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1.  Gene expression analysis of novel genes in the prefrontal cortex of major depressive disorder subjects 
Dysregulation of the glutamatergic system has been implicated not only in the treatment of major depressive disorder (MDD), but also in the excitotoxic effects of stress and anxiety on the prefrontal cortex, which may precede the onset of a depressive episode. Our previous studies demonstrate marked deficits in prominent postsynaptic proteins involved in glutamate neurotransmission in the prefrontal cortex (PFC), Brodmann’s area 10 (BA 10) from subjects diagnosed with major depressive disorder (MDD). In the same group of subjects we have identified deficits in expression and phosphorylation level of key components of the mammalian target of rapamycin (mTOR) signalling pathway, known to regulate translation initiation. Based on our previous findings, we have postulated that glutamate-dependent dysregulation of mTOR- initiated protein synthesis in the PFC may underlie the pathology of MDD. The aim of this study was to use the NanoString nCounter System to perform analysis of genes coding for glutamate transporters, glutamate metabolizing enzymes, neurotrophic factors and other intracellular signaling markers involved in glutamate signaling that were not previously investigated by our group in the PFC BA10 from subjects with MDD. We have analyzed a total of 200 genes from 16 subjects with MDD and 16 healthy controls. These are part of the same cohort used in our previous studies. Setting our cutoff p-value ≤ 0.01, marked upregulation of genes coding for mitochondrial glutamate carrier (GC1; p=0.0015), neuropilin 1 (NRP-1; p=0.0019), glutamate receptor ionotropic N-methyl-D-aspartate-associated protein 1 (GRINA; p=0.0060), and fibroblast growth factor receptor 1 (FGFR-1; p=0.010) was identified. No significant differences in expression of the remaining 196 genes were observed between MDD subjects and controls. While upregulation of FGFR-1 has been previously shown in MDD; abnormalities in GC-1, GRINA, and NRP-1 have not been reported. Therefore, this postmortem study identifies GC1, GRINA, and NRP-1 as novel factors associated with MDD; however, future studies will be needed to address the significance of these genes in the pathophysiology of depression and antidepressant activity.
doi:10.1016/j.pnpbp.2012.12.010
PMCID: PMC4089971  PMID: 23261523
prefrontal cortex; major depressive disorder; postmortem; gene expression; digital PCR
2.  Dopamine decreases NMDA currents in the oval bed nucleus of the stria terminalis of cocaine self-administering rats☆ 
Dopamine (DA) and N-methyl-D-aspartate receptors (NMDARs) contribute in the neural processes underlying drug-driven behaviors. DA is a potent modulator of NMDAR, but few studies have investigated the functional interaction between DA and NMDAR in the context of substance abuse. We combined the rat model of cocaine self-administration with brain slice electrophysiology to study DA modulation of NMDA currents in the oval bed nucleus of the stria terminalis (ovBNST), a dense DA terminal field involved in maintenance of cocaine self-administration amongst other drug related behaviors. Long-Evans rats self-administered intravenous cocaine (0.75 mg/kg/injection) on a progressive ratio (PR) schedule of reinforcement for 15 days and whole-cell patch-clamp recordings were done on the 16th day. DA reduced NMDA currents in brain-slices from cocaine self-administering rats, but not in those of drug-naïve and sucrose self-administering, or when cocaine exposure was passive (yoked), revealing a mechanism unique to voluntary cocaine intake. DA reduced NMDA currents by activating G-protein-coupled D1- and D2-like receptors that converged on phospholipase C and protein phosphatases. Accordingly, our study reveals a mechanism that may contribute to dysfunctional synaptic plasticity associated with drug-driven behaviors during acute withdrawal.
doi:10.1016/j.pnpbp.2014.01.011
PMCID: PMC4011798  PMID: 24472317 CAMSID: cams4372
Brain slice electrophysiology; Cocaine; Dopamine; NMDA; Self-administration
3.  Response prediction to antidepressants using scalp and source-localized loudness dependence of auditory evoked potential (LDAEP) slopes 
The loudness-dependence of the auditory evoked potential (LDAEP) slope may be inversely related to serotonin (5-HT) neurotransmission. Thus, steep LDAEPs tend to predict a positive response to selective serotonin reuptake inhibitor (SSRI) antidepressants, which augment 5-HT. However, LDAEPs also predict outcome to antidepressants indirectly altering 5-HT (e.g. bupropion). Hence, the LDAEP’s predicative specificity and sensitivity to antidepressant response/outcome remains elusive. Scalp N1, P2 and N1/P2 LDAEP slopes and standardized low resolution brain electromagnetic tomography (sLORETA)-localized N1 and P2 LDAEP slopes were assessed in depressed individuals (N=51) at baseline, 1 and 12 weeks post-treatment with one of three antidepressant regimens [escitalopram (ESC) + bupropion (BUP), ESC or BUP]. Clinical response was greatest with ESC+BUP at week 1. Treatment responders had steep N1 sLORETA-LDAEP baseline slopes while non-responders had shallow ones. P2 sLORETA-LDAEP slope increases at 1 week existed in responders; decreases were noted in non-responders. Exploratory analyses indicated that more BUP and ESC responders versus non-responders had steep baseline N1 sLORETA-LDAEP slopes. Additionally, slight decreases in scalp P2 LDAEP by week 1 existed for ESC treatment, while slope increases existed with ESC+BUP treatment. Only baseline N1 sLORETA-LDAEP discriminated treatment responders/non-responders. This work confirms that certain LDAEP measures are associated with treatment outcome and appear to be differentially modulated with varying antidepressant drug regimens, though this should be confirmed using larger samples.
