Corticosterone Signaling and a Lateral Habenula-Ventral Tegmental Area Circuit Modulate Compulsive Self-Injurious Behavior in a Rat Model.

Self-injurious behavior (SIB) is commonly observed in patients with neuropsychiatric disorders, as well as in nonclinical populations with stress-related mental-health problems. However, the exact circuitry mechanisms underlying SIB have remained poorly understood. Here, with bilateral injection of muscimol into the entopeduncular nucleus (EP), we established a rat model of SIB. Following the muscimol injection, the male rats exhibited in a dose-dependent manner stereotypic self-biting behavior that lasted for hours and often resulted in wounds of various severities. The SIB was associated with an elevated level of serum corticosterone and could be exacerbated by enhancing the corticosterone signaling and, conversely, alleviated by inhibiting the corticosterone signaling. Activity mapping using c-fos immunostaining, combined with connectivity mapping using herpes simplex virus-based anterograde tracing from the EP and pseudorabies virus-based retrograde tracing from the masseter muscle, revealed the potential involvement of many brain areas in SIB. In particular, the lateral habenula (LHb) and the ventral tegmental area (VTA), the two connected brain areas involved in stress response and reward processing, showed a significant increase in neuronal activation during SIB. Furthermore, suppressing the LHb activity or modulating the GABAergic transmission in the VTA could significantly reduce the occurrence of SIB. These results demonstrate the importance of stress hormone signaling and the LHb-VTA circuit in modulating SIB resulting from EP malfunction, and suggest potential targets for therapeutic intervention of SIB and related disorders.SIGNIFICANCE STATEMENT Self-injurious behavior (SIB) occurs in ∼4% of the general population, with substantially higher occurrence among adolescents and patients of neuropsychiatric disorders. Stress has been linked to the occurrence of SIB, yet the underlying mechanisms have remained unclear. Using a rat model of SIB induced by disruption of activity in the entopeduncular nucleus (EP), we found that the behavior is regulated by stress and linked to corticosterone signaling. Viral tracing and c-fos immunostaining revealed the involvement of various subcortical areas, especially the EP-lateral habenula (LHb)-ventral tegmental area (VTA) circuit, in SIB. Furthermore, regulating activity in the LHb or the VTA alleviates SIB. These results may have implications in the development of new strategies for treating SIB.

Downregulation of apolipoprotein A-IV in plasma & impaired reverse cholesterol transport in individuals with recent acts of deliberate self-harm.

Background & objectives: The major limiting factor in the prevention of suicide is the limited knowledge on molecular insights in individuals at risk. Identification of peripheral protein markers which can classify individuals at high-risk of suicide might aid in early diagnosis and effective medical intervention. The aim of the present study was, therefore, to analyze the differential regulation of plasma proteins in individuals with deliberate self-harm compared to controls. Methods: Using two-dimensional gel electrophoresis coupled with matrix-assisted laser desorption-ionization mass spectrometry, differentially expressed plasma proteins were identified in study participants with deliberate self-harm compared to age- and gender-matched controls. The finding was validated using mass spectrometry-based isotope-labelled relative quantification and Western blot analysis in a new set of individuals with deliberate self-harm and controls. Results: The plasma proteomic analysis showed that apolipoprotein A-IV (Apo A-IV ) was downregulated by 2.63-fold (confidence interval: 1.52-4.54) in individuals with deliberate self-harm (n=10) compared to matched controls, which was consistent in mass spectrometry-based relative quantification and Western blot analysis performed in an independent set of individuals with deliberate self-harm (n=18). In addition, plasma levels of total cholesterol, esterified cholesterol and high-density lipoprotein (HDL) were observed to be significantly lower individuals with deliberate self-harm compared to controls. Interpretation & conclusions: Apo A-IV, which plays a crucial role in the esterification of free cholesterol, was found to be downregulated with concomitantly decreased levels of HDL, esterified cholesterol and total cholesterol in individuals with deliberate self-harm compared to matched controls. The present findings might provide a link between the differential regulation of plasma proteins and the previously reported results on altered cholesterol levels in individuals with deliberate self-harm.

