Comparison of Postoperative Complications and Outcomes in Anterior Cervical Spine Surgery: Ossification of the Posterior Longitudinal Ligament Versus Cervical Spondylotic Myelopathy.

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: To compare the frequency of complications and outcomes between patients with ossification of the posterior longitudinal ligament (OPLL) of the cervical spine and those with cervical spondylotic myelopathy (CSM) who underwent anterior surgery. SUMMARY OF BACKGROUND DATA: Anterior cervical spine surgery for OPLL is an effective surgical procedure; however, it is complex and technically demanding compared with the procedure for CSM. Few reports have compared postoperative complications and clinical outcomes after anterior surgeries between the 2 pathologies. METHODS: Among 1434 patients who underwent anterior cervical spine surgery at 3 spine centers within the same spine research group from January 2011 to March 2021, 333 patients with OPLL and 488 patients with CSM were retrospectively evaluated. Demographics, postoperative complications, and outcomes were reviewed by analyzing medical records. In-hospital and postdischarge postoperative complications were investigated. Postoperative outcomes were evaluated 1 year after the surgery using the Japanese Orthopaedic Association score. RESULTS: Patients with OPLL had more comorbid diabetes mellitus preoperatively than patients with CSM ( P <0.001). Anterior cervical corpectomies were more often performed in patients with OPLL than in those with CSM (73.3% and 14.5%). In-hospital complications, such as reoperation, cerebrospinal fluid leak, C5 palsy, graft complications, hoarseness, and upper airway complications, occurred significantly more often in patients with OPLL. Complications after discharge, such as complications of the graft bone/cage and hoarseness, were significantly more common in patients with OPLL. The recovery rate of the Japanese Orthopaedic Association score 1 year postoperatively was similar between patients with OPLL and those with CSM. CONCLUSION: The present study demonstrated that complications, both in-hospital and after discharge following anterior spine surgery, occurred more frequently in patients with OPLL than in those with CSM.

A parent-rating scale of postpartum depression: Maternity-monitoring scale by parents (MMSP).

Postpartum depression (PPD) is an illness that is difficult for the affected women themselves to recognize. Moreover, many mothers believe that mothers should not complain about the mental difficulties of taking care of their children. Therefore, in addition to self-evaluation for PPD, evaluation from others is also necessary. We aimed to develop a novel measure to screen for PPD based on a parent-rating scale that is administered to the parents of postpartum mothers. The 15-item maternity-monitoring scale by parents (MMSP) was designed and applied to the feasibility cohort (n = 61) and the emergency cohort (n = 55). The Edinburgh Postnatal Depression Scale (EPDS) (threshold score of 8/9) was used to evaluate a high risk of PPD. An egogram-based index, the over-adaptation index for depression (OAID), was performed along with the EPDS and MMSP. In the feasibility cohort, MMSP was moderately correlated with EPDS. In the emergency cohort, under the circumstance of the state of emergency declaration over the coronavirus disease 2019 in Japan, application of the MMSP was delayed, resulting in the proportion of parents who overlooked PPD symptoms in their daughters increasing from 33 % to 50 %. Our findings suggest that a novel approach of parent-rated PDD screening of postpartum women is potentially possible, and the MMSP is a potential candidate for screening. Moreover, the OAID is also helpful in identifying women with hidden PPD, along with the EPDS. The performance of the MMSP should be confirmed in the parents of patients with PPD diagnosed by psychiatrists.

Cannabinoid CB2 receptors and hypersensitivity to methamphetamine: Vulnerability to schizophrenia.

The human cannabinoid receptor 2 (CB2R) gene CNR2 has been associated with schizophrenia development. Inbred mice treated with the CB2R inverse agonist AM630 and challenged with methamphetamine (MAP) showed reduced prepulse inhibition (%PPI) response and locomotor hyperactivity, both behavioral measures in rodents that correlate with psychosis. Mice lacking CB2R on striatal dopaminergic neurons exhibit a hyperdopaminergic tone and a hyperactivity phenotype. Hyperdopaminergia plays a role in the etiology of schizophrenia. This study aimed to determine the direct role of CB2R, heterozygous Cnr2 gene knockout (Het) mice treated with MAP to induce behavioral sensitivity mimicking a schizophrenia-like human phenotype. Additionally, the study aims to explore the unique modulation of dopamine activity by neuronal CB2R. Conditional knockout DAT-Cnr2-/- mice were evaluated in response to MAP treatments for this purpose. Sensorimotor gating deficits in DAT-Cnr2-/- mice were also evaluated. Het mice developed reverse tolerance (RT) to MAP-enhanced locomotor activity, and RT reduced the %PPI compared to wild-type (WT) mice. DAT-Cnr2-/- mice showed an increased sensitivity to stereotypical behavior induced by MAP and developed RT to MAP. DAT-Cnr2-/- mice exhibit a reduction in %PPI and alter social interaction, another core symptom of schizophrenia. These results demonstrate that there is an interaction between neuronal CB2R and MAP treatment, which increases the risk of schizophrenia-like behavior in this mouse model. This finding provides evidence for further studies targeting CB2R as a potential schizophrenia therapy.