doi:10.1016/j.pnpbp.2013.01.012
PMCID: PMC3654010  PMID: 23360662
antidepressants; classification; serotonin; major depressive disorder (MDD); loudness-dependence of auditory evoked potentials (LDAEP)
4.  The Effect of Short-term Stress on Serotonin Gene Expression in High and Low Resilient Macaques 
Female cynomolgus monkeys exhibit different degrees of reproductive dysfunction with moderate metabolic and psychosocial stress. When stressed with a paradigm of relocation and diet for 60 days, or 2 menstrual cycles, highly stress resilient monkeys continue to ovulate during both stress cycles (HSR); medium stress resilient monkeys ovulate once (MSR) and stress sensitive monkeys do not ovulate for the entire 60 days (SS). This study examines serotonin-related gene expression in monkeys with different sensitivity to stress and exposed to 5 days of moderate stress. Monkeys were first characterized as HSR, MSR or SS. After resumption of menstrual cycles, each monkey was re-stressed for 5 days in the early follicular phase. The expression of 3 genes pivotal to serotonin neural function was assessed in the 3 groups of monkeys (n=4-5/group). Tryptophan hydroxylase 2 (TPH2), the serotonin reuptake transporter (SERT), and the 5HT1A autoreceptor mRNAs expression were determined at 4 morphological levels of the dorsal raphe nucleus with in situ hybridization (ISH) using digoxygenin-incorporated riboprobes. In addition, cFos was examined with immunohistochemistry. Positive pixel area and/or cell number were measured. All data were analyzed with ANOVA (3 groups) and with a t-test (2 groups). After 5 days of stress, TPH2, SERT, 5HT1A and cFos were significantly lower in the SS group than the HSR group (p < 0.05, all). This pattern of expression was the same as the pattern observed in the absence of stress in previous studies. Therefore, the ratio of the HSR/SS expression of each serotonergic gene was calculated in the presence and absence of stress. There was little or no difference in the ratio of HSR/SS gene expression in the presence or absence of stress. Moreover, cFos expression indicates that overall, cell activation in the dorsal raphe nucleus and periaquaductal gray is lower in SS than HSR animals. These data suggest that the serotonin system may set the sensitivity or resilience of the individual, but serotonin-related gene expression may not rapidly respond to moderate stress in nonhuman primates.
doi:10.1016/j.pnpbp.2013.01.013
PMCID: PMC3654014  PMID: 23357537
Stress; stress resilient; ovulation; amenorrhea; serotonin; macaques; gene expression
5.  Symptom Dimensions are Associated with Age of Onset and Clinical Course of Obsessive-Compulsive Disorder 
Meta-analysis of the heterogeneous symptoms of obsessive-compulsive disorder (OCD) has found a four-factor structure of symptom dimensions consisting of cleaning, forbidden thoughts, symmetry, and hoarding. Research into age of onset of symptom dimensions has yielded inconsistent results, and it is unknown whether symptoms along these dimensions differ in their clinical course. We assessed age of onset and clinical course of different OCD symptom dimensions in a large cohort of adult patients. Nine-hundred fifty-five subjects were assessed using the Dimensional Yale-Brown Obsessive-Compulsive Scale. For age of onset analysis, we tested across three methods of classification: (1) primary (more severe) symptom dimension (2) clinically significant symptoms within a dimension or (3) any symptoms within a dimension. Age of onset was defined as the earliest age of onset reported for any individual item within a symptom dimension. For analysis of different types of clinical course, we used chi-square tests to assess for differences between primary symptom dimensions. OCD symptoms in the symmetry dimension had an earlier age of onset than other OCD symptom dimensions. These findings remained significant across all three methods of classification and controlling for gender and comorbid tics. No significant differences were found between the other dimensions. Subjects with primary OCD symptoms in the forbidden thoughts dimension were more likely to report a waxing-and-waning course, whereas symmetry symptoms were less likely to be associated with a waxing-and-waning course.
