European Neuropsychopharmacology (v.24, #2)

Contents (OBC).

Pharmacological management of alcohol dependence: From mono-therapy to pharmacogenetics and beyond by Fabio Caputo; Teo Vignoli; Alice Grignaschi; Mauro Cibin; Giovanni Addolorato; Mauro Bernardi (181-191).
Almost 10% of the world's population is affected by alcohol use disorders, and the treatment of alcohol dependence (AD) still remains a challenge. Patients with AD can differ in many traits. Three drugs (disulfiram, naltrexone, and acamprosate) have been approved by the FDA for the treatment of AD, and in some European countries sodium oxybate is also approved for this purpose. Combined pharmacological therapy has not provided such convincing results. Considering the fact that the “ideal” and effective drug for all types of alcoholic patients does not exists, the future challenge will be to identify a personalized approach. Recent data has shown that this objective can be achieved by investigating the genetic variability of the patient. Moreover, the use of replacement molecules can probably be considered an advantageous therapeutic opportunity (i.e. sodium oxybate). In addition, reduction of alcohol consumption is increasingly accepted as a viable treatment goal, and the use of nalmefene “as-needed” (a pharmacological approach similar to naltrexone, but, possibly, with lower hepatotoxicity) may help in the treatment of AD. Thus, it is important to stress that a pharmacological approach to treat AD should be preceded by the definition of patient characteristics; this may help in the choice of the most appropriate drug and it can be done more easily when more pharmacological options approved for the treatment of AD are also available.
Keywords: Alcohol dependence; Pharmacological treatment; Typologies of alcoholics; Monotherapy; Combined pharmacological therapy; Pharmacogenomic era;

Baclofen for alcohol dependence in France: Incidence of treated patients and prescription patterns—A cohort study by Julie Dupouy; Jean-Pascal Fournier; Émilie Jouanjus; Aurore Palmaro; Jean-Christophe Poutrain; Stéphane Oustric; Maryse Lapeyre-Mestre (192-199).
Recently, baclofen has been widely promoted for treatment of alcohol dependence in France. Our aim was firstly to describe the incidence of patients newly treated with baclofen for alcohol dependence in France from 2007 to 2011, and secondly to describe baclofen prescription patterns and prescribers. A retrospective cohort study of patients newly treated with baclofen was conducted using the “Echantillon Généraliste des Bénéficiaires” database (EGB). Patients with a first dispensation of baclofen between 01/01/2007 and 31/12/2011, followed by a second in the next 120 days, were included. Patients were considered treated with baclofen for neurological conditions if at least one of the following conditions was found to be true: (1) presence of a neurological condition for which baclofen could be prescribed, (2) dispensation of dantrolene, another anti-spastic drug, or (3) hospitalization for a neurological condition for which baclofen could be prescribed. We assumed that all the remaining patients were treated for alcohol dependence. During the 5-year period, 676 patients were incident users. While the annual incidence rate of patients newly treated with baclofen for neurological conditions remained stable, the annual incidence rate of patients newly treated with baclofen for alcohol dependence increased by a factor of 2.9 between 2007 (0.09/1000 person-years) and 2011 (0.26/1000 person-years). In the alcohol dependence group, median duration of baclofen treatment was 143.5 [74.0; 377.0] days; median daily dose was 24.4 [14.8; 39.5] mg. This study demonstrated the rapidly increasing use of baclofen in France for treatment of alcohol dependence.
Keywords: Addictive behavior; Alcoholism; Baclofen; Cohort studies; Incidence; General practitioners;