Clinical and molecular delineation of classical-like Ehlers-Danlos syndrome through a comprehensive next-generation sequencing-based screening system.

Classical-like Ehlers-Danlos syndrome (clEDS) is an autosomal recessive disorder caused by complete absence of tenascin-X resulting from biallelic variation in TNXB. Thus far, 50 patients from 43 families with biallelic TNXB variants have been identified. Accurate detection of TNXB variants is challenging because of the presence of the pseudogene TNXA, which can undergo non-allelic homologous recombination. Therefore, we designed a genetic screening system that is performed using similar operations to other next-generation sequencing (NGS) panel analyses and can be applied to accurately detect TNXB variants and the recombination of TNXA-derived sequences into TNXB. Using this system, we identified biallelic TNXB variants in nine unrelated clEDS patients. TNXA-derived variations were found in >75% of the current cohort, comparable to previous reports. The current cohort generally exhibited similar clinical features to patients in previous reports, but had a higher frequency of gastrointestinal complications (e.g., perforation, diverticulitis, gastrointestinal bleeding, intestinal obstruction, rectal/anal prolapse, and gallstones). This report is the first to apply an NGS-based screening for TNXB variants and represents the third largest cohort of clEDS, highlighting the importance of increasing awareness of the risk of gastrointestinal complications.

Depression and Associated Factors Among the Elderly Population in an Urban Tertiary Geriatric Hospital in Bangladesh.

Background: Geriatric depression becoming a serious concern worldwide, but no studies addressed depression among patients attending outpatient department of a tertiary geriatric care hospital in Bangladesh. Methods: This cross-sectional study was conducted in face-to-face interview using the Geriatric Depression Scale (GDS-15) to measure depression among 230 elderly outpatients (60-80 years old) who visited the hospital for medical reasons in Dhaka city; a variety of socio-demographic, behavioral, and psycho-social variables as well as history of chronic diseases were assessed to detect factors associated with depression. Results: The prevalence of depression was 81.7%; 52.6%, 25.2%, and 3.9% showed mild, moderate and severe depression (the GDS scores 5-8, 9-11, and 12-15), respectively. In logistic regression models, the associated factors included marital status, occupational status, educational status, physical activity, and history of cerebrovascular diseases or stroke. The prevalence of depression was generally higher than other reports elsewhere, and the reason behind this may include the use of the GDS-15 and the setting to carry out this study. Conclusion: Nationally representative investigations are warranted to further address depression among the elderly in Bangladesh; these findings would be helpful for future studies and intervention programs.

Lysophosphatidylinositol Induced Morphological Changes and Stress Fiber Formation through the GPR55-RhoA-ROCK Pathway.

We previously reported that lysophosphatidylinositol (LPI) functions as an endogenous agonist of GPR55, a novel cannabinoid receptor. However, the physiological roles of LPI-GPR55 have not yet been elucidated in detail. In the present study, we found that LPI induced morphological changes in GPR55-expressing HEK293 cells. LPI induced the cell rounding of GPR55-expressing HEK293 cells but not of empty-vector-transfected cells. LPI also induced the activation of small GTP-binding protein RhoA and increased stress fiber formation in GPR55-expressing HEK293 cells. The inhibition of RhoA and Rho kinase ROCK by the C3 exoenzyme and the ROCK inhibitor reduced LPI-induced cell rounding and stress fiber formation. These results clearly indicated that the LPI-induced morphological changes and the assembly of the cytoskeletons were mediated through the GPR55-RhoA-ROCK pathway.

Potential Role of Cannabinoid Type 2 Receptors in Neuropsychiatric and Neurodegenerative Disorders.