doi:10.1016/j.pnpbp.2013.02.003
PMCID: PMC3654083  PMID: 23410525
Obsessive-Compulsive Disorder; Symptom Dimensions; Age of Onset; Clinical Course
6.  Angiotensin II’s role in sodium lactate-induced panic-like responses in rats with repeated urocortin 1 injections into the basolateral amygdala 
Rats treated with three daily urocortin 1 (UCN) injections into the basolateral amygdala (BLA; i.e., UCN/BLA-primed rats) develop prolonged anxiety-associated behavior and vulnerability to panic-like physiological responses (i.e., tachycardia, hypertension and tachypnea) following intravenous infusions of 0.5 M sodium lactate (NaLac, an ordinarily mild interoceptive stressor). In these UCN-primed rats, the osmosensitive subfornical organ (SFO) may be a potential site that detects increases in plasma NaLac and mobilizes panic pathways since inhibiting the SFO blocks panic following NaLac in this model. Furthermore, since SFO neurons synthesize angiotensin II (A-II), we hypothesized that the SFO projects to the BLA and releases A-II to mobilizing panic responses in UCN/BLA-primed rats following NaLac infusions. To test this hypothesis, rats received daily bilateral injections of UCN or vehicle into the BLA daily for 3 days. Five to seven days following the intra-BLA injections, we microinjected either the nonspecific A-II type 1 (AT1r) and 2 (AT2r) receptor antagonist saralasin, or the AT2r-selective antagonist PD123319 into the BLA prior to the NaLac challenge. The UCN/BLA-primed rats pre-injected with saralasin, but not PD123319 or vehicle, had reduced NaLac-induced anxiety-associated behavior and panic-associated tachycardia and tachypnea responses. We then confirmed the presence of AT1rs in the BLA using immunohistochemistry which, combined with the previous data, suggest that A-II’s panicogenic effects in the BLA is AT1r dependent. Surprisingly, the SFO had almost no neurons that directly innervate the BLA, which suggests an indirect pathway for relaying the NaLac signal. Overall these results are the first to implicate A-II and AT1rs as putative neurotransmitter-receptors in NaLac induced panic-like responses in UCN/BLA-primed rats.
doi:10.1016/j.pnpbp.2013.02.014
PMCID: PMC3665353  PMID: 23523745
Anxiety; panic; angiotensin; circumventricular organ; amygdala; GABA; saralasin
7.  Effects of Naltrexone on Post-Abstinence Alcohol Drinking in C57BL/6NCRL and DBA/2J Mice 
The present experiment evaluated the effects of naltrexone, a non-selective opioid receptor antagonist, on post-abstinence alcohol drinking in C57BL/6NCRL and DBA/2J male mice. Home cage 2-bottle (alcohol vs. water) free-choice procedures were employed. During the pre-abstinence period, alcohol intake was much lower for the DBA/2J mice relative to the C57BL/6NCRL mice, and this strain difference was observed for groups receiving either 3% or 10% alcohol concentrations. The four-day abstinence period effectively reduced alcohol intakes (i.e., a negative alcohol deprivation effect, negative ADE) in both groups of DBA/2J mice, but had no effect on alcohol intakes in either group of C57BL/6NCRL mice. Both groups trained with 3% alcohol received the second four-day abstinence period, where the effects of acute administration of either naltrexone or saline on post-abstinence alcohol drinking were assessed. Naltrexone was more effective in reducing post-abstinence drinking of 3% alcohol in the DBA/2J mice than in the C57BL/6NCRL mice. In the DBA/2J mice, naltrexone further reduced, relative to saline-injected controls, the low levels of post-abstinence alcohol intake. Thus, the low baseline levels of alcohol drinking in DBA/2J mice were further diminished by the four-day abstinence period (negative ADE), and this suppressed post-abstinence level of alcohol drinking was still further reduced by acute administration of naltrexone. The results indicate that naltrexone is effective in reducing further the low levels of alcohol drinking induced by the negative ADE.
doi:10.1016/j.pnpbp.2013.03.002
PMCID: PMC3713418  PMID: 23499782
Alcohol; C57BL/6NCRL; DBA/2J; Naltrexone; Negative ADE
8.  Decreased GABA levels in anterior cingulate cortex/medial prefrontal cortex in panic disorder 
Changes of various brain metabolites including γ-aminobutyric acid (GABA), measured by 1H-magnetic resonance spectroscopy (MRS), have been reported in panic disorder (PD). Deficits in GABA have been implicated in the pathophysiology of PD. Furthermore, it has been suggested that cortical metabolite changes in PD are familial. Eleven PD patients, including five with and six without a PD family history, and eight age- and gender-matched healthy controls without a family history of psychopathology were recruited. Each subject underwent MRS exams and behavioral assessments (resting visual analog anxiety level and the Panic Disorder Severity Scale). GABA was detected with a MEGA-PRESS J-editing sequence and fitted to minimize mac-romolecule contaminations. A significant decrease in GABA, expressed as the ratio of GABA over total creatine (GABA/tCr), was detected in the anterior cingulate cortex (ACC)/medial prefrontal cortex (mPFC) in PD patients (p<0.05), which tends to be pronounced in patients with a PD family history. No other patient/control differences in metabolites were noted in the ACC/mPFC or occipital cortex (OCC). Overall, our results indicate that deficits in GABA levels in PD patients vary by brain regions and possibly by family history status.
