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Loss of ovarian function has important effects on neurotransmitter production and release with corresponding effects on cognitive performance. To date, there has been little direct comparison of the effects of surgical and transitional menopause on neurotransmitter pathways in the brain. In this study, effects on monoamines, monoamine metabolites, and the amino acids tryptophan (TRP) and tyrosine (TYR) were evaluated in adult ovariectomized (OVX) rats and in rats that underwent selective and gradual ovarian follicle depletion by daily injection of 4-vinylcyclohexene-diepoxide (VCD). Tissues from the hippocampus (HPC), frontal cortex (FCX), and striatum (STR) were dissected and analyzed at 1- and 6-weeks following OVX or VCD treatments. Tissues from gonadally intact rats were collected at proestrus and diestrus to represent neurochemical levels during natural states of high and low estrogens. In gonadally intact rats, higher levels of serotonin (5-HT) were detected at proestrus than at diestrus in the FCX. In addition, the ratio of 5-hydroxyindoleacetic acid (5-HIAA)/5HT in the FCX and HPC was lower at proestrus than at diestrus, suggesting an effect on 5-HT turnover in these regions. No other significant differences between proestrus and diestrus were observed. In OVX- and VCD-treated rats, changes were observed which were both brain region- and time point-dependent. In the HPC levels of norepinephrine, 5-HIAA, TRP and TYR were significantly reduced at 1 week, but not 6 weeks, in both OVX and VCD-treated rats relative to proestrus and diestrus. In the FCX, dopamine levels were elevated at 6 weeks after OVX relative to diestrus. A similar trend was observed at 1 week (but not 6 weeks) following VCD treatment. In the STR, norepinephrine levels were elevated at 1 week following OVX, and HVA levels were elevated at 1 week, but not 6 weeks, following VCD treatment, relative to proestrus and diestrus. Collectively, these data provide the first comprehensive analysis comparing the effects of two models of menopause on multiple neuroendocrine endpoints in the brain. These effects likely contribute to effects of surgical and transitional menopause on brain function and cognitive performance that have been reported.

Neurosteroids are both endogenous and exogenous steroids that rapidly alter neuronal excitability through interactions with ligand-gated ion channels and other cell surface receptors. They are originated from cholesterol and have important implications for schizophrenia (SZ) pathophysiology and treatment strategies. Specifically, pregnenolone (PREG), progesterone (PROG) and allopregnanolone (ALLO) exhibit similar psychotropic properties. Using enzyme immunoassay, we compared the neurosteroids in PREG downstream pathways in plasma between healthy controls (HC, n = 43) and first-episode antipsychotic-naive patients with SZ (FEAN-SZ, n = 53) before antipsychotic drug (APD) treatment. Comparisons were also made particularly along PREG-PROG-ALLO pathway in the same FEAN-SZ patients across multiple time points following initiation of treatment for 12 months (m). Firstly, at baseline, levels of PREG were significantly higher and those of ALLO were lower in FEAN-SZ than in HC, whereas PROG, cortisol, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) were not different. Consequently, the molar ratios of ALLO/PREG and ALLO/PROG in FEAN-SZ were significantly reduced. Secondly, in response to APD at 1 month, ALLO levels in FEAN-SZ were markedly elevated, whereas PREG and PROG levels decreased. Thirdly, among FEAN-SZ, lower levels of PROG (reflecting higher conversion to ALLO) at baseline may predict better therapeutic outcome after 1 month of APD treatment. These findings point to the perturbations of the PREG-PROG-ALLO pathway early in psychosis, and further study of this pathway may inform alternative and innovative therapeutic targets for SZ.

The skin flush response to niacin is abnormally blunted among a subset of patients with schizophrenia (SZ), preferentially associates with SZ compared to other mental illnesses, occurs frequently in nonpsychotic members of SZ-affected families, appears heritable, and shows evidence of genetic association. The niacin response abnormality (NRA) may prove to be a useful SZ endophenotype. Using a laser Doppler flowmeter, we undertook this study to estimate the prevalence of NRA in SZ (n = 70), bipolar disorder (BP, n = 59), and healthy control (HC, n = 87) groups, and to estimate its specificity for the illness. From the dose-response curves, we calculated the concentration of methylnicotinate required to elicit a half-maximal blood flow (MBF) response (EC50 value) and MBF value for each subject. The median log10EC50 of the SZ was above the third quartile of log10EC50 of either the HC or BP groups, whereas the MBF was significantly lower in the SZ than in the HC or BP groups. With a definition of NRA of having both EC50 above the ninetieth percentile of the control samples and MBF response below the sixtieth percentile for the control range, the NRA predicted SZ with 31% sensitivity and 97% specificity. Moreover, the NRA was not influenced by age, gender, race, and cigarette smoking. In summary, the NRA may define a SZ subtype with a clinically significant phospholipid signaling defect. Understanding its molecular origins may shed light on the pathophysiology of SZ and suggest new tools for its early diagnosis and treatment.

