The screen for cognitive impairment in psychiatry (SCIP) is associated with disease severity and cognitive complaints in major depression.

OBJECTIVE: To assess the relationship between the Screen for Cognitive Impairment in Psychiatry (SCIP) score and illness severity, subjective cognition and functioning in a cohort of major depressive disorder (MDD) patients. METHODS: Patients (n = 40) diagnosed with MDD (DSM-IV-TR) completed the SCIP, a brief neuropsychological test, and a battery of self-administered questionnaires evaluating functioning (GAF, SDS, WHODAS 2.0, EDEC, PDQ-D5). Disease severity was evaluated with the Hamilton Depression Rating Scale (HDRS) and the Clinical Global Impression (CGI). RESULTS: Age and sex were associated with performance in the SCIP. The SCIP-Global index score was associated with disease severity (r = -0.316, p < .05), the SDS, a patient self-assessment of daily functioning (r = -0.368, p < .05), and the EDEC subscales of patient-reported cognitive deficits (r = -0.388, p < .05) and their functional impacts (r = -0.335, p < .05). Multivariate analysis adjusted for age and sex confirmed these tests are independent predictors of performance in the SCIP (CGI-S, F[3,34] = 4.478, p = .009; SDS, F[3,34] = 3.365, p = .030; EDEC-perceived cognitive deficits, F[3,34] = 5.216, p = .005; EDEC-perceived impacts of functional impairment, F[3,34] = 5.154, p = .005). CONCLUSIONS: This study confirms that the SCIP can be used during routine clinical evaluation of MDD, and that cognitive deficits objectively assessed in the SCIP are associated with disease severity and self-reported cognitive dysfunction and impairment in daily life.

Sex and Gender Roles in Relation to Mental Health and Allostatic Load.

OBJECTIVES: Beyond male/female binaries, gender roles represent masculine and feminine traits that we assimilate and enact throughout life span development. Bem proposed that "androgynous" individuals adeptly adapt to different contexts by alternating from a strong repertoire of both masculine and feminine gender roles. By contrast, "undifferentiated" individuals may not adapt as well to social norms because of weak self-endorsed masculinity and femininity. METHODS: Among 204 adults (mean [standard error] age = 40.4 [0.9] years; 70% women) working in a psychiatric hospital, we hypothesized that androgynous individuals would present better mental health and less physiological dysregulations known as allostatic load (AL) than undifferentiated individuals. AL was indexed using 20 biomarkers using the conventional "all-inclusive" formulation that ascribes cutoffs without regard for sex or an alternative "sex-specific" formulation with cutoffs tailored for each sex separately while controlling for sex hormones (testosterone, estradiol, progesterone). Well-validated questionnaires were used. RESULTS: Independent of sex, androgynous individuals experienced higher self-esteem and well-being and lower depressive symptoms than did undifferentiated individuals. Men manifested higher AL than did women using the all-inclusive AL index (p = .044, ηP = 0.025). By contrast, the sex-specific AL algorithm unmasked a sex by gender roles interaction for AL (p = .043, ηP = 0.048): with the highest AL levels in undifferentiated men. Analysis using a gender index based on seven gendered constructs revealed that a greater propensity toward feminine characteristics correlated only with elevated sex-specific AL (r = 0.163, p = .025). CONCLUSIONS: Beyond providing psychobiological evidence for Bem's theory, this study highlights how sex-specific AL formulations detect the effects of sociocultural gender.

Serotonin Transporter mRNA Expression Is Reduced in the Peripheral Blood Mononuclear Cells of Subjects with Major Depression but Normal in Fibromyalgia.

BACKGROUND: Fibromyalgia (FM) and major depression disorder (MDD) frequently co-occur. Both disorders may share common serotonergic alterations, although there is less evidence of such alterations in FM. It is also unclear as to whether these alterations are persistent over time or transient. The objectives of this study were to (i) examine the changes in mRNA expression of serotonin transporter (SERT) on the surface of peripheral blood mononuclear cells (PBMCs) in FM, MDD, and the FM + MDD subjects compared to healthy controls, and to (ii) evaluate the effect of drug treatment on SERT expression. METHODS: PBMCs were isolated from FM, MDD, FM + MDD, and control subjects. SERT expression was analyzed at the mRNA level via quantitative real-time polymerase chain reaction. Statistical analyses were performed using analyses of variance and linear mixed-effects models. RESULTS: SERT mRNA expression was significantly reduced in MDD subjects compared to controls (p < 0.001), but not in FM nor in FM + MDD subjects. Although the drug treatments improved symptoms in FM, MDD, and FM + MDD subjects, they had no significant effect on SERT mRNA expression. CONCLUSIONS: These results corroborate the role of the SERT in the pathophysiology of MDD, but not in FM, and show that the decreased mRNA expression of SERT is a persistent, rather than transient, phenomenon.