doi:10.1016/j.pnpbp.2013.01.020
PMCID: PMC3758115  PMID: 23391588
Family history; GABA; MRS; Panic disorder
9.  Anxiogenic effects of brief swim stress are sensitive to stress history 
Stressors that are controllable not only protect an individual from the acute consequences of the stressor, but also the consequences of stressors that occur later. This phenomenon, termed “behavioral immunization”, is studied in the rat by first administering tailshocks each of which can be terminated (escapable tailshock) by an instrumental wheel-turn response prior to exposure to a second stressor. Previous research has shown that exposure to escapable tailshock blocks the neurochemical and behavioral consequences of later inescapable tailshock or social defeat stress. Here we explored the generality of behavioral immunization by examining the impact of prior escapable tailshock on the behavioral consequences of cold swim stress. Exposure to a 5 min cold-water (19 °C) swim caused an anxiety-like reduction in social interaction that was dependent upon 5-HT2C receptor activation. Rats with prior exposure to escapable tailshock did not develop the swim-induced anxiety. Plasticity in the medial prefrontal cortex, a hypothetical neural mechanism underlying behavioral immunization, is discussed.
doi:10.1016/j.pnpbp.2013.01.011
PMCID: PMC4075115  PMID: 23357538
5-HT2C; Anxiety; Learned helplessness; Rat; Social interaction
10.  Correlates of Insight Level in Obsessive-Compulsive Disorder with Dimensions of Symptomology 
Background
Cross-sectional studies have associated poor insight in patients with obsessive-compulsive disorder (OCD) with increased OCD symptom severity, earlier age of comorbid depression, and treatment response. The goal of this current study was to examine the relationship between dimensions of OCD symp tomatology and insight in a large clinical cohort of Brazilian patients with OCD. We expect poor insight to be associated with total symptom severity as well as with hoarding symptoms severity.
Methods
824 outpatients underwent a detailed clinical assessment for OCD, including the Yale–Brown Obsessive–Compulsive Scale (Y-BOCS), the Dimensional Yale–Brown Obsessive–Compulsive Scale (D-YBOCS), the Brown Assessment of Beliefs Scale (BABS), a socio-demographic questionnaire, and the Stuctured Clinical Interview for axis I DSM-IV disorders (SCID-P). Tobit regression models were used to examine the association between level of insight and clinical variables of interest.
Results
Increased severity of current and worst-ever hoarding symptoms was associated with poor insight in OCD after controlling for current OCD severity, age and gender. Poor insight was also correlated with increased current OCD symptom severity.
Conclusion
Hoarding and overall OCD severity explained were significantly but weakly associated with level of insight in OCD patients. Further studies should examine insight as a moderator and mediator of treatment response in OCD in both behavioral therapy and pharmacological trials. Behavioral techniques aimed at enhancing insight may be potentially beneficial in OCD, especially among patients with hoarding.
doi:10.1016/j.pnpbp.2011.05.012
PMCID: PMC4048951  PMID: 21640153
obsessive-compulsive disorder; insight; hoarding; symptom dimension
11.  Perioperative delirium and its relationship to dementia 
A number of serious clinical cognitive syndromes occur following surgery and anesthesia. Postoperative delirium is a behavioral syndrome that occurs in the perioperative period. It is diagnosed through observation and characterized by a fluctuating loss of orientation and confusion. A distinct syndrome that requires formalized neurocognitive testing is frequently referred to as postoperative cognitive dysfunction (POCD). There are serious concerns as to whether either postoperative delirium or postoperative cognitive dysfunction lead to dementia. These concerns are reviewed in this article.
doi:10.1016/j.pnpbp.2012.11.005
PMCID: PMC3612127  PMID: 23220565
Postoperative Delirium; Postoperative Cognitive Dysfunction; Long term cognitive impairment; Dementia
12.  Conditional Tat protein expression in the GT-tg bigenic mouse brain induces gray matter density reductions 
Tat (Trans-activator of transcription) is implicated in the neuropathogenesis of HIV-1 infection and known to contribute to neuronal damage and learning and memory impairments. However, direct neuroanatomical demonstration of Tat pathobiology is limited. GT-tg bigenic mice with a doxycycline (Dox)-inducible and brain-selective tat gene were used to test the hypotheses that conditional induction of Tat activity in brain can induce gray matter density abnormalities. Ultra high spatial resolution ex vivo magnetic resonance imaging (MRI) combined with a voxel based morphometry (VBM) analysis revealed gray matter density reductions in the sublenticular extended amygdala, the amygdala, the amygdala-hippocampal area, piriform and peri-/entorhinal cortices, and hypothalamus, in Tat-expressing GT-tg mice compared to Dox-treated C57Bl/6J mice. These neuroanatomical abnormalities are consistent with regions expected to be abnormal based on behavioral deficits exhibited by Tat-expressing mice (Carey et al., 2012). These experiments provide the first neuroimaging evidence that conditional Tat protein expression in the GT-tg bigenic mouse model alters brain structure. The findings warrant future studies to further characterize effects of conditional Tat expression on brain structure. Such studies may improve our understanding of the neurological underpinnings of neuroAIDS and the neurodegeneration associated with HIV-1 infection, potentially leading to new treatments.