The endocannabinoid system (ECS) is composed of the two canonical receptor subtypes; type-1 cannabinoid (CB1R) and type 2 receptor (CB2R), endocannabinoids (eCBs) and enzymes responsible for the synthesis and degradation of eCBs. Recently, with the identification of additional lipid mediators, enzymes and receptors, the expanded ECS called the endocannabinoidome (eCBome) has been identified and recognized. Activation of CB1R is associated with a plethora of physiological effects and some central nervous system (CNS) side effects, whereas, CB2R activation is devoid of such effects and hence CB2Rs might be utilized as potential new targets for the treatment of different disorders including neuropsychiatric disorders. Previous studies suggested that CB2Rs were absent in the brain and they were considered as peripheral receptors, however, recent studies confirmed the presence of CB2Rs in different brain regions. Several studies have now focused on the characterization of its physiological and pathological roles. Studies done on the role of CB2Rs as a therapeutic target for treating different disorders revealed important putative role of CB2R in neuropsychiatric disorders that requires further clinical validation. Here we provide current insights and knowledge on the potential role of targeting CB2Rs in neuropsychiatric and neurodegenerative disorders. Its non-psychoactive effect makes the CB2R a potential target for treating CNS disorders; however, a better understanding of the fundamental pharmacology of CB2R activation is essential for the design of novel therapeutic strategies.

New Insights and Potential Therapeutic Targeting of CB2 Cannabinoid Receptors in CNS Disorders.

The endocannabinoid system (ECS) is ubiquitous in most human tissues, and involved in the regulation of mental health. Consequently, its dysregulation is associated with neuropsychiatric and neurodegenerative disorders. Together, the ECS and the expanded endocannabinoidome (eCBome) are composed of genes coding for CB1 and CB2 cannabinoid receptors (CB1R, CB2R), endocannabinoids (eCBs), and the metabolic enzyme machinery for their synthesis and catabolism. The activation of CB1R is associated with adverse effects on the central nervous system (CNS), which has limited the therapeutic use of drugs that bind this receptor. The discovery of the functional neuronal CB2R raised new possibilities for the potential and safe targeting of the ECS for the treatment of CNS disorders. Previous studies were not able to detect CB2R mRNA transcripts in brain tissue and suggested that CB2Rs were absent in the brain and were considered peripheral receptors. Studies done on the role of CB2Rs as a potential therapeutic target for treating different disorders revealed the important putative role of CB2Rs in certain CNS disorders, which requires further clinical validation. This review addresses recent advances on the role of CB2Rs in neuropsychiatric and neurodegenerative disorders, including, but not limited to, anxiety, depression, schizophrenia, Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD) and addiction.

Clonazepam for pain due to muscle spasm in a patient with vertebral compression fractures caused by multiple myeloma: a case report.

BACKGROUND: Vertebral compression fractures can cause severe back pain. Although many types of analgesics and interventional treatments are available, they are sometimes ineffective in mitigating the pain. We encountered a case where clonazepam was effective for the management of severe low back pain caused by lumbar vertebral compression fractures. CASE PRESENTATION: A 44-year-old male was diagnosed with multiple myeloma and had vertebral compression fractures of the first and second lumbar vertebrae. He had been suffering from severe low back pain on movement with muscle spasm and pain-associated anxiety. We considered this breakthrough low back pain to be caused by facet joint pain; thus, we prescribed clonazepam as a muscle relaxant and anxiolytic. Following this treatment, the intractable breakthrough pain was dramatically relieved. CONCLUSION: Clonazepam, which has both muscle relaxant and anxiolytic effects, might be helpful in mitigating pain, associated anxiety, and muscle spasms due to vertebral compression fractures.

Ehlers-Danlos Syndrome in the Field of Psychiatry: A Review.

Ehlers-Danlos syndrome (EDS) comprises a series of rare hereditary connective tissue diseases characterized by joint hypermobility, joint dislocation, and hyperextensibility of the skin, as well as cardiovascular involvement. EDS is often associated with chronic widespread physical pain, which can lead to psychological pain. Poor awareness and limited diagnosis of EDS and related symptoms result in decreased self-esteem and confusion regarding physical sensation. Furthermore, EDS imposes substantial psychological burden on patients due to exercise restriction, scars, keloids, and subcutaneous fat accumulation on the extremities, which leads to parental overprotection and bullying experiences from other children at school age. Recent large-scale studies have suggested that patients with EDS have a higher risk of mood disorders than the general population. Other cohort studies indicated high prevalence of anorexia nervosa, addiction, obsessive compulsive disorder, and anxiety disorder were found in patients with EDS. Case reports instead indicated that some psychiatric disorders were secondary symptoms due to physical problems from EDS. Therefore, psychiatrists must be more knowledgeable and proactive about EDS in their practice. We review the previous case reports and literature for patients with EDS, along with our own case of complicated psychiatric problems, which are strongly related to early stressful situations through childhood and adolescence. This is to aid general psychiatrists in the discussion of appropriate medical management in such infrequent, yet challenging conditions.