Cognitive effects of methylphenidate and levodopa in healthy volunteers by A.M.W. Linssen; A. Sambeth; E.F.P.M. Vuurman; W.J. Riedel (200-206).
Our previous study showed enhanced declarative memory consolidation after acute methylphenidate (MPH) administration. The primary aim of the current study was to investigate the duration of this effect. Secondary, the dopaminergic contribution of MPH effects, the electrophysiological correlates of declarative memory, and the specificity of memory enhancing effects of MPH to declarative memory were assessed. Effects of 40 mg of MPH on memory performance were compared to 100 mg of levodopa (LEV) in a placebo-controlled crossover study with 30 healthy volunteers. Memory performance testing included a word learning test, the Sternberg memory scanning task, a paired associates learning task, and a spatial working memory task. During the word learning test, event-related brain potentials (ERPs) were measured. MPH failed to enhance retention of words at a 30 min delay, but it improved 24 h delayed memory recall relative to PLA and LEV. Furthermore, during encoding, the P3b and P600 ERP latencies were prolonged and the P600 amplitude was larger after LEV compared to PLA and MPH. MPH speeded response times on the Sternberg Memory Scanning task and improved performance on the Paired Associates Learning task, relative to LEV, but not PLA. Performance on the Spatial working memory task was not affected by the treatments. These findings suggest that MPH and LEV might have opposite effects on memory
Keywords: Memory; Event-related potentials; Dopamine; Methylphenidate; Levodopa;

Depression could be an independent risk factor for cardiovascular disease. We assessed bupropion response in depressed patients by polysomnography (PSG) and cardiopulmonary coupling (CPC) variables. Nineteen subjects participated in a two-session, two consecutive night PSG protocol. Participants received either placebo or bupropion-SR 150 mg, orally, in a randomized, double-blind cross-over fashion on night two. Outcome variables were: sleep stages, REM latency, stable, unstable sleep and very low frequency coupling (VLFC). CPC analysis uses heart rate variability and the electrocardiogram's R-wave amplitude fluctuations associated with respiration to generate frequency maps. Bupropion increased REM latency (p=0.043) but did not impact PSG sleep continuity, architecture and CPC variables. A trend (p=0.092) was observed towards increasing VLFC duration. Bupropion increased the number of stable–unstable sleep transitions (p=0.036). Moderate to strong correlations between PSG and CPC variables were found on placebo and bupropion nights. Limitations include a small sample size, limited power to detect CPC changes and lack of normal controls for comparison. Increased stable–unstable sleep transitions and VLFC duration may indicate vulnerability to cardiovascular disease due to their association with low heart rate variability that has been associated with increased mortality raising the question whether the beneficial effects of the antidepressant medication outweighs the impact on cardiopulmonary dynamics.
Keywords: Depression; Cardiopulmonary coupling; Bupropion; Sleep quality;

Twelve months of electronic monitoring (MEMS®) in the Swedish COAST-study: A comparison of methods for the measurement of adherence in schizophrenia by Cecilia Brain; Birgitta Sameby; Katarina Allerby; Eva Lindström; Jonas Eberhard; Tom Burns; Margda Waern (215-222).
The primary aim was to compare objective and subjective measures of adherence in a naturalistic cohort of schizophrenia outpatients over 12 months between October 2008 and June 2011. Antipsychotic medication adherence was monitored in 117 outpatients diagnosed with schizophrenia or schizophrenia-like psychosis according to DSM-IV criteria in a naturalistic prospective study. Adherence was determined by the Medication Event Monitoring System (MEMS®), pill count, plasma levels and patient, staff, psychiatrist and close informant ratings. The plasma level adherence measure reflects adherence to medication and to lab visits. Relationships between MEMS® adherence and other measures were expressed as a concordance index and kappa (K). Non-adherence (MEMS® ≤0.80) was observed in 27% of the patients. MEMS® adherence was highly correlated with pill count (concordance= 89% and K=0.72, p<0.001). Concordance and K were lower for all other adherence measures and very low for the relationship between MEMS® adherence and plasma levels (concordance=56% and K=0.05, p=0.217). Adherence measures were also entered into a principal component analysis that yielded three components. MEMS® recordings, pill count and informant ratings had their highest loadings in the first component, plasma levels alone in the second and patient, psychiatrist and staff ratings in the third. The strong agreement between MEMS® and pill count suggests that structured pill count might be a useful tool to follow adherence in clinical practice. The large discrepancy between MEMS® and the adherence measure based on plasma levels needs further study in clinical settings.
Keywords: Adherence; Schizophrenia; Antipsychotics; Medication Event Monitoring System; Pill count; Plasma levels;