doi:10.1016/j.pnpbp.2012.12.018
PMCID: PMC3612135  PMID: 23269344
HIV-1; neuroAIDS; Tat; magnetic resonance imaging; voxel based morphometry
13.  What is the bed nucleus of the stria terminalis? 
doi:10.1016/j.pnpbp.2009.07.006
PMCID: PMC4011829  PMID: 19602427 CAMSID: cams4378
14.  Nuclei-and condition-specific responses to pain in the bed nucleus of the stria terminalis 
The bed nucleus of the stria terminalis (BST) is a basal forebrain structure considered to be part of a cortico-striato-pallidal system that coordinates autonomic, neuroendocrine and behavioural physiological responses.
Recent evidence suggests that the BST plays a role in the emotional aspect of pain. The objective of the present study was to further understand the neurophysiological bases underlying the involvement of the BST in the pain experience, in both acute and chronic pain conditions. Using c-Fos as an indicator of neuronal activation, the results demonstrated that a single toe-pinch in rats produced nuclei-and condition-specific neuronal responses within the anterior region of the BST (antBST). Specifically, acute noxious stimulation increased c-Fos in the dorsal medial (dAM) and fusiform (FU) nuclei. Chronic neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve decreased the number of c-Fos positive cells following acute mechanical stimulation in the dAM and FU nuclei, and increased c-Fos immunoreactivity in the ventral medial (vAM) aspect of the BST. In addition, the results revealed a nuclei-specific sensitivity to the surgical procedure. Following noxious stimulation to animals that received a sham surgery, c-Fos immunoreactivity was blunted in the FU nucleus while it increased in the oval (OV) nucleus of the BST.
Altogether, this study demonstrates that pain induces nuclei-and condition-specific neuronal activation in the BST revealing an intriguing supraspinal neurobiological substrate that may contribute to the physiology of acute nociception and the pathophysiology of chronic pain.
doi:10.1016/j.pnpbp.2007.11.003
PMCID: PMC4011831  PMID: 18164529 CAMSID: cams4380
Bed nucleus of the stria terminalis (BST); c-Fos; Mechanical noxious stimulation; Neuropathic pain
15.  Viral infection, inflammation and schizophrenia 
Schizophrenia is a severe neurodevelopmental disorder with genetic and environmental etiologies. Prenatal viral/bacterial infections and inflammation play a major role in the genesis of schizophrenia. In this review, we describe a viral model of schizophrenia tested in mice whereby the offspring of mice prenatally infected with influenza at E7, E9, E16, and E18 show significant gene, protein, and structural abnormalities postnatally. Similarly, we describe data on rodents exposed to bacterial infection or injected with a synthetic viral mimic (PolyI:C) also demonstrating brain structural and behavioral abnormalities. Moreover, human serologic data has been indispensible in supporting the viral theory of schizophrenia. Individuals born seropositive for bacterial and viral agents are at a significantly elevated risk of developing schizophrenia. While the specific mechanisms of prenatal viral/bacterial infections and brain disorder are unclear, recent findings suggest the maternal inflammatory response may be associated with fetal brain injury. Preventive and therapeutic treatment options are also proposed. This review presents data related to epidemiology, human serology, and experimental animal models which support the viral model of schizophrenia.
doi:10.1016/j.pnpbp.2012.02.001
PMCID: PMC3408569  PMID: 22349576
viral infection; inflammation; schizophrenia; autism; influenza
16.  The impact of self-reported life stress on current impulsivity in cocaine dependent adults 
Current cocaine treatments may be enhanced with a better understanding of the underlying mechanisms that contribute to the onset and maintenance of the disease, such as life stress and impulsivity. Life stress and impulsivity have previously been studied independently as contributors to drug use, and the current study expands upon past research by examining how these factors interact with one another. The aim of the current study was to evaluate the role of life stress in predicting impulsivity in a non-treatment seeking cocaine-dependent sample (N = 112). Analyses revealed that trait impulsivity (as measured by the Barratt Impulsiveness Scale) was associated with education (r = −3.09, p < 0.01), as those who had higher educational attainment also reported lower rates of trait impulsivity. In addition, those over the age of 30 demonstrated lower impulsivity in decision-making (as measured by delay discounting) than those under 30 (t = 2.21, p = 0.03). Overall exposure to life stress was not significantly correlated to either aspect of impulsivity. However several specific life stressors were significantly related to greater impulsivity including having been put up for adoption or in foster care (t = −2.96, p < 0.01), and having a child taken away against their will (t = −2.68, p = 0.01). These findings suggest that age and education relate to impulsivity; and that while an overall compilation of life stress scores was not related to impulsivity, specific types of stress related to either being taken away from a parent or having a child taken away were. Future studies should assess these constructs longitudinally to restrict response bias.