Defective Fas expression exacerbates neurotoxicity in a model of Parkinson's disease.

Fas (CD95), a member of the tumor necrosis factor-receptor superfamily, has been studied extensively as a death-inducing receptor in the immune system. However, Fas is also widely expressed in a number of other tissues, including in neurons. Here, we report that defects in the Fas/Fas ligand system unexpectedly render mice highly susceptible to neural degeneration in a model of Parkinson's disease. We found that Fas-deficient lymphoproliferative mice develop a dramatic phenotype resembling clinical Parkinson's disease, characterized by extensive nigrostriatal degeneration accompanied by tremor, hypokinesia, and loss of motor coordination, when treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at a dose that causes no neural degeneration or behavioral impairment in WT mice. Mice with generalized lymphoproliferative disease, which express a mutated Fas ligand, display an intermediate phenotype between that of lymphoproliferative and WT mice. Moreover, Fas engagement directly protects neuronal cells from MPTP/1-methyl-4-phenylpyridinium ion toxicity in vitro. Our data show that decreased Fas expression renders dopaminergic neurons highly susceptible to degeneration in response to a Parkinson-causing neurotoxin. These findings constitute the first evidence for a neuroprotective role for Fas in vivo.

Rapid screening for cognitive deficits in attention deficit and hyperactivity disorders with the screen for cognitive impairment in psychiatry.

Cognitive impairments constitute a core feature of attention deficit and hyperactivity disorders (ADHD), but are infrequently assessed in the clinical setting. We have previously demonstrated the ability of an objective cognitive battery, the Screen for Cognitive Impairment in Psychiatry (SCIP), to differentiate adult ADHD patients from healthy controls in five cognitive domains. Here, we further characterize these subtle cognitive deficits by conducting additional univariate analyses on our ADHD dataset to assess the contributions of various demographic characteristics on SCIP performance and to determine correlations between SCIP scores and scores on other measures evaluating illness severity, perceived cognitive deficits, and overall functioning. Age and years of education were moderately associated with performance on the SCIP and/or its subscales in our ADHD cohort. The SCIP global index score was moderately correlated with clinician-rated measures of illness severity and weakly associated with clinician-rated overall functional status. Intriguingly, overall SCIP performance was only weakly associated with patient self-reported measures of cognitive functioning. Of practical importance, small-to-moderate associations were consistently observed between performances on two subscales of the SCIP and the other measures evaluating illness severity, overall functioning, and patient self-reported cognitive functioning (the working memory and visuomotor tracking subscales). Thus, these data demonstrate that the SCIP, particularly the working memory and visuomotor tracking subscales, is sensitive enough to detect cognitive deficits in adult patients with ADHD, and that these deficits are correlated with functional impairments. Furthermore, these data highlight the importance of integrating both objective and subjective evaluations of cognition in adult ADHD.

Endogenous cannabinoids in patients with schizophrenia and substance use disorder during quetiapine therapy.

Disturbances in the endogenous cannabinoid (ECB) system in schizophrenia may contribute to their enhanced sensitivity to psychoactive substances, and the beneficial effects of second-generation antipsychotics for substance abuse in schizophrenia may involve modulatory effects on ECB. To verify these two assumptions, 29 patients (24 completers) with schizophrenia and substance use disorders (SUD) were treated with quetiapine for 12 weeks, and peripheral ECB levels were measured, using high-performance liquid chromatography/mass spectrometry, in patients (weeks 0, 6 and 12) and 17 healthy volunteers. Baseline anandamide levels were significantly higher in patients, relative to controls. This result is consistent with studies describing ECB dysfunctions in schizophrenia. SUD parameters improved during treatment, but no changes in ECB occurred over time. Improvements in substance abuse were probably not mediated by modulatory effects of quetiapine on ECB. Lastly, baseline anandamide predicted endpoint SUD scores (alcohol/ cannabis). Anandamide is a potential target for medications aimed at relieving SUD in schizophrenia.