Activation in Children and Adolescents Treated With Selective Serotonin Reuptake Inhibitors: A Weighty Reason?

BACKGROUND: Activation is a behavioral adverse event related to the use of psychotropic medication. Its high incidence in pediatrics and in childhood-onset neuropsychiatric disorders suggests it may be linked to neurodevelopment. However, previous studies have scarcely examined the role that factors relevant to developmental pharmacokinetics, such as body weight, may play in the onset of activation in children and adolescents. METHODS: We conducted a retrospective analysis of hospitalized patients to identify the risk factors for activation in children and adolescents treated with selective serotonin reuptake inhibitors. Our focus was on factors related to development, including body weight, to explore the relationship between activation and neurodevelopmental processes. RESULTS: Among the 139 participants (mean age, 14 ± 2.3 years), activation appeared in 29 (20.9%). Age 12 years or younger and comorbid diagnosis of autism spectrum disorder were associated with statistically significant increases in the risk of activation, but no association was found regarding body weight. CONCLUSIONS: Our findings support the hypothesis that activation is closely linked to brain development processes. Longitudinal studies are needed to explore this line of research further.

Routine biological tests in self-poisoning patients: results from an observational prospective multicenter study.

CONTEXT: Routine biological tests are frequently ordered in self-poisoning patients, but their clinical relevance is poorly studied. MATERIALS AND METHODS: This is a prospective multicentric observational study conducted in the emergency departments and intensive care units of 5 university and nonuniversity French hospitals. Adult self-poisoning patients without severely altered vital status on admission were prospectively included. RESULTS: Routine biological test (serum electrolytes and creatinine, liver enzymes, bilirubin, blood cell count, prothrombin time) ordering and results were analyzed. A total of 1027 patients were enrolled (age, 40.2 ± 14 years; women, 61.5%); no patient died during the hospital stay. Benzodiazepine was suspected in more than 70% of cases; 65% (range, 48%-80%) of patients had at least 1 routine biological test performed. At least 1 abnormal test was registered in 23% of these patients. Three factors were associated with abnormal test results: age older than 40 years, male sex, and poisoning with a drug known to alter routine tests (ie, acetaminophen, NSAIDs, metformine, lithium). Depending on these factors, abnormal results ranged from 14% to 48%. Unexpected severe life-threatening conditions were recorded in 6 patients. Only 3 patients were referred to the intensive care unit solely because of abnormal test results. CONCLUSION: Routine biological tests are commonly prescribed in nonsevere self-poisoning patients. Abnormal results are frequent but their relevance at bedside remains limited.

The effects of acute tryptophan depletion on impulsivity and mood in adolescents engaging in non-suicidal self-injury.

OBJECTIVE: Non-suicidal self-injury (NSSI) is associated with impaired emotion regulation and impulsivity. Low serotonin (5-hydroxytryptamine) function is associated with NSSI, impaired emotion regulation and impulsivity. We investigated the effects of experimentally lowered 5-hydroxytryptamine activity, via acute tryptophan depletion (ATD), on impulsive action, reflection impulsivity and mood in female adolescents engaging in NSSI. METHODS: Thirty-two female adolescents engaging in NSSI participated in a parallel group ATD study. Following ATD, impulsive action was assessed using the Continuous Performance Test, Identical Pairs Version. Reflection impulsivity was assessed using the Matching Familiar Figures Test. Mood-lowering was examined using the Profile of Mood States. RESULTS: Following ATD, the participants showed an impulsive response style (as reflected in their low ß) and increased attentional capacity (as reflected in their elevated d'). ATD did not affect reflection impulsivity or mood. CONCLUSIONS: Acute tryptophan depletion caused an impulsive response style and increased attentional capacity. Importantly, the findings suggest that low serotonin function is a vulnerability among female adolescents for engaging in NSSI when in emotional distress.

Relationship between saliva opiorphin levels, pain threshold, and cutting number in adolescents with non suicidal self injury.