Estrogens have many beneficial effects in the brain. Previously, we evaluated the effects of two models of menopause (surgical vs. transitional) on multiple monoaminergic endpoints in different regions of the adult rat brain in comparison with levels in gonadally intact rats. Here we evaluated the effects of estrogen receptor (ER) agonist treatments in these same two models of menopause. Neurochemical endpoints were evaluated in the hippocampus (HPC), frontal cortex (FCX), and striatum (STR) of adult ovariectomized (OVX) rats and in rats that underwent selective and gradual ovarian follicle depletion by daily injection of 4-vinylcyclohexene-diepoxide (VCD), after 1- and 6-weeks treatment with 17β-estradiol (E2), or with selective ERα (PPT), ERβ (DPN), or GPR30 (G-1) agonists. Endpoints included serotonin (5-HT) and 5-Hydroxyindoleacetic acid, dopamine (DA), 3,4-Dihydroxyphenylacetic acid and homovanillic acid, norepinephrine (NE) and epinephrine, as well as the amino acids tryptophan (TRP) and tyrosine (TYR). Significant differences between the models were detected. OVX rats were much more sensitive to ER agonist treatments than VCD-treated rats. Significant differences between brain regions also were detected. Within OVX rats, more agonist effects were detected in the HPC than in any other region. One interesting finding was the substantial decrease in TRP and TYR detected in the HPC and FCX in response to agonist treatments, particularly in OVX rats. This is on top of the substantial decreases in TRP and TYR previously reported one week after OVX or VCD-treatments in comparison with gonadally intact controls. Other interesting findings included increases in the levels of 5-HT, DA, and NE in the HPC of OVX rats treated with DPN, increases in DA detected in the FCX of OVX rats treated with any of the ER agonists, and increases in 5-HT and DA detected in the STR of OVX rats treated with E2. Many effects that were observed after 1-week of treatment were no longer observed after 6-weeks of treatment, demonstrating that effects were temporary despite continued agonist treatment. Collectively, the results demonstrate significant differences in the effects of ER agonists on monoaminergic endpoints in OVX vs. VCD-treated rats that also were brain region-specific and time dependent. The fact that agonist treatments had lesser effects in VCD treated rats than in OVX rats may help to explain reports of lesser effects of estrogen replacement on cognitive performance in women that have undergone transitional vs. surgical menopause.

Background: There is excess and premature mortality in schizophrenia (SZ), from both natural and unnatural causes, when compared to the general population. In a 15-year follow-up study of SZ patients, 22% had died, of which greater than 50% died from cardiovascular and respiratory diseases. Inflammation has been linked to all stages of atherosclerosis. Recent studies suggest a role of C-reactive protein (CRP) as a risk marker for cardiovascular disease (CVD). CRP is a blood-borne protein that is produced by hepatocytes and regulated by inflammatory cytokines. The purpose of this study was to test whether high risk of cardiovascular disease was associated with increased levels of serum high-sensitivity CRP (hsCRP) progressively during the course of schizophrenia development. Methods: Serum hsCRP contents were compared among first-episode antipsychotic-naive patients with SZ (FEAN-SZ, n = 24), early course SZ patients with duration of illness 20 years patients currently with (n = 21) and those without (n = 19) treatment with lipid lowering drugs (LLD). In addition, age- and gender-matched healthy control subjects (HC, n = 25) were used for baseline comparisons with FEAN-SZ group. The high risk of CVD in human subjects was determined according to the National Cholesterol Education Program Adult Treatment Panel III (ATP-III) guidelines. The hsCRP measures were categorized as low risk, 3 mg/l. Results: Similar to HC subjects, 79% FEAN-SZ patients had low-risk hsCRP values with only 8% and 13% in average- and high-risk values, respectively. However, as disease progressed, 33% of clinically stable ECSZ patients who were not identified at high risk of CVD had average- and high-risk values, respectively. Among CSZ patients without LLD, 79% had high risk and 21% had average risk of hsCRP values. Following LLD therapy, these values remained relative high with 62%, 29%, and 9% in high-, average-, and low-risk hsCRP values, respectively. In addition, levels of hsCRP were inversely correlated with levels of HDL cholesterol. Conclusion: Our present data support the notion that the addition of hsCRP to the ATP-III global risk score provides a more accurate assessment of CVD risk in SZ patients. Serum hsCRP may also be an early marker of CVD risk in schizophrenia. On the other hand, Lp(a) levels, considering as a “Heart Attack” cholesterol and a strongly inherited risk factor for CVD, were not elevated in either ECSZ or CSZ patients in the present study. (Supported in part by the American Heart Association and MH58141 grants.)