doi:10.1016/j.pnpbp.2013.06.002
PMCID: PMC3955062  PMID: 23796525
Addiction; Cocaine; Dependence; Impulsivity; Life stress
17.  Genotype-independent decrease in plasma dopamine beta-hydroxylase activity in Alzheimer’s disease 
The noradrenergic system is involved in the etiology and progression of Alzheimer’s disease (AD) but its role is still unclear. Dopamine beta-hydroxylase (DBH) as a catecholamine-synthesizing enzyme plays a central role in noradrenaline (NA) synthesis and turnover. Plasma DBH (pDBH) activity shows wide inheritable interindividual variability that is under genetic control. The aim of this study was to determine pDBH activity, DBH (C-970T; rs1611115) and DBH (C1603T; rs6271) gene polymorphisms in 207 patients with AD and in 90 healthy age-matched controls. Plasma DBH activity was lower, particularly in the early stage of AD, compared to values in middle and late stages of the disease, as well as to control values. Two-way ANOVA revealed significant effect of both diagnosis and DBH (C-970T) or DBH (C1603T) genotypes on pDBH activity, but without significant diagnosis×genotype interaction. No association was found between AD and DBH C-970T (OR=1.08, 95% CI 1.13–4.37; p=0.779) and C1603T (OR=0.89; 95% CI 0.36–2.20; p=0.814) genotypes controlled for age, gender, and ApoE4 allele. The decrease in pDBH activity, found in early phase of AD suggests that alterations in DBH activity represent a compensatory mechanism for the loss of noradrenergic neurons, and that treatment with selective NA reuptake inhibitors may be indicated in early stages of AD to compensate for loss of noradrenergic activity in the locus coeruleus.
doi:10.1016/j.pnpbp.2013.02.002
PMCID: PMC3952071  PMID: 23416088
Alzheimer’s disease; Cognitive decline; DBH gene polymorphisms; Dopamine beta-hydroxylase; Plasma DBH activity
18.  Spice drugs are more than harmless herbal blends: a review of the pharmacology and toxicology of synthetic cannabinoids 
“K2” and “Spice” drugs (collectively hereafter referred to as Spice) represent a relatively new class of designer drugs that have recently emerged as popular alternatives to marijuana, otherwise characterized as “legal highs”. These drugs are readily available on the Internet and sold in many head shops and convenience stores under the disguise of innocuous products like herbal blends, incense, or air fresheners. Although package labels indicate “not for human consumption”, the number of intoxicated people presenting to emergency departments is dramatically increasing. The lack of validated and standardized human testing procedures and an endless supply of potential drugs of abuse are primary reasons why researchers find it difficult to fully characterize clinical consequences associated with Spice. While the exact chemical composition and toxicology of Spice remains to be determined, there is mounting evidence identifying several synthetic cannabinoids as causative agents responsible for psychoactive and adverse physical effects. This review provides updates of the legal status of common synthetic cannabinoids detected in Spice and analytical procedures used to test Spice products and human specimens collected under a variety of clinical circumstances. The pharmacological and toxicological consequences of synthetic cannabinoid abuse are also reviewed to provide a future perspective on potential short- and long-term implications.
doi:10.1016/j.pnpbp.2012.04.017
PMCID: PMC3936256  PMID: 22561602
synthetic cannabinoid; Spice; K2; ‘legal highs’; intoxication; marijuana alternative
19.  Reduced phosphorylation of the mTOR signaling pathway components in the amygdala of rats exposed to chronic stress 
The activity of the mammalian target of rapamycin (mTOR), an ubiquitously expressed serine/threonine kinase, is central to the regulation of translation initiation and, consequently protein synthesis required for long-term potentiation and new synaptic connections. Recent studies show that activation of the mTOR signaling pathway is required for the rapid antidepressant actions of glutamate N-methyl-D-aspartate (NMDA) receptor antagonists such as ketamine. Our prior work documented the first evidence of robust deficits in the mTOR signaling pathway in the prefrontal cortex (PFC) from subjects diagnosed with major depressive disorder (MDD). The goal of this study was to determine whether alterations in mTOR signaling can be observed in rats exposed to the chronic unpredictable stress (CUS) model of depression. In the present study, we examined the effect of CUS on the expression of phosphorylated mTOR and its downstream signaling components in the frontal cortex, hippocampus, amygdala, and dorsal raphe. We also examined the effect of CUS on the expression of kinases that phosphorylate mTOR such as extracellular signal-regulated kinase (ERK1/2) and protein kinase B/Akt (Akt1). In addition, we examined the effect of stress on the phosphorylation of GluR1 an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit. We found that eight-weeks of CUS exposure significantly decreased the phosphorylation levels of mTOR and its downstream signaling components in the amygdala. Reduced level of phospho-mTOR in the amygdala was accompanied by decreased phosphorylation of ERK-1/2, Akt-1, and GluR1. No significant changes were seen in the frontal cortex, hippocampus, or dorsal raphe. Our study demonstrates that long-term stress exposure results in brain region-specific abnormalities in signaling pathways previously linked to novel mechanisms for rapid antidepressant effects. These observations are in line with evidence showing that mTOR and its upstream and downstream signaling partners could be important targets for the development of novel antidepressants.