Transient middle cerebral artery occlusion influence on systemic oxygen homeostasis and erythropoiesis in Wistar rats.

BACKGROUND AND PURPOSE: Systemic hypoxia is a common complication in stroke patients and may exacerbate ischemic brain damage. Expression of the hypoxia-inducible cytokine erythropoietin (Epo) is upregulated in the brain in both stroke patients and in animal stroke models and exerts local neuroprotective effects in the ischemic brain. Epo is also well known to stimulate red blood cell (RBC) production. The purpose of the present study was to evaluate whether poststroke systemic hypoxia is present in the rat model and whether it is associated with increased peripheral Epo and RBC production. METHODS: Wistar rats underwent 1-hour transient middle cerebral artery occlusion (MCAO) under mechanical ventilation, followed by reperfusion without further ventilation. Groups of MCAO and sham-operated animals were evaluated at extended times after reperfusion for assessment of arterial blood gases, plasma Epo, and complete blood count. RESULTS: Arterial oxygen saturation was significantly lower in the infarct group between 6 and 24 hours after reperfusion (P=0.0005), and plasma Epo levels were increased 6 hours after reperfusion (P<0.05). RBC counts and hematocrit were transiently increased 2 to 7 days after reperfusion in animals with MCAO compared with sham. Maximal increases were seen at day 7 (22% and 16% increases of RBC count and hematocrit, respectively; P<0.001). In contrast, the white blood cell counts in animals with MCAO decreased by >30% in the same time period. CONCLUSIONS: Plasma Epo levels, RBC counts, and hematocrit are all increased in response to systemic hypoxia after cerebral ischemia in rats.

Temporal effects of left versus right middle cerebral artery occlusion on spleen lymphocyte subsets and mitogenic response in Wistar rats.

The left and right neocortex of the brain has been shown to exert asymmetrical effects on the immune system. In the present study, we used a middle cerebral artery (MCA) occlusion model in Wistar rats to analyze the influence of unilateral CNS ischemia on spleen cell number and function. The occlusion time was 1 h, followed by reperfusion with survival for 0, 2, 7, 14, and 28 days. Changes in plasma norepinephrine levels were used as an index of peripheral sympathetic activity. Results showed that the total number of spleen cells significantly decreased after 2-28 days of survival in animals with cerebral ischemia compared to sham-operated controls. There was no change in the percentage of CD5(+)-CD4(+) T cells, MHC class II(+) cells, or ED1(+) macrophages. However, the percentage of CD5(+)-CD8(+) T cells decreased at 2 days, resulting in an increased CD4/CD8 ratio, and both parameters returned to control levels after 7 days. Mitogen-induced T and B lymphocyte proliferation increased after 0-28 days post-ischemia independently of the mitogen used. There was no difference in immune response or norepinephrine levels between left and right MCA occlusions. These results are consistent with the notion that cerebral ischemia induces mobilization of certain immune cells from the periphery to the brain, where they may contribute to the local inflammatory response. Additionally, the data indicate that cerebral ischemia is followed by a systemic activation of T and B lymphocytes. Absence of asymmetric effects of left versus right stroke, and failure to demonstrate any suppressive effects of left-sided lesions on lymphocyte proliferation, probably reflects the fact that these large cerebral ischemic lesions affect both cortical and subcortical areas.

Prolongation of human neutrophil survival by low-level mercury via inhibition of spontaneous apoptosis.