Background Healthy individuals performing response suppression tasks activate anterior cingulate cortex with occurrence of false alarm error responses to nontargets. Fundamental questions include whether this error-related activation provides a signal contributing to behavioral control and, given generally poorer performance on such tasks by addicts, whether this signal is disrupted in addiction. Methods We used rapid, event-related functional magnetic resonance imaging to study 13 individuals with opiate dependence and 26 healthy control individuals performing a Go/NoGo task. Results Compared with controls, opiate addicts exhibited an attenuated anterior cingulate cortex error signal and significantly poorer task performance. In controls, the individual level of event-related anterior cingulate cortex activation accompanying false alarm error positively predicted task performance, particularly sensitivity in discriminating targets from nontargets. Conclusions The attenuation of this error signal in anterior cingulate cortex may play a role in loss of control in addiction and other forms of impulsive behavior.

SUMMARY This paper studies a functional-type linear measurement-error model, in which k data sets of observations are assumed to have in common a set of linear restrictions on their respective unobservable constant vectors. Each data set consists of replicated measurements of each one of several, generally unequal, constant vectors, with normal error assumed independent for each measurement made. The error covariance matrices are unspecified, and are equal for measurements within a data set but in general unequal among the data sets. This work generalises the results of Anderson (1951, 1984), who derived maximum likelihood estimators for the constant vectors and error covariance matrix of a single such data set. The model recalls the common-space analysis described by Flury (1987; 1988, pp. 131-4), but differs by the presence of a fixed effects subspace. Maximum likelihood estimation of the model parameters requires special numerical methods. An example from electroencephalography is used to introduce and illustrate the method.

Targeted metabolomics provides an approach to quantify metabolites involved in specific molecular pathways. We applied an electrochemistry-based, targeted metabolomics platform to define changes in tryptophan, tyrosine, purine and related pathways in the depressed and remitted phases of major depressive disorder (MDD). Biochemical profiles in the cerebrospinal fluid of unmedicated depressed (n = 14; dMDD) or remitted MDD subjects (n = 14; rMDD) were compared against those in healthy controls (n = 18; HC). The rMDD group showed differences in tryptophan and tyrosine metabolism relative to the other groups. The rMDD group also had higher methionine levels and larger methionine-to-glutathione ratios than the other groups, implicating methylation and oxidative stress pathways. The dMDD sample showed nonsignificant differences in the same direction in several of the metabolic branches assessed. The reductions in metabolites associated with tryptophan and tyrosine pathways in rMDD may relate to the vulnerability this population shows for developing depressive symptoms under tryptophan or catecholamine depletion.

Background: The antioxidant defense system, which is known to be dysregulated in schizophrenia, is closely linked to the dynamics of purine pathway. Thus, alterations in the homeostatic balance in the purine pathway may be involved in the pathophysiology of schizophrenia. Methodology/Principal Findings: Breakdown products in purine pathway were measured using high-pressure liquid chromatography coupled with a coulometric multi-electrode array system for 25 first-episode neuroleptic-naive patients with schizophrenia at baseline and at 4-weeks following initiation of treatment with antipsychotic medication. Associations between these metabolites and clinical and neurological symptoms were examined at both time points. The ratio of uric acid and guanine measured at baseline predicted clinical improvement following four weeks of treatment with antipsychotic medication. Baseline levels of purine metabolites also predicted clinical and neurological symtpoms recorded at baseline; level of guanosine was associated with degree of clinical thought disturbance, and the ratio of xanthosine to guanosine at baseline predicted degree of impairment in the repetition and sequencing of actions. Conclusions/Significance: Findings suggest an association between optimal levels of purine byproducts and dynamics in clinical symptoms and adjustment, as well as in the integrity of sensory and motor processing. Taken together, alterations in purine catabolism may have clinical relevance in schizophrenia pathology.