doi:10.1016/j.pnpbp.2012.08.001
PMCID: PMC3519947  PMID: 22889863
mTOR signaling pathway; chronic unpredictable stress; rats; frontal cortex; hippocampus; amygdala; dorsal raphe
20.  Ghrelin and Eating Disorders 
There is growing evidence supporting a multifactorial etiology that includes genetic, neurochemical, and physiological components for eating disorders above and beyond the more conventional theories based on psychological and sociocultural factors. Ghrelin is one of the key gut signals associated with appetite, and the only known circulating hormone that triggers a positive energy balance by stimulating food intake. This review summarizes recent findings and several conflicting reports on ghrelin in eating disorders. Understanding these findings and inconsistencies may help in developing new methods to prevent and treat patients with these disorders.
doi:10.1016/j.pnpbp.2012.08.011
PMCID: PMC3522761  PMID: 22960103
Ghrelin; Anorexia Nervosa; Bulimia Nervosa; Binge Eating Disorder; Des-acyl Ghrelin
21.  Allele-Specific Associations of 5-HTTLPR/rs25531 with ADHD and Autism Spectrum Disorder 
Background
The aims of the present study were to examine the association between a common serotonin transporter gene (SLC6A4) polymorphism 5-HTTLPR/rs25531 with severity of attentiondeficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) symptoms.
Methods
Mothers and teachers completed a validated DSM-IV-referenced rating scale for ADHD and ASD symptoms in 118 children with ASD.
Results
Analyses indicated that children with at least one copy of the S or LG allele obtained significantly more severe maternal ratings of hyperactivity (p=0.001; ηp2=0.097) and impulsivity (p=0.027; ηp2=0.044) but not inattention (p=0.061; ηp2=0.032), controlling for ASD severity, than children homozygous for the LA allele. Conversely, mothers’ ratings indicated that children with LA/LA genotype had more severe ASD social deficits than S+ or LG allele carriers (p=0.003; ηp2=0.081), controlling for ADHD symptom severity. Teachers’ ratings though consistent with mothers’ ratings of hyperactivity and social deficits were marginally significant (p=0.07/p=0.09). There was some evidence that the magnitude of parent-teacher agreement regarding symptom severity varied as a function of the child’s genotype.
Conclusion
The 5-HTTLPR/rs25531 polymorphism or its correlates may modulate severity of ADHD and ASD symptoms in children with ASD, but in different ways. These tentative, hypothesis-generating findings require replication with larger independent samples.
doi:10.1016/j.pnpbp.2012.10.019
PMCID: PMC3522768  PMID: 23123360
5-HTTLPR; attention-deficit hyperactivity disorder; autism spectrum disorder; serotonin; SLC6A4 gene
22.  Alterations in the Cerebral White Matter of Genetic High Risk Offspring of Patients with Schizophrenia Spectrum Disorder 
Alterations in White Matter (WM) may be seen in young relatives at risk and may underlie vulnerability to Schizophrenia. We were interested in exploring which of the WM regions were altered in adolescent offspring at familial risk for Schizophrenia. We examined structural alterations in the offspring of subjects with Schizophrenia or Schizoaffective disorder (HR; n=65; 36 males) and healthy controls (HC; n=80: 37 males) matched for age and education. MRI images were collected using a GE 1.5T scanner at the University of Pittsburgh Medical Center. Image processing was done using FreeSurfer (MGH) by an experienced rater blind to clinical data. We used multivariate analysis of covariance, with intracranial volume (p> 0.05) and age as covariates. High Risk offspring had significant reductions in total WM, hemispheric WM and WM within left parietal and left cingulate cortices. Male offspring had more pronounced right hemisphere WM reductions than females.
doi:10.1016/j.pnpbp.2012.08.003
PMCID: PMC3635091  PMID: 22910323
Schizophrenia; Genetic High-Risk; Offspring; FreeSurfer; MRI
23.  Structural Neurobiological Correlates of Mayer-Salovery-Caruso Emotional Intelligence Test Performance in Early Course Schizophrenia 
Objective
The Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) is a key measure of social cognition in schizophrenia that has good psychometric properties and is recommended by the MATRICS committee. As a way to further investigate the validity of the MSCEIT, this study sought to examine the neurobiological correlates of MSCEIT performance in patients with early course schizophrenia.