Effects of raloxifene on cognition in postmenopausal women with schizophrenia: A double-blind, randomized, placebo-controlled trial by Elena Huerta-Ramos; Raquel Iniesta; Susana Ochoa; Jesús Cobo; Eva Miquel; Mercedes Roca; Antoni Serrano-Blanco; Fernando Teba; Judith Usall (223-231).
Studies of estrogen therapy in postmenopausal women provide evidence of an effect of sex hormones on cognitive function. Estrogen has demonstrated some utility in the prevention of normal, age-related decline in cognitive functions, especially in memory. The potential therapeutic utility of estrogens in schizophrenia is increasingly being recognized. Raloxifene, a selective estrogen receptor modulator (SERM), appears to act similarly to conjugated estrogens on dopamine and serotonin brain systems, and may be a better option since it lacks the possible negative effects of estrogen on breast and uterine tissue. We assessed the utility of raloxifene as an adjuvant treatment for cognitive symptoms in postmenopausal women with schizophrenia in a 12-week, double-blind, randomized, placebo-controlled study. Patients were recruited from both the inpatient and outpatient departments. Thirty-three postmenopausal women with schizophrenia (DSM-IV) were randomized to receive either adjuvant raloxifene (16 women) or adjuvant placebo (17 women) for three months. The main outcome measures were: Memory, attention and executive functions. Assessment was conducted at baseline and week 12. The total sample is homogenous with respect to: age, years of schooling, illness duration, baseline symptomatology and pharmacological treatment. The addition of raloxifene (60 mg) to regular antipsychotic treatment showed: we found significant differences in some aspects of memory and executive function in patients treated with raloxifene. This improvement does not correlate with clinical improvement. The use of raloxifene as an adjuvant treatment in postmenopausal women with schizophrenia seems to be useful in improving cognitive symptoms.
Keywords: Raloxifene; Schizophrenia; Cognitive function; Postmenopausal women;

The association of substance use disorders (SUD) with attention-deficit disorder (ADHD), co-morbid mental disorders, and medication has only been studied in isolation and in rather small samples.Data were based on four Danish national registers covering a total of 20,742 patients with ADHD, their dispensed medications, co-morbid mental disorders, and associated SUD between 1994 and 2010. The analyses considered the risk of various medications (methylphenidate only, antidepressants only, antipsychotic only, mixed medication) in comparison to a control group of non-medicated patients with ADHD, various co-morbid disorders, duration of medication, age at diagnosis, year of birth, and sex for developing SUD.The observation period of the cohort ranged between 2.25 and 66.21 years and the prevalence for SUD was 9.51%. The SUD rates were significantly higher prior to, compared to following the onset of medication in the methylphenidate and the mixed medication subgroup, whereas they were significantly higher following onset of medication in the antidepressants and the antipsychotics subgroups. However, the SUD rates were significantly higher in all drug conditions except for methylphenidate after onset of medication compared to the non-medicated subgroup. Risk factors obtained by regression analysis did not include methylphenidate but did include antidepressants, antipsychotics, and mixed medications, in combination with co-morbid mood, anxiety, personality, and conduct disorders, and older age at diagnosis. Longer duration of medication and female sex were protective factors.This representative study based on a large nationwide psychiatric sample provides solid evidence into the patterns of SUD in patients with ADHD based on medication use and co-morbidities.
Keywords: Attention-deficit/hyperactivity disorder; Substance use disorder; Co-morbid disorders; Medication;