One branch of the tryptophan catabolic cascade is the kynurenine pathway, which produces neurotoxic (3-hydroxykynurenine (3-OHKY), quinolinic acid) and neuroinhibitory (kynurenic acid) compounds. Kynurenic acid acts as a competitive antagonist at the glycine site of N-methyl-D-asparate receptors at high concentrations and as a non-competitive antagonist on the a7-nicotinic acetylcholine receptor at low concentrations. Kynurenine compounds also influence cognitive functions known to be disrupted in schizophrenia. Alterations in tryptophan metabolism are therefore of potential significance for the pathophysiology of this disorder. In this paper, tryptophan metabolites were measured from plasma using high-pressure liquid chromatography coupled with electrochemical coulometric array detection, and re- lationships were tested between these metabolic signatures and clinical symptoms for 25 first-episode neuroleptic-naive schizophrenia patients. Blood samples were collected and clinical and neurological symptoms were rated at baseline and again at 4 wk following initiation of treatment. Level of 3-OHKY and total clinical symptom scores were correlated when patients were unmedicated and neuroleptic-naive, and this relationship differed significantly from the correlation observed for patients 4 wk after beginning treatment. Baseline psychosis symptoms were predicted only by neurological symptoms. Moreover, baseline 3-OHKY predicted clinical change at 4 wk, with the lowest concentrations of 3-OHKY being associated with the greatest improvement in symptoms. Taken together, our findings suggest a neurotoxic product of tryptophan metabolism, 3-OHKY, predicts severity of clinical symptoms during the early phase of illness and before exposure to antipsychotic drugs. Baseline level of 3-OHKY may also predict the degree of clinical improvement following brief treatment with antipsychotics.

BackgroundPurine catabolism may be an unappreciated, but important component of the homeostatic response of mitochondria to oxidant stress. Accumulating evidence suggests a pivotal role of oxidative stress in schizophrenia pathology.Methodology/principal findingsUsing high-pressure liquid chromatography coupled with a coulometric multi-electrode array system, we compared 6 purine metabolites simultaneously in plasma between first-episode neuroleptic-naïve patients with schizophrenia (FENNS, n = 25) and healthy controls (HC, n = 30), as well as between FENNS at baseline (BL) and 4 weeks (4w) after antipsychotic treatment. Significantly higher levels of xanthosine (Xant) and lower levels of guanine (G) were seen in both patient groups compared to HC subjects. Moreover, the ratios of G/guanosine (Gr), uric acid (UA)/Gr, and UA/Xant were significantly lower, whereas the ratio of Xant/G was significantly higher in FENNS-BL than in HC. Such changes remained in FENNS-4w with exception that the ratio of UA/Gr was normalized. All 3 groups had significant correlations between G and UA, and Xan and hypoxanthine (Hx). By contrast, correlations of UA with each of Xan and Hx, and the correlation of Xan with Gr were all quite significant for the HC but not for the FENNS. Finally, correlations of Gr with each of UA and G were significant for both HC and FENNS-BL but not for the FENNS-4w.Conclusions/significanceDuring purine catabolism, both conversions of Gr to G and of Xant to Xan are reversible. Decreased ratios of product to precursor suggested a shift favorable to Xant production from Xan, resulting in decreased UA levels in the FENNS. Specifically, the reduced UA/Gr ratio was nearly normalized after 4 weeks of antipsychotic treatment. In addition, there are tightly correlated precursor and product relationships within purine pathways; although some of these correlations persist across disease or medication status, others appear to be lost among FENNS. Taken together, these results suggest that the potential for steady formation of antioxidant UA from purine catabolism is altered early in the course of illness.