Various opinions have been suggested regarding non suicidal self-injury (NSSI) and pain relationship. Opiorphin is a recently found peptide that inhibits enkephaline-catabolizing enzymes. Analgesia caused by opiorphine has been demonstrated in animal experiments. No studies have examined the relationship between opiorphin and pain sensation until today. We aimed to investigate opiorphine and pain threshold among self-injuring adolescents. Adolescents aged 14-18 years were included in the study. The NSSI group consisted of 37 adolescents diagnosed with NSSI according to DSM-V Section 3, and the non-NSSI group consisted of 36 adolescents without any psychiatric disorder. We measured pain threshold with a pressure sensitive algometer device and analyzed saliva opiorphin levels by ELISA method. Mediation analysis was performed using Process Macro developed by Hayes. NSSI group had statistically significantly higher pain threshold and opiorphin levels than the non-NSSI group. There was a positive correlation between pain threshold values and opiorphin levels in the NSSI group. Also, a positive correlation between opiorphin levels and total cutting episode number was found. We searched for a probable relationship of pain threshold with episode number of each type of NSSI act. Accordingly, a positive correlation with two major act and a negative correlation with two minor act was shown. The opiorphine was found to be a mediator variable in the relationship between the pain threshold and the cutting number. The relationship between opiorphin, pain threshold and cutting number and their mediating effects with each other may highlight the pain-based biological origins of NSSI.

Increased IL-1ß reactivity upon a glucose challenge in patients with deliberate self-harm.

OBJECTIVE: A disturbed glucose metabolism has been observed in patients with aggressive behaviour. Interleukin (IL)-1ß is a pro-inflammatory cytokine that can induce hypoglycaemia, but has also been suggested to be involved in the generation of hostility and aggression. Our group has previously shown an altered glucose metabolism in patients with self-inflicted aggressive behaviour. We investigated the hypothesis that the levels of IL-1ß would be increased in these patients, because this might explain the aberrant glucose metabolism and add further knowledge to the aetiology of self-inflicted aggressive behaviour. METHOD: We investigated plasma cytokine changes in 13 patients with borderline personality disorder and 13 healthy controls during a 5-h glucose challenge. Plasma samples were analysed for cytokines IL-1ß, TNF-α and IL-6 using high-sensitivity multiplex ELISA. Psychiatric symptoms were rated using the Aggression Questionnaire Revised Swedish Version. RESULTS: Basal plasma levels of the three cytokines did not differ between patients and controls. All three cytokines reacted significantly upon the glucose challenge. The increase in IL-1ß levels in response to glucose was significantly greater in patients than in controls. Furthermore, IL-1ß reactivity was associated with symptoms of hostility. CONCLUSION: An increased reactivity of IL-1ß might be part of a pathogenetic mechanism in patients with deliberate self-harm.

A prospective study of lipids and serotonin as risk markers of violence and self-harm in acute psychiatric patients.

Cross-sectional studies have reported an association between lipids and serotonin levels and aggression, but a literature search revealed a paucity of prospective studies. Subjects of the present naturalistic study were 254 of all (489) involuntary and voluntary acutely admitted patients to a psychiatric hospital during 1year. Serum lipids and platelet serotonin at admission were prospectively compared with recorded intra-institutional and 1-year post-discharge violence and self-harm. Total cholesterol had a significant negative relationship to inpatient suicidal behaviour and inpatient violent behaviour and to 3-month post-discharge violent behaviour. Triglycerides were a significant marker of inpatient self-mutilation and of self-mutilation in combination with suicidal behaviour at 3 and 12 months of follow-up. High-density lipoprotein (HDL) had a significant negative relationship to violence at 12-months, and to repeated violence in seven patients with two or more admissions. The post-discharge relationships between total cholesterol and violence and between triglycerides and self-harm remained significant even when controlling for other possible explanatory variables in a multivariate model. Results did not change after controlling for current medication at admission. There was no association between platelet serotonin and violence or self-harm. Future research may examine if lipid measurements add incremental validity to established clinical risk assessment procedures of violent and self-harm behaviour.

Coupling of autism genes to tissue-wide expression and dysfunction of synapse, calcium signalling and transcriptional regulation.