Low levels of organic and inorganic mercury compounds have been reported previously to induce cell death by apoptosis in human peripheral blood mononuclear cells (MNC). but little is known about their potential effects on the viability and death of polymorphonuclear neutrophils (PMN). In contrast to MNC, PMN are known to undergo readily spontaneous apoptosis both in vivo and in vitro. Therefore, it was hypothesized that PMN may differ from MNC in their reactions to low mercury levels. The effects of methylmercuric chloride (MeHgCl) and mercuric chloride (HgCl2) were evaluated in concentration-response and time-course studies on human PMN viability and on their modes of cell death after in vitro incubation at 37 degrees C. Cell death by apoptosis or necrosis was assessed by annexin V-fluorescein isothiocyanate binding to externalized phosphatidylserine in conjunction with propidium iodide, and flow cytometry analysis. Morphologic counting of pyknotic nuclei and the fluorescence properties of the DNA-binding dye Hoechst 33342 in combination with propidium iodide were used to further confirm apoptotic cell death and to characterize the sequence of Hg-induced cell death. Results show that low concentrations of MeHgCl (1-7.5 microM) that were cytotoxic to MNC actually inhibited PMN spontaneous apoptosis. Low-level HgCl, reproduced the anti-apoptotic effects of MeHgCl on PMN, but to a lower extent. Higher concentrations of MeHgCl and HgCl2 were necrogenic to PMN, but MeHgCl was about an order of magnitude more toxic, and discrete differences were observed in the modalities of cell death induced by both species. These data reveal for the first time that (1) low levels of organic and inorganic mercury species protect human PMN from cell death via inhibition of spontaneous apoptosis, and (2) PMN are more resistant than MNC to mercury-induced cytotoxicity. Since delayed apoptosis and increased resistance to toxicant-induced cell death may lead to excessive accumulation of senescent PMN, evidence indicates that findings of this study may have implications for mercury-induced autoimmunity and inflammation.

Mechanisms involved in methylmercuric chloride (MeHgCl)-induced suppression of human neutrophil apoptosis.

We have previously demonstrated that concentrations of 1-10 microM of methylmercuric chloride (MeHgCl) that are cytotoxic to monocytes-macrophages can curiously inhibit neutrophil apoptosis by a yet unknown mechanism. In the present study, we demonstrate that, as with the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF), a classical inhibitor of neutrophil apoptosis, treatment of cells with 5 microM MeHgCl induces de novo protein synthesis and prevents the loss of expression of the antiapoptotic Mcl-1 protein. The expression of the cytoskeletal proteins gelsolin, paxillin and vinculin was similar in MeHgCl- or GM-CSF-induced suppression of apoptosis. However, MeHgCl prevents the degradation of vimentin differently than GM-CSF. Apoptosis was further confirmed by flow cytometry (FITC annexin-V), and by monitoring CD16 cell surface expression. Curiously, unlike GM-CSF, MeHgCl did not prevent CD16 shedding. We conclude that, like GM-CSF, MeHgCl can delay neutrophil apoptosis by inducing de novo protein synthesis and by preventing the loss of the antiapoptotic Mcl-1 protein. However, unlike GM-CSF, MeHgCl induces an atypical degradation of vimentin without preventing CD16 shedding.

Quetiapine fumarate extended-release for the treatment of major depression with comorbid fibromyalgia syndrome: a double-blind, randomized, placebo-controlled study.

OBJECTIVE: Fibromyalgia and major depressive disorder (MDD) frequently co-occur. Quetiapine fumarate extended-release (quetiapine XR) has demonstrated efficacy in the treatment of MDD and has been shown to have analgesic properties in patients with depression. The primary objectives of this study were to evaluate the effects of quetiapine XR on depressive and pain symptoms in patients with MDD and comorbid fibromyalgia, and to assess its safety and tolerability. METHODS: This was an 8-week, single-center, double-blind, randomized, controlled trial. A total of 120 nonpsychotic adult outpatients who fulfilled the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnostic criteria for MDD and whose diagnosis of fibromyalgia was confirmed according to the American College of Rheumatology criteria were enrolled. The primary end point was the mean change from baseline to week 8 on the 17-item Hamilton Depression Rating (HAM-D) scale. Secondary end points included other depression-rating scores, pain scores, fibromyalgia scores, measures of quality of life and global functioning, and adverse events. RESULTS: The mean change in the HAM-D score from baseline to week 8 was significantly greater in the quetiapine XR group compared with the placebo group (-10.0 versus -5.8; P = 0.001). Improvements in most secondary outcomes were also significantly greater in the quetiapine XR group. Quetiapine XR was generally well tolerated. CONCLUSION: This study is the first to demonstrate that measures of depression, pain, and quality of life are significantly improved with quetiapine XR compared with placebo in patients with a dual diagnosis of MDD and fibromyalgia.

Antipsychotics' effects on blood levels of cytokines in schizophrenia: a meta-analysis.