Methods
A total of 51 patients diagnosed with early course, stabilized schizophrenia or schizoaffective disorder completed structural magnetic resonance imaging (MRI) scans and the MSCEIT. Investigation of the associations between MSCEIT performance and gray matter morphology was examined by conducting voxel-based morphometry (VBM) analyses across hypothesized social-cognitive regions of interest using automated anatomical labeling in Statistical Parametric Mapping Software, version 5 (SPM5). All VBM analyses utilized general linear models examining gray matter density partitioned images, adjusting for demographic and illness-related confounds. VBM results were then followed up with confirmatory volumetric analyses.
Results
Patients with poorer overall and Facilitating, Understanding, and Managing Emotions subscale performances on the MSCEIT showed significantly reduced gray matter density in the left parahippocampal gyrus. Additionally, attenuated performance on the Facilitating and Managing Emotions subscales was significantly associated with reduced right posterior cingulate gray matter density. All associations observed between MSCEIT performance and gray matter density were supported with confirmatory gray matter volumetric analyses, with the exception of the association between the right posterior cingulate and the facilitation of emotions.
Conclusion
These findings provide additional evidence for the MSCEIT as a valid social-cognitive measure by elucidating its correlates with neurobiological structures commonly implicated in emotion processing. These findings provide additional biological evidence supporting the use of the MSCEIT in cognitive enhancing clinical trials in schizophrenia.
doi:10.1016/j.pnpbp.2012.09.013
PMCID: PMC3635092  PMID: 23041620
Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT); social cognition; structural MRI; neurobiological correlates; schizophrenia
24.  Sex-specific variation of MRI-based cortical morphometry in adult healthy volunteers: The effect on cognitive functioning 
Progress in neuro-psychopharmacology & biological psychiatry  2011;35(2):10.1016/j.pnpbp.2011.01.005.
Previous investigations have revealed sex-specific differences in brain morphometry. The effect of sex on cortical thickness may be influencing cognitive differences between sexes. With this exploratory study, we aimed to investigate the effect of sex in MRI-based cerebral cortex morphometry in healthy young volunteers and how the variability in cortical measures might affect cognitive functioning in men and women. 76 young healthy volunteers (45 men and 31 women) underwent a 1.5 T MR scan and 53 of them completed a comprehensive cognitive battery. Overall no gross significant differences between sexes were found in cortical thickness, surface area and curvature indexes. However, there was a significant group by hemisphere interaction in the total cortical thickness (F(1,72)=5.02; p=0.03). A greater leftward asymmetry was observed in cortical thickness in males. Only females show significant associations between cortical thickness and cognitive functioning (IQ and executive functioning). In conclusion, our findings do not support the notion of sexual dimorphism in cortical mantle morphology. The results also suggest that variability in cortical thickness may affect cognitive functioning in females but not in males.
doi:10.1016/j.pnpbp.2011.01.005
PMCID: PMC3880827  PMID: 21237230
Cognitive functioning; Cortical morphometry; MRI
25.  Is schizophrenia a dopamine supersensitivity psychotic reaction?☆ 
Adolf Meyer (1866–1950) did not see schizophrenia as a discrete disorder with a specific etiology but, rather, as a reaction to a wide variety of biopsychosocial factors. He may have been right. Today, we have evidence that gene mutations, brain injury, drug use (cocaine, amphetamine, marijuana, phencyclidine, and steroids), prenatal infection and malnutrition, social isolation and marginalization, can all result in the signs and symptoms of schizophrenia. This clinical picture is generally associated with supersensitivity to dopamine, and activates dopamine neurotransmission that is usually alleviated or blocked by drugs that block dopamine D2 receptors. While the dopamine neural pathway may be a final common route to many of the clinical symptoms, the components of this pathway, such as dopamine release and number of D2 receptors, are approximately normal in schizophrenia patients who are in remission. Postmortem findings, however, reveal more dimers of D1D2 and D2D2 receptors in both human schizophrenia brains and in animal models of schizophrenia. Another finding in animal models is an elevation of high-affinity state D2High receptors, but no radioactive ligand is yet available to selectively label D2High receptors in humans.
It is suggested that synaptic dopamine supersensitivity in schizophrenia is an attempt at compensation for the original damage by heightening dopamine neurotransmission pathways (preparing the organism for fight or fiight). The dopamine overactivity is experienced subjectively as overstimulation, which accounts for some of the clinical symptoms, with attempts at dampening down the stimulation leading to still other symptoms. Reaction and counter-reaction may explain the symptoms of schizophrenia.
doi:10.1016/j.pnpbp.2013.10.003
PMCID: PMC3858317  PMID: 24128684 CAMSID: cams3645
D1D2 receptor dimer; D2 receptor; D2D2 receptor dimer; Dopamine release; Mutation; Psychosis; Psychotogens

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