age was 43 years (20 months to 80 years). No significant toxicities occurred.

Discussion

Although intravenous MTX toxicity can be severe, this does not appear to be a phenomenon associated with either acute unintentional or suicidal oral ingestion.     

Chronic social defeat stress model: behavioral features, antidepressant action, and interaction with biological risk factors

Rationale

Chronic social defeat stress (CSDS) has been proposed as a model of depression. However, most CSDS studies rely only on the analysis of stress-induced social avoidance. Moreover, the predictive validity of the model has been poorly analyzed, let alone its interaction with biological risk factors.

Objectives

Here, we explore the validity of CSDS as a depression model. Further, the effect of decreased vesicular glutamate transporter 1 (VGLUT1), as a potential factor enhancing a depressive-like phenotype, was studied.

Methods

Mice were exposed to CSDS (10?days) followed by saline, venlafaxine, fluoxetine, or tianeptine treatment (30?days). The battery of behaviors included motor activity, memory, anxiety, social interaction, helplessness, and anhedonic-like behavior. Moreover, the behavioral effect of CSDS in VGLUT1 heterozygous (VGLUT1+/?) mice was studied, as well as the regulation of VGLUT1 mRNA.

Results

CSDS induced anhedonia, helplessness, hyperactivity, anxiety, social avoidance, and freezing, as well as downregulation of VGLUT1 mRNA in the amygdala. Repeated venlafaxine showed antidepressant-like activity and both venlafaxine and tianeptine behaved as effective anxiolytics. CSDS-induced social avoidance was reverted by tianeptine. Fluoxetine failed to revert most of the behavioral alterations. VGLUT1+/? mice showed an enhanced vulnerability to stress-induced social avoidance.

Conclusion

We suggest that CSDS is not a pure model of depression. Indeed, it addresses relevant aspects of anxiety-related disorders. Firstly, CSDS-induced anhedonia and social avoidance are not associated in this model. Moreover, CSDS might be affecting brain areas mainly involved in the processing of social behavior, such as the amygdala, where the glutamatergic mechanism could play a key role.