Schizophrenia is characterized by complex and dynamically interacting perturbations in multiple neurochemical systems. In the past, evidence for these alterations has been collected piecemeal, limiting our understanding of the interactions among relevant biological systems. Earlier, both hyper- and hyposerotonemia were variously associated with the longitudinal course of schizophrenia, suggesting a disturbance in the central serotonin (5-hydroxytryptamine (5-HT)) function. Using a targeted electrochemistry-based metabolomics platform, we compared metabolic signatures consisting of 13 plasma tryptophan (Trp) metabolites simultaneously between first-episode neuroleptic-naive patients with schizophrenia (FENNS, n=25) and healthy controls (HC, n=30). We also compared these metabolites between FENNS at baseline (BL) and 4 weeks (4w) after antipsychotic treatment. N-acetylserotonin was increased in FENNS-BL compared with HC (P=0.0077, which remained nearly significant after Bonferroni correction). N-acetylserotonin/Trp and melatonin (Mel)/serotonin ratios were higher, and Mel/N-acetylserotonin ratio was lower in FENNS-BL (all P-values

The cognitive impact of occupational exposure to organic solvents has primarily been studied with neuropsychologic and behavioral measures (Hartman 1995). A small literature has addressed aberrations in event-related potentials (ERPs) in persons with clinical complaints associated with neurotoxic chemical exposure (El Massioui et al 1986; Morrow et al 1992, 1996; Teo and Ferguson 1985; Wasch et al 1989). For these exposed individuals, prolongation of latency of the P300 component of the ERP is the most consistently reported finding. Prolongation of P300 latency also has been associated with acquired brain damage such as dementia (Goodin et al 1978) and posttraumatic amnesia (Onofrj et al 1991). ERP data are presented from painters with ongoing workplace exposures who had not previously presented with occupationally-related impairments.

Die Autoren beschreiben eine periodische stationare Versorgung („respite care“) chronisch psychiatrischer Patienten in einem Veterans Administration Hospital, die sie „Ambulantes Langzeitprogramm“ (ALP) nennen (engl. „Community Maintenance Program“ = CMP). Das ALP ist ein Programm, das kurzfristig festgelegte Krankenhausaufnahmen fur entlassene chronisch kranke psychiatrische Patienten vorsieht, um das Ruckfallrisiko zu senken. Das ALP zielt darauf ab, das die Patienten weiterhin in der Gesellschaft verbleiben konnen, indem der Familie die schwere Aufgabe, fur einen chronisch kranken Angehorigen zu sorgen, von Zeit zu Zeit abgenommen wird. Die vorlaufigen Daten zeigen, das das ALP die Anzahl der Akutaufnahmen reduziert. Zukunftige kontrollierte Studien sind notwendig, um zu bestatigen, das die periodischen Aufnahmen, ohne das eine Krise oder ein Ruckfall vorliegt, die Ruckfallquote entlassener Patienten tatsachlich verringern, die Lebensqualitat der Patienten und ihrer Betreuer verbessern und die Kosten des Krankenhausaufenthaltes senken konnen.

The augmentation of the rat stereotypy response with repeated amphetamine doses, put forward as a model of human amphetamine psychosis, was examined during concurrent reserpinization. The effects of reserpinization, amphetamine treatment, and amphetamine dose on four dependent variables representing the time course of stereotypy ratings after a post-treatment amphetamine dose, were tested by three-way MANOVA. An earlier onset of stereotypy , as occurred in nonreserpinized rats, was not detected in reserpinized rats, but an earlier offset of stereotypy with repeated amphetamine occurred in these rats when high amphetamine doses were used.

An experiment was designed to test the ability of chronic intra-accumbens amphetamine injections to produce the augmentation of locomotor activity noted with repeated intraperitoneal injections. Results revealed increased response variability with chronic injections; but no augmentation or tolerance occurred, in spite of preservation of a dose dependent locomotor response to amphetamine in the nucleus accumbens.

The construction of a multiple-cannula headpiece, its implantation into the rat brain, and its use in intracranial injections is described. The headpiece is rapidly and cheaply produced from common hospital and laboratory supplies once several machined metal parts have been made, and its construction is easily adapted to changes in injection technique, e.g., infusion by osmotic minipump.

Gamma-butyrolactone (GBL) is well known to reduce dopamine neuronal impulse flow, but the effects of the drug on dopamine-dependent behavioral states is not well studied. Qualitative and quantitative data are presented, detailing the influence of GBL on stereotypy when this drug is given after administration of the indirectly-acting dopamine mimetics amphetamine and methylphenidate, and the direct dopamine agonist apomorphine. GBL reversed the stereotypy produced by all three drugs, given at moderate doses producing comparable intensities of stereotypy. GBL unexpectedly proved effective in reversing stereotypy after higher-dose apomorphine while producing a rather weak influence on that of higher-dose amphetamine and methylphenidate. The results are discussed in terms of the dopamine impulse flow, and possible GABA-potentiating, effects of GBL, and the sedative effects of apomorphine.