In vivo type 1 cannabinoid receptor availability in Alzheimer's disease by Rawaha Ahmad; Karolien Goffin; Jan Van den Stock; François-Laurent De Winter; Evy Cleeren; Guy Bormans; Jos Tournoy; Philippe Persoons; Koen Van Laere; Mathieu Vandenbulcke (242-250).
The endocannabinoid system (ECS) is an important modulatory and potentially neuroprotective homeostatic system in the brain. In Alzheimer's disease (AD), the role of type 1 cannabinoid receptor (CB1R) is unclear, with contradictory findings in post-mortem studies showing upregulation, downregulation or unchanged CB1R status. We have investigated CB1R availability in vivo in patients with AD, in relation to amyloid deposition, cognitive functioning and apolipoprotein E (ApoE) genotype. Eleven AD patients and 7 healthy volunteers (HV) underwent combined [18F]MK-9470 PET and [11C]PIB PET scans to assess CB1R availability and amyloid deposition, respectively, and T1 volumetric MRI for partial volume correction. We found no difference in CB1R availability between AD and HV, VOI-based fractional uptake values (FUR) were 0.043±0.01 for AD and 0.045±0.01 for controls (p=0.9). CB1R availability did not correlate with neuropsychological test scores and was not modulated by ApoE genotype. As expected, global [11C]PIB SUVR (standardized uptake value ratio) was increased in AD (SUVR 1.9±0.3) compared to HV (1.2±0.1) with p<0.001, but no correlation was found between amyloid β (Aβ) deposition and CB1R availability. In conclusion, we found no in vivo evidence for a difference in CB1R availability in AD compared to age-matched controls. Taken together with recently reported in vivo CB1R changes in Parkinson's and Huntington's disease, these data suggest that the CB1R is differentially involved in neurodegenerative disorders.
Keywords: Alzheimer's disease; Cannabinoid receptor; Amyloid; PET scan; MMSE; ApoE;

Tesofensine (TE) is a novel triple monoamine re-uptake inhibitor inducing a potent inhibition of the re-uptake process in the synaptic cleft of the neurotransmitters dopamine, norepinephrine, and serotonin. In recent preclinical and clinical evaluations TE showed a robust anti-obesity effect, but the specific mechanism of this triple monoamine re-uptake inhibitor still needs to be further elucidated. This positron emission tomography (PET) study, using [11C]βCIT-FE, aimed to assess the degree of the dopamine transporter (DAT) occupancy, at constant TE plasma levels, following different oral, multiple doses of TE during totally 8–12 days. In addition, the relationships between DAT occupancy and TE plasma concentrations, or doses, were investigated to enable assessment of DAT occupancies in subsequent clinical trials. The results demonstrated that TE induced a dose-dependent blockade of DAT following multiple doses of 0.125–1 mg TE at anticipated steady-state conditions. The mean striatal DAT occupancy varied dose-dependently between 18% and 77%. A sigmoid E max model well described the relationship between striatal DAT occupancy and TE plasma concentrations or doses. It was estimated that the maximum achievable DAT occupancy was about 80% and that half of this effect was accomplished by approximately 0.25 mg TE and a plasma drug concentration of 4 ng/ml. The results indicated an important mechanism of action of TE on DAT. Further, these results suggest that the previously reported dose-dependent weight loss, in TE treated subjects, was in part mediated by an up-regulation of dopaminergic pathways due to enhanced amounts of synaptic dopamine after blockade of DAT.
Keywords: Positron emission tomography; Dopamine re-uptake; DAT; Chronic treatment; Neurochemistry; Drug development;

Exposure to emotionally arousing experiences elicits a robust and persistent memory and enhances anxiety. The amygdala complex plays a key role in stress-induced emotional processing and in the fear memory formation. It is well known that ERK activation in the amygdala is a prerequisite for fear memory consolidation. Moreover, stress elevates p-ERK2 levels in several areas of the brain stress circuitry. Therefore, given that the ERK1/2 cascade is activated following stress and that the role of this cascade is critical in the formation of fear memory, the present study investigated the potential involvement of p-ERK2 in amygdala subnuclei in the promoting influence of stress on fear memory formation and on anxiety-like behavior. A robust and persistent ERK2 activation was noted in the Basolateral amygdala (BLA), which was evident at 5 min after restraint and lasted at least one day after the stressful experience. Midazolam, a short-acting benzodiazepine ligand, administered prior to stress prevented the increase in the p-ERK2 level in the BLA. Pretreatment with intra-BLA infusion of U0126 (MEK inhibitor), but not into the adjacent central nucleus of the amygdala, attenuated the stress-induced promoting influence on fear memory formation. Finally, U0126 intra-BLA infusion prevented the enhancement of anxiety-like behavior in stressed animals. These findings suggest that the selective ERK2 activation in BLA following stress exposure is an important mechanism for the occurrence of the promoting influence of stress on fear memory and on anxiety-like behavior.
Keywords: Basolateral amygdala; Stress; ERK1/2 pathway; Fear memory; Anxiety;