Autism Spectrum Disorder (ASD) is a heterogeneous disorder that is often accompanied with many co-morbidities. Recent genetic studies have identified various pathways from hundreds of candidate risk genes with varying levels of association to ASD. However, it is unknown which pathways are specific to the core symptoms or which are shared by the co-morbidities. We hypothesised that critical ASD candidates should appear widely across different scoring systems, and that comorbidity pathways should be constituted by genes expressed in the relevant tissues. We analysed the Simons Foundation for Autism Research Initiative (SFARI) database and four independently published scoring systems and identified 292 overlapping genes. We examined their mRNA expression using the Genotype-Tissue Expression (GTEx) database and validated protein expression levels using the human protein atlas (HPA) dataset. This led to clustering of the overlapping ASD genes into 2 groups; one with 91 genes primarily expressed in the central nervous system (CNS geneset) and another with 201 genes expressed in both CNS and peripheral tissues (CNS+PT geneset). Bioinformatic analyses showed a high enrichment of CNS development and synaptic transmission in the CNS geneset, and an enrichment of synapse, chromatin remodelling, gene regulation and endocrine signalling in the CNS+PT geneset. Calcium signalling and the glutamatergic synapse were found to be highly interconnected among pathways in the combined geneset. Our analyses demonstrate that 2/3 of ASD genes are expressed beyond the brain, which may impact peripheral function and involve in ASD co-morbidities, and relevant pathways may be explored for the treatment of ASD co-morbidities.

Cholesterol in coronary heart disease and psychiatric disorders: same or opposite effects on morbidity risk?

The goal of this article is to review the studies that have linked low cholesterol levels with psychiatric symptoms or behavioral disorders in order to clarify which cholesterol fractions may influence psychological well being and mental health. The distinction between "bad" (i.e., pro-atherogenic) and "good" (i.e., anti-atherogenic) cholesterol is crucial to decide if the clinical benefits of low cholesterol levels for cardiovascular health might turn into a risk factor for psychiatric morbidity. Although the data from studies linking low cholesterol to aggression, suicide and self-harm, impulsivity, negative mood, postnatal depression, and cognitive dysfunction are far from unequivocal, the balance of evidence from new randomized controlled trials is reassuring. However, there are some subgroups of vulnerable individuals who, unlike the majority of persons in the general population, are susceptible to the psychological and behavioral adverse outcomes associated with low cholesterol levels. Because in some cases pro-atherogenic lipid and lipoprotein fractions are involved in this vulnerability, reaching the double goal of promoting both cardiovascular and mental health may be problematic for some individuals. A major task of future research is to identify these vulnerable individuals.

Acute tryptophan depletion and self-injurious behavior in aggressive patients and healthy volunteers.

RATIONALE: An association between serotonin (5-HT) activity and self-injurious (i.e., self-aggressive) behavior across the spectrum of lethality (from self-mutilation through completed suicide) is a well-replicated finding. Studies to date, however, have relied on nonexperimental designs to examine this relationship, limiting the causal inferences that can be drawn about the role of 5-HT in self-aggressive behavior. OBJECTIVE: Examine the effect of experimentally altered 5-HT activity (via dietary tryptophan depletion) on self-aggressive behavior among adults with and without intermittent explosive disorder (IED). Individuals with a marked history of aggression, such as those with IED, are characterized by compromised 5-HT and heightened risk for self-aggression, making this a population of interest for examining the proposed relations. MATERIALS AND METHODS: IED patients (n = 16) and healthy controls (n = 16) received a tryptophan depletion and a placebo drink on separate days at least 1 week apart. Self-aggressive behavior was assessed on both study days using a well-validated laboratory-based behavioral assessment with self-aggression defined as the intensity of shock self-administered. RESULTS: Tryptophan depletion facilitated selection of more intense shocks, on average, in both groups. Patients with IED were also more self-aggressive overall than healthy volunteers. No IED by drink condition interactions were found. CONCLUSION: Experimentally lowered 5-HT bioavailability enhances overall self-injurious behavior irrespective of aggression history.

Degranulated mast cells in the skin of adults with self-injurious behavior and neurodevelopmental disorders.