Low Basal CB2R in Dopamine Neurons and Microglia Influences Cannabinoid Tetrad Effects.

There are two well-characterized cannabinoid receptors (CB1R and CB2R and other candidates): the central nervous system (CNS) enriched CB1R and peripheral tissue enriched CB2R with a wide dynamic range of expression levels in different cell types of human tissues. Hepatocytes and neurons express low baseline CB1R and CB2R, respectively, and their cell-type-specific functions are not well defined. Here we report inducible expression of CB1R in the liver by high-fat and high sugar diet and CB2R in cortical neurons by methamphetamine. While there is less controversy about hepatocyte CB1R, the presence of functional neuronal CB2R is still debated to date. We found that neuron CB2R basal expression was higher than that of hepatocyte CB1R by measuring mRNA levels of specific isoform CB2A in neurons isolated by fluorescence-activated cell sorting (FACS) and CB1A in hepatocytes isolated by collagenase perfusion of liver. For in vivo studies, we generated hepatocyte, dopaminergic neuron, and microglia-specific conditional knockout mice (Abl-Cnr1Δ, Dat-Cnr2Δ, and Cx3cr1-Cnr2Δ) of CB1R and CB2R by crossing Cnr1f/f and Cnr2f/f strains to Abl-Cre, Dat-Cre, and Cx3cr1-Cre deleter mouse strains, respectively. Our data reveals that neuron and microglia CB2Rs are involved in the "tetrad" effects of the mixed agonist WIN 55212-2, CB1R selective agonist arachidonyl-2'-chloroethylamide (ACEA), and CB2R selective agonist JWH133. Dat-Cnr2Δ and Cx3cr1-Cnr2Δ mice showed genotypic differences in hypomobility, hypothermia, analgesia, and catalepsy induced by the synthetic cannabinoids. Alcohol conditioned place preference was abolished in DAT-Cnr2Δ mice and remained intact in Cx3cr1-Cnr2Δ mice in comparison to WT mice. These Cre-loxP recombinant mouse lines provide unique approaches in cannabinoid research for dissecting the complex endocannabinoid system that is implicated in many chronic disorders.

Transvestism Recognized in Ehlers-Danlos Syndrome: Report of Two Cases.

Ehlers-Danlos syndrome (EDS) comprises a series of rare hereditary connective tissue diseases characterized by musculoskeletal, skin, and cardiovascular involvements. EDS may be associated with physical as well as psychological pain that can lead to psychiatric problems. EDS imposes substantial psychological burden on patients, and recent large-scale studies have suggested that patients with EDS have a higher risk of mood disorders than the general population. To the best of our knowledge, we describe, for the first time, the cases of two Japanese patients with EDS complicated with mood disorders who secondarily developed transvestism that was judged strongly related to early stressful situations through childhood and adolescence. The first case was of a man in his mid-30s and the second of a woman in her late 20s. We report on detailed psychosocial data to further discuss the medical management and genetic counseling of such infrequent but challenging conditions. Physicians are advised to be aware of various potential psychological and psychiatric issues that may accompany EDS.

Neuronal cell adhesion molecule regulating neural systems underlying addiction.