OBJECTIVES: Evidence-based medicine suggests that schizophrenia is associated with an inflammatory syndrome, but the extent to which this syndrome is normalized by antipsychotic treatment has yet to be determined. METHODS: A systematic quantitative review of the effects of antipsychotics on peripheral cytokine levels in schizophrenia was performed, using follow-up studies providing in vivo cytokine assessments before and after treatment. RESULTS: We retrieved 23 studies (total of 762 subjects) which showed that antipsychotic treatment significantly increases plasma levels of soluble interleukin-2 receptor and reduces the plasma levels of interleukin-1ß and interferon-γ. CONCLUSIONS: These results show that antipsychotics produce anti-inflammatory effects in schizophrenia.

Plasma Endocannabinoid Alterations in Individuals with Substance Use Disorder are Dependent on the "Mirror Effect" of Schizophrenia.

Schizophrenia is a complex psychiatric disorder strongly associated with substance use disorders. Theoretically, schizophrenia and SUD may share endocannabinoid alterations in the brain reward system. The main endocannabinoids, anandamide, and 2-arachidonoylglycerol, are lipids which bind cannabinoid receptors. Oleoylethanolamide (OEA), a fatty-acid ethanolamide, binds peroxisome proliferator-activated receptors. The endocannabinoid system has been shown to be impaired in schizophrenia, and recently, our group has shown that schizophrenia patients with SUD have elevated peripheral levels of anandamide and OEA that do not normalize after 3-month treatment with quetiapine. Objective For comparative purposes, we aimed to measure endocannabinoids in non-psychosis substance abusers and non-abusing schizophrenia patients. Methods Using liquid chromatography and mass spectrometry, we measured plasma levels of anandamide and OEA in non-psychosis SUD patients, non-abusing schizophrenia patients, and healthy controls. In an open-label manner, all patients received 12-week treatment with quetiapine. Results Anandamide and OEA were reduced in substance abusers without schizophrenia, relative to healthy controls (p < 0.05). Both endocannabinoids were unchanged in non-abusing schizophrenia patients. After quetiapine, anandamide, and OEA levels remained significantly reduced the SUD group (p < 0.05). Discussion Taken together with results of our previous study performed in dual-diagnosis patients, our results suggest that peripheral anandamide and OEA levels are impaired in patients with SUD in opposite ways according to the presence or absence of schizophrenia. Endocannabinoid alterations did not change with treatment, suggesting that they are trait markers. Further studies are necessary to understand the role of endocannabinoids in substance abusers with and without schizophrenia and to examine therapeutic implications.

Soluble interleukin-2 receptor levels correlated with positive symptoms during quetiapine treatment in schizophrenia-spectrum disorders.

BACKGROUND: Some but not all antipsychotics have been shown to modulate plasma cytokine levels in schizophrenia patients. Thus far, the most consistent finding has been the increase in plasma levels of soluble interleukin (IL)-2 receptor (sIL-2R) associated with clozapine treatment. Quetiapine is a second-generation antipsychotic with a pharmacological profile similar to that of clozapine, but its immunomodulatory effects have not been investigated in schizophrenia yet. The purpose of this exploratory study was to examine the changes in plasma levels of sIL-2R in schizophrenia during quetiapine treatment and association with psychopathology. METHODS: Participants were 29 schizophrenia-spectrum disorder patients (DSM-IV criteria), and 28 healthy controls. Patients had a comorbid substance use disorder (cannabis>alcohol>cocaine), since quetiapine is increasingly used in this population of dual diagnosis. No participant suffered from infection or overt inflammatory diseases. On baseline, patients taking mostly second-generation antipsychotics were switched to quetiapine for a 12-week open-label trial. Five patients were drop-outs. Mean dose of quetiapine for trial completers (n=24) was 466.6mg±227.3. Psychiatric variables were evaluated with the Positive and Negative Syndrome Scale and the Calgary Depression Scale for Schizophrenia. Plasma sIL-2R levels were assessed at baseline, weeks 6 and 12 in patients, and in healthy controls, using sandwich immunoassay. Plasma IL-6 and IL-1 receptor antagonist (IL-1RA) were measured for comparison purposes. RESULTS: On baseline, plasma sIL-2R, IL-6 and IL-1RA levels were higher in dual-diagnosis patients, compared to controls. Plasma sIL-2R further increased after quetiapine treatment (p=0.037), while plasma IL-6 and IL-1RA did not change. Clinical improvements were observed in positive, negative and depressive symptoms, and substance abuse severity (all p<0.01). Interestingly, changes in sIL-2R levels during treatment were inversely correlated with changes in positive symptoms (r=-0.524; p=0.009). That is, increases in sIL-2R levels were associated with reductions in positive symptoms. CONCLUSION: These data show that quetiapine elevates, like clozapine, sIL-2R levels in schizophrenia. Furthermore, the results suggest that sIL-2R alterations in schizophrenia rely on complex interplays between antipsychotics and the positive symptoms of the disorder. Future randomized controlled trials involving larger samples of schizophrenia patients are warranted to determine whether changes in plasma sIL-2R are quetiapine-related.

Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review.

BACKGROUND: Cytokines play an important role in infection and inflammation and are crucial mediators of the cross-talk between the brain and the immune system. Schizophrenia would be associated with an imbalance in inflammatory cytokines, leading to a decrease in Th1 and an increase in Th2 cytokine secretion. However, data published so far have been inconsistent. The primary objective of the present meta-analysis was to verify whether the cytokine imbalance hypothesis of schizophrenia is substantiated by evidence. METHODS: Cross-sectional studies were included if they assessed in vivo plasma or serum cytokine concentrations and/or in vitro secretion of cytokines by peripheral blood leukocytes from schizophrenia patients and healthy volunteers. RESULTS: Data from 62 studies involving a total sample size of 2298 schizophrenia patients and 1858 healthy volunteers remained for analysis. Ten cytokines were assessed, including the prototypic Th1 and Th2 cytokines gamma interferon (IFN-gamma) and interleukin 4 (IL-4) as well as IL-2, soluble IL-2 receptor (sIL-2R), IL-1beta, IL-1 receptor antagonist (IL-1RA), tumor necrosis factor-alpha (TNF-alpha), IL-6, soluble IL-6 receptor (sIL-6R), and IL-10. The results show that an increase occurs in in vivo IL-1RA, sIL-2R, and IL-6 and a decrease occurs in in vitro IL-2 in schizophrenia. No significant effect sizes were obtained for the other cytokines. CONCLUSIONS: These findings provide the first evidence of establishment of an inflammatory syndrome in schizophrenia, which refutes the current hypothesis of a Th2 slant. Caveats are presented to data interpretation, including the role of stress and the effect of weight gain that develops in schizophrenia.

Proteasome inhibitor model of Parkinson's disease in mice is confounded by neurotoxicity of the ethanol vehicle.

Defects in the ubiquitin-proteasome system have been implicated in Parkinson's Disease (PD). Recently, a rat model of PD was developed using a synthetic proteasome inhibitor (PSI), (Z-lle-Glu(OtBu)-Ala-Leu-al). We attempted to transfer this model to mouse studies, where genetics can be more readily investigated due to the availability of genetically modified mice. We treated C57BL/6 (B6) mice with six intraperitoneal injections of 6 mg/kg PSI in 50 mul of 70% ethanol over a 2-week-period. We found significant decreases in nigrostriatal dopamine in PSI-treated mice compared with saline-treated mice. However, we observed similar decreases in the ethanol-treated vehicle control group. Administration of ethanol alone led to significant long-term alterations in dopamine levels. Ethanol significantly eclipses the effects of PSI in the dopamine system, and therefore is a confounding vehicle for this model.

5-HT1A-mediated promotion of mitogen-activated T and B cell survival and proliferation is associated with increased translocation of NF-kappaB to the nucleus.

Mitogenic activation of T and B lymphocytes induces expression of the 5-HT(1A) receptor through an NF-kappaB-dependent signaling pathway. In the present study, it is shown that serotonin (5-HT), as well as the selective 5-HT(1A) receptor agonist R-DPAT, increase cell survival and S phase transition in mouse splenocytes stimulated by T or B cell mitogens. Further examination of the mechanisms underlying increased cell survival revealed that 5-HT and R-DPAT inhibited apoptotic cell death, assessed both by soluble DNA content, internucleosomal DNA cleavage, and hypodiploid DNA content. Additionally, 5-HT and R-DPAT treatment increased intranuclear levels of the p50 and p65 subunits of NF-kappaB. Potentiation by 5-HT and R-DPAT of mitogen-activated cell survival, S phase transition, and nuclear localization of NF-kappaB, as well as inhibition of apoptosis, were all reversed by the selective 5-HT(1A) receptor antagonist WAY-100635. These results indicate that 5-HT(1A)-mediated promotion of cell survival and proliferation of mitogen-activated T and B lymphocytes is associated with increased translocation of NF-kappaB in the nucleus.