The role of nociceptive processes in relation to chronic, tissue-damaging self-injury among individuals with neurodevelopmental disorders is poorly understood. Scientific investigation has been limited, in part, by the clinical reality that the majority of individuals with severe intellectual impairments have co-morbid communicative impairments making it difficult to ascertain information regarding pain. Recently, we found abnormal patterns of peripheral epidermal nerve fiber (ENF) innervation and increased neuropeptide (substance P; SP) content among a subset of individuals with chronic self-injury. Here, we provide initial evidence for peripheral neuro-immune activity specific to self-injury. Skin samples from non-injury body-matched sites were compared between non-verbal adults with and without self-injury matched on gender and disability level. Relative to disability-matched controls, individuals with chronic self-injury had significantly more degranulated mast cells and were more responsive to tactile stimulation during a sensory testing procedure. Thus, nociceptive mechanisms and peripheral afferent sensitization may play a part in mediating and maintaining chronic self-injury.

The Pemoline Model of Self-Injurious Behavior: An Update.

Neurodevelopmental disorders typically comprise a complex constellation of behavioral symptoms and neurochemical abnormalities. However, many of the symptoms are inconsistently expressed within any one particular patient group or overlap between patient groups. In other words, there is usually heterogeneity of symptoms between diagnostic groups, and there is often partial homogeneity of symptoms across these groups. These include cognitive deficits, emotional lability, and perseverative or aberrant behaviors. Animal models of neurodevelopmental disorders typically reproduce or mimic specific genetic, neurochemical, and/or behavioral sequelae, although they typically fail to replicate the entire spectrum of biological and behavioral characteristics. Indeed, it may be impractical or even impossible to model the entire spectrum of characteristics of a disorder in any single animal model. A focus on one or more specific behavioral characteristics that occur in multiple neurodevelopmental disorders (e.g., self-injury) may be a fruitful strategy. The development of these behaviorally focused models may yield increased understanding of the endogenous and environmental factors that confer vulnerability for aberrant behaviors that commonly occur in these disorders. One such behaviorally focused animal model is the pemoline model of self-injurious behavior.

Adolescent nonsuicidal self-injury and cortisol response to the retrieval of adversity: A sibling study.

BACKGROUND: There is evidence for alterations in hypothalamus-pituitary-adrenal (HPA) axis response to the retrieval of traumatic events among individuals with Posttraumatic Stress Disorder. However, no study has so far investigated HPA response to trauma retrieval among individuals engaging in non-suicidal self-injury (NSSI). In the present study, we compared reports of childhood adversity (CA) between adolescents engaging in NSSI and their siblings and tested for differences in the cortisol response to the retrieval of CA. METHODS: The sample consisted of 32 adolescents engaging in NSSI (Mage = 15.8 years) and their siblings (Mage = 15.6 years). Standardized interviews were used for the assessment of CA, NSSI, and axis I diagnoses. Salivary cortisol was measured before and after the trauma interview. Basal HPA axis activity was measured in hair. RESULTS: Reports of CA were moderately interrelated between siblings. Adolescents engaging in NSSI reported more severe CA. A significant decrease of salivary cortisol during the trauma interview was found only in the NSSI group. The NSSI group had significantly higher hair cortisol levels. CONCLUSIONS: Moderate relations in siblings' reports of CA point to non-shared experiences that may play a role in the development of NSSI. In the NSSI group, the decrease of salivary cortisol during the interview may be explained by a downregulation of the HPA axis subsequent to the retrieval of former experience of CA.

L-DOPA-induced activation of striatal p38MAPK and CREB in neonatal dopaminergic denervated rat: relevance to self-injurious behavior.