AIMS: The human NRCAM gene is associated with polysubstance use. Nrcam knockout mice do not acquire a preference for addictive substances. We aimed to elucidate the role of Nrcam in specific neural circuits underlying congenital preference for substances and the acquisition of addiction. METHODS: We analyzed gene expression patterns of neural molecules to find a common addiction pathway dependent on Nrcam function. We examined monoaminergic, glutamatergic, and GABAergic systems in the brains of Nrcam knockout mice following treatment with methamphetamine (METH) or saline (SAL) using micro-array gene expression analysis, which was replicated using TaqMan gene expression analysis. To find a common addiction pathway, we examined similarities and differences between the expression patterns of molecules in METH-treated mice and in Nrcam knockout mice treated with cocaine (COC). RESULTS: Glutaminase expression in brain was reduced in Nrcam heterozygous mice after METH and COC treatment, consistent with our previous study. Metabotropic glutamate receptor 2 expression was reduced in Nrcam heterozygous mice that received either METH or COC treatment. Several other molecules could act in independent addiction pathways involving METH or COC. We also found that GABA receptor subunit g2 expression was reduced in Nrcam heterozygous mice that underwent SAL treatment, and that METH treatment attenuated this reduction. CONCLUSION: Nrcam differentially regulates glutamatergic and GABAergic molecules in naive brains and in brains of animals with acquired addiction. Elucidating the complex neural mechanisms underlying polysubstance use will uncover biological features of addiction and may contribute to the development of effective pharmaceutical treatments.

Behavioral Evaluation of Seeking and Preference of Alcohol in Mice Subjected to Stress.

The alcohol preference model is one of the most widely used animal models relevant to alcoholism. Stressors increase alcohol consumption. Here we present a protocol for a rapid and useful tool to test alcohol preference and stress-induced alcohol consumption in mice. In this model, animals are given two bottles, one with a diluted solution of ethanol in water, and the other with tap water. Consumption from each bottle is monitored over a 24-h period over several days to assess the animal's relative preference for the ethanol solution over water. In the second phase, animals are stressed by restraining them for an hour daily and their subsequent preference of tap water or the ethanol solution is evaluated. Preference is measured by the volume and/or weight or liquid consumed daily, which is then converted to a preference ratio. The alcohol preference model was combined with the conditioned place preference paradigm to determine alcohol conditioning and preference following the deletion of CB2 cannabinoid receptors in dopaminergic neurons in the DAT-Cnr2 Cre-recombinant conditional knockout (cKO) mice in comparison with the wild-type control mice.

Cannabinoid CB2 Receptor Gene and Environmental Interaction in the Development of Psychiatric Disorders.

CB2 cannabinoid receptor (CB2R) gene is associated with depression. We investigated the gene-environment interaction between CB2R function and diverse stressors. First, anxiety-like behavior during chronic-mild-stress (CMS) was evaluated in C57BL/6JJmsSlc mice following treatment with CB2R agonist JWH015 or inverse-agonist AM630. Second, locomotor activity and anxiety-like behavior were measured following exposure to an immune poly I:C stressor. Gene expressions of HPA axis related molecules, Fkbp5, Nr3c1 and Crf and pro-inflammatory cytokine Il-1b, as well as Bdnf as a key neurotrophin that supports neuron health, function, and synaptic plasticity, were determined in hippocampus of Cnr2 knockout mice, as indicators of stressful environment. CMS-induced anxiety-like behavior was enhanced by AM630 and reduced by JWH015 and fluvoxamine. Poly I:C reduced locomotor activity and increased anxiety-like behavior, and these effects were pronounced in the heterozygote than in the wild type mice. Fkbp5 and Nr3c1 expression were lower in the Cnr2 heterozygotes than in the wild type mice with Poly I:C treatment. These findings indicate that interaction between CB2R gene and stressors increases the risk of depression-like behaviors that may be linked with neuro-immune crosstalk. Further studies in human subjects are necessary to determine the role of CB2R and environmental interaction in the development of depression.

Association between alcoholism and the gene encoding the endocannabinoid synthesizing enzyme diacylglycerol lipase alpha in the Japanese population.

The endocannabinoid system has been recognized to be involved in neuropsychiatric diseases. 2-arachidonoyl glycerol (2-AG) is one of the two main endocannabinoids, and their regulation could play roles in disorders under environmental influence. This study investigated the involvement of the 2-AG biosynthesizing enzyme diacylglycerol lipase alpha (DAGLA) in the pathogenesis of alcoholism. We investigated a possible association between alcoholism and single nucleotide polymorphisms (SNPs) of the human DAGLA gene in the Japanese population. To discern any environmental influences on Dagla function in an animal study, the Dagla gene expression in the brain from stressed model mice was analyzed. The SNPs, including missense polymorphism Pro899Leu in the DAGLA gene, showed associations with alcoholism in the Japanese population. Dagla expression in mice was found to be influenced by chronic mild stress and by the acquisition of alcohol preference. Our findings indicated the involvement of DAGLA in alcoholism, possibly by its genetic dysfunction and also by the influence of stress.