The destruction of nigrostriatal dopaminergic neurons with 6-hydroxydopamine (6OHDA) during the neonatal period results in dopamine (DA) loss and susceptibility for self-injurious behavior (SIB) when challenged with L-dihydroxyphenylalanine (L-DOPA), via a supersensitive D1 receptor-mediated mechanism. However, there are no changes in D1 receptor binding or mRNA levels, suggesting a potential postreceptor signaling mechanism(s). Here, we examined whether L-DOPA-induced SIB is associated with altered MAPK signaling (p38MAPK, ERK1/2, and JNK) and their nuclear target, CREB. Neonatal dopaminergic lesioned animals were challenged, as adults, with L-DOPA, observed for SIB for 6 hr, and then sacrificed. The data were grouped as follows: control, lesioned rats without SIB (SIB(-)), and lesioned rats that were positive for SIB (SIB(+)). HPLC analysis of striatal extracts revealed a more significant loss of DA and an increase of serotonin in the SIB(+) than in the SIB(-) group. The striatal levels of TH protein were severely decreased, but D1 receptor levels were unaltered in the lesioned groups. These results confirm and extend previous studies indicating that SIB is associated with a near-total loss of DA and TH, an increase in serotonin, and no change in D1 receptor levels. The present studies further revealed that the levels of active phosphorylated forms of p38MAPK and CREB were significantly higher in the SIB(+) group than in the SIB(-) group in the striatum, but not in cortex or olfactory tubercle. The results indicate an induction of striatal p38MAPK and an activation of its nuclear target, CREB, as additional mechanisms in the genesis of L-DOPA-induced SIB.

Development of a mouse test for repetitive, restricted behaviors: relevance to autism.

Repetitive behavior, a core symptom of autism, encompasses stereotyped responses, restricted interests, and resistance to change. These studies investigated whether different components of the repetitive behavior domain could be modeled in the exploratory hole-board task in mice. Four inbred mouse strains, C57BL/6J, BALB/cByJ, BTBR T+tf/J, and FVB/NJ, and mice with reduced expression of Grin1, leading to NMDA receptor hypofunction (NR1neo/neo mice), were tested for exploration and preference for olfactory stimuli in an activity chamber with a 16-hole floor-board. Reduced exploration and high preference for holes located in the corners of the chamber were observed in BALB/cByJ and BTBR T+tf/J mice. All inbred strains had initial high preference for a familiar olfactory stimulus (clean cage bedding). BTBR T+tf/J was the only strain that did not demonstrate a shift in hole preference towards an appetitive olfactory stimulus (cereal or a chocolate chip), following home cage exposure to the food. The NR1neo/neo mice showed lower hole selectivity and aberrant olfactory stimulus preference, in comparison to wildtype controls. The results indicate that NR1neo/neo mice have repetitive nose poke responses that are less modified by environmental contingencies than responses in wildtype mice. 25-30% of NMDA receptor hypomorphic mice also show self-injurious responses. Findings from the olfactory studies suggest that resistance to change and restricted interests might be modeled in mice by a failure to alter patterns of hole preference following familiarization with an appetitive stimulus, and by high preference persistently demonstrated for one particular olfactory stimulus. Further work is required to determine the characteristics of optimal mouse social stimuli in the olfactory hole-board test.

Glutamate-mediated neuroplasticity in an animal model of self-injurious behaviour.

Self-injurious behaviour (SIB) is exhibited by individuals with a broad variety of developmental disorders and genetic abnormalities, including autism and Lesch-Nyhan, Prader-Willi and Rett syndromes. Most research has focused on environmental factors that reinforce SIB, and less is known about the biological basis of this behaviour disorder. However, animal models have been developed to study the neurochemical pathology that underlies SIB. In one model, rats exhibit self-biting after repeated daily administration of moderately high doses of pemoline (100-200mg/kg). Dopaminergic and glutamatergic neurotransmission have been implicated in this model. Accordingly, we investigated the role of glutamatergic neurotransmission in pemoline-induced SIB, using the N-methyl-d-aspartate (NMDA) receptor antagonists MK-801 and memantine. MK-801 is a high affinity antagonist which blocks glutamate-mediated neuroplasticity and behavioural sensitization to other psychostimulants. It lessened the incidence of SIB, the time spent self-injuring, and the area of tissue damage in the pemoline model. Memantine, on the other hand, is a low affinity antagonist which does not disrupt glutamate-mediated neuroplasticity, and it had little if any effect on any measure of pemoline-induced SIB. These results suggest that repeated pemoline administration induces glutamate-mediated neuroplastic changes that lead to the eventual expression of SIB. Further investigation of these changes may reveal specific neurochemical factors that contribute to SIB in this animal model of self-injury.

Prefrontal cortex activation during cognitive interference in nonsuicidal self-injury.

Nonsuicidal self-injury (NSSI), deliberate behavior resulting in self-inflicted damage to oneself, is common, particularly among female adolescents, and may be a form of maladaptive emotion regulation. Cognitive interference, a specific type of processing associated with inhibiting prepotent responses in favor of less automatic ones, is utilized in treatment strategies to shift patients' thoughts and behaviors away from maladaptive responses and replace them with more adaptive ones. We examined cognitive interference processing using the Multi-Source Interference Task (MSIT) in females with NSSI behavior (n=15) and healthy control females (n=15). Functional magnetic resonance imaging (fMRI) data were collected concurrently. Results revealed similar between-group performance on the MSIT; however, women with NSSI behavior exhibited altered patterns of neural activation during the MSIT. Specifically, the NSSI group demonstrated increased cingulate cortex (CC) and decreased dorsolateral prefrontal cortex (DLPFC) activation compared to the control group. Further, within the NSSI group, DLPFC activation inversely correlated with emotional reactivity and self-reported impulsivity, suggesting that decreased DLPFC activation is associated with poorer emotional control and increased impulsivity. Taken together, these results indicate that women with NSSI behavior utilize different cortical areas during cognitive interference processing, which may have broader implications regarding the treatment efficacy of cognitive-based therapies.

Differential effects of the ascorbyl and tocopheryl derivative on the methamphetamine-induced toxic behavior and toxicity.

A previous study showed that high doses of methamphetamine induce self-injurious behavior (SIB) in rodents. Furthermore, the combination of methamphetamine and morphine increased lethality in mice. We recently surmised that the rise in SIB and mortality induced by methamphetamine and/or morphine may be related to oxidative stress. The present study was designed to determine whether an antioxidant could inhibit SIB or mortality directly induced by methamphetamine and/or morphine. The SIB induced by 20mg/kg of methamphetamine was abolished by the administration of Na L-ascorbyl-2-phosphate (APS: 300 mg/kg), but not Na DL-alpha-tocopheryl phosphate (TPNa: 200mg/kg). In contrast, APS (300 mg/kg) and TPNa (200mg/kg) each significantly attenuated the lethality induced by methamphetamine and morphine. The present study showed that the signal intensity of superoxide adduct was increased by 20mg/kg of methamphetamine in the heart and lungs, and methamphetamine plus morphine tended to increase superoxide adduct in all of the tissues measured by ESR spin trap methods. Adduct signal induced in brain by methamphetamine administration increased in significance, but in mouse administrated methamphetamine plus morphine. There are differential effects of administration of methamphetamine and coadministration of methamphetamine plus morphine on adduct signal. These results suggest that APS and TPNa are effective for reducing methamphetamine-induced toxicity and/or toxicological behavior. While APS and TPNa each affected methamphetamine- and/or morphine-induced toxicology and/or toxicological behavior, indicating that both drugs have antioxidative effects, their effects differed.

Functional imaging, serotonin and the suicidal brain.

The involvement of the serotonergic system in the pathophysiology of suicidal behaviour has been established through indirect and direct research on serotonin and its metabolites and on serotonin transporters and receptors. Indirect research results include a reduced 5-HIAA in cerebrospinal fluid in violent suicide attempters and a blunted increase in prolactin after a fenfluramine challenge. Direct post-mortem research demonstrated an increase in 5-HT2A receptors. Direct in vivo functional imaging with PET or SPECT demonstrated a reduction in 5-HT2A binding index in suicide attempts in anxious and depressed suicide attempters and an increase in 5-HT2A binding in impulsive suicide attempters. These results are in keeping with 5-HT2A binding studies in depressed patients and impulsive animal research. Interestingly, both an increase and a decrease in 5-HT2A binding index seem to normalize with SSRI treatment.