Cannabinoid type 2 receptors in dopamine neurons inhibits psychomotor behaviors, alters anxiety, depression and alcohol preference.

Cannabinoid CB2 receptors (CB2Rs) are expressed in mouse brain dopamine (DA) neurons and are involved in several DA-related disorders. However, the cell type-specific mechanisms are unclear since the CB2R gene knockout mice are constitutive gene knockout. Therefore, we generated Cnr2-floxed mice that were crossed with DAT-Cre mice, in which Cre- recombinase expression is under dopamine transporter gene (DAT) promoter control to ablate Cnr2 gene in midbrain DA neurons of DAT-Cnr2 conditional knockout (cKO) mice. Using a novel sensitive RNAscope in situ hybridization, we detected CB2R mRNA expression in VTA DA neurons in wildtype and DAT-Cnr2 cKO heterozygous but not in the homozygous DAT-Cnr2 cKO mice. Here we report that the deletion of CB2Rs in dopamine neurons enhances motor activities, modulates anxiety and depression-like behaviors and reduces the rewarding properties of alcohol. Our data reveals that CB2Rs are involved in the tetrad assay induced by cannabinoids which had been associated with CB1R agonism. GWAS studies indicates that the CNR2 gene is associated with Parkinson's disease and substance use disorders. These results suggest that CB2Rs in dopaminergic neurons may play important roles in the modulation of psychomotor behaviors, anxiety, depression, and pain sensation and in the rewarding effects of alcohol and cocaine.

A decrease in protein level and a missense polymorphism of KIF17 are associated with schizophrenia.

It has been shown that the dysfunction of N-methyl-d-asparate (NMDA) receptors-mediated neurotransmission plays a role in the pathophysiology of schizophrenia. Especially, GluN2B, a subunit of NMDA receptors, associated trafficking complex is altered in the prefrontal cortex of schizophrenia. The kinesin superfamily motor protein 17 (KIF17) is known as a transporter of NR2B.Previous studies showed that a structural variant of KIF17 gene is associated with a schizophrenic phenotype. Therefore, here we investigated KIF17 levels in postmortem prefrontal cortex in schizophrenia and the association of a missense polymorphism (Ile341Val) in KIF17 with schizophrenia. The protein expression of KIF17 in schizophrenic postmortem brains was significantly lower than that in controls. Next, the association of missense polymorphisms (rs631375, rs13375609, rs522496 and rs2296225) of KIF17 gene in 567 schizophrenia and 710 healthy subjects was examined. Both genotypic distribution and allelic frequency of rs2296225 polymorphism were significantly different between the chronic schizophrenia subjects and controls. However, our findings described above were not replicated with the independent subjects (555 schizophrenia and 814 healthy controls). Furthermore, the two alleles of rs2296225 polymorphism did not affect the mRNA expression of KIF17. These results suggest that the dysfunction of KIF17 might be involved in the pathophysiology of schizophrenia.

NrCAM-regulating neural systems and addiction-related behaviors.

We have previously shown that a haplotype associated with decreased NrCAM expression in brain is protective against addiction vulnerability for polysubstance abuse in humans and that Nrcam knockout mice do not develop conditioned place preferences for morphine, cocaine or amphetamine. In order to gain insight into NrCAM involvement in addiction vulnerability, which may involve specific neural circuits underlying behavioral characteristics relevant to addiction, we evaluated several behavioral phenotypes in Nrcam knockout mice. Consistent with a potential general reduction in motivational function, Nrcam knockout mice demonstrated less curiosity for novel objects and for an unfamiliar conspecific, showed also less anxiety in the zero maze. Nrcam heterozygote knockout mice reduced alcohol preference and buried fewer marbles in home cage. These observations provide further support for a role of NrCAM in substance abuse including alcoholism vulnerability, possibly through its effects on behavioral traits that may affect addiction vulnerability, including novelty seeking, obsessive compulsion and responses to aversive or anxiety-provoking stimuli. Additionally, in order to prove glutamate homeostasis hypothesis of addiction, we analyzed glutamatergic molecules regulated by NRCAM expression. Glutaminase appears to be involved in NrCAM-related molecular pathway in two different tissues from human and mouse. An inhibitor of the enzyme, prolyl-leucyl-glycinamide, treatment produced, at least, some of the phenotypes of mice shown in alcohol preference and in anxiety-like behavior. Thus, NrCAM could affect addiction-related behaviors via at least partially modulation of some glutamatergic pathways and neural function in brain.