Prenatal MAM administration affects histone H3 methylation in postnatal life in the rat medial prefrontal cortex by Marzena Maćkowiak; Ewelina Bator; Joachim Latusz; Patrycja Mordalska; Krzysztof Wędzony (271-289).
Several findings have indicated that schizophrenia may be connected with the impaired epigenetic regulation of gene transcription. The present study investigated the epigenetic modifications connected with histone H3 methylation at lysine (K)4 and K9 in the medial prefrontal cortex (mPFC) in a neurodevelopmental model of schizophrenia based on prenatal administration of methylazoxymethanol (MAM) at embryonic day 17, which impairs the sensorimotor gating process in adult but not adolescent animals. The effect of MAM was determined at different postnatal ages, pre-puberty (P15, P30 and P45) and post-puberty (P60 and P70), using western blot analyses. MAM treatment altered the levels of H3K9me2 before puberty. H3K9me2 was decreased at P15 and P45 but was increased at P30. In contrast, H3K4me3 was noticeably decreased in adult rats. Immunofluorescence experiments revealed that H3K9me2 protein levels were increased in neuronal cells at P30 and that H3K4me3 levels were decreased in astrocytes at P60 after MAM administration. Decreases in the methyltransferase ASH2L protein levels at P45, P60 and P70 were also observed, while the protein levels of the methyltransferase G9a did not change. In addition, levels of the demethylases LSD1 and JARID1c were analysed after MAM administration. LSD1 protein levels were increased at P15 but decreased at P30. JARID1c protein levels were increased in the MAM-treated animals at P60. Decreased Gad1 mRNA levels were found in adult MAM-treated animals, similar to alternation observed in schizophrenia. The present study indicates that prenatal MAM administration evokes changes in the methylation patterns of histone H3 during postnatal life.
Keywords: Schizophrenia; Epigenetics; Neurodevelopment;

Adolescent peer-rejection persistently alters pain perception and CB1 receptor expression in female rats by Peggy Schneider; Christin Hannusch; Christian Schmahl; Martin Bohus; Rainer Spanagel; Miriam Schneider (290-301).
Peer-interactions are particularly important during adolescence and teenagers display enhanced sensitivity toward rejection by peers. Social rejection has been shown to induce alterations in pain perception in humans. However, the neurobiological consequences of adolescent social rejection have yet to be extensively characterized, and no appropriate animal model is available. Here, we propose inadequate playful interactions in adolescent rats as a novel animal model for social peer-rejection and examine potential long-term consequences into adulthood. Acute social pairing of female adolescent Wistar rats with an age-matched rat from the less playful Fischer344 strain was found to alter social play and decrease pain reactivity, indicating Fischer rats as inadequate social partners for Wistar animals. Therefore, in a second experiment, adolescent female Wistar rats were either reared with another Wistar rat (adequate social rearing; control) or with a Fischer rat (inadequate social rearing; play-deprived). Beginning on day 50, all Wistar rats were group housed with same-strain partners and tested for behavioral, neurobiological and endocrine differences in adulthood. Playful peer-interactions were decreased during adolescence in play-deprived animals, without affecting social contact behavior. Consequently, adult play-deprived rats showed decreased pain sensitivity and increased startle reactivity compared to controls, but did not differ in activity, anxiety-related behavior or social interaction. Both groups also differed in their endocrine stress-response, and expression levels of the cannabinoid CB1 receptor were increased in the thalamus, whereas FAAH levels were decreased in the amygdala. The present animal model therefore represents a novel approach to assess the long-term consequences of peer-rejection during adolescence.
Keywords: Social rejection; Adolescence; Social play behavior; Pain; CB1 receptor; FAAH;

Aside from the well-known biologically active angiotensin II, other biologically active angiotensins have been discovered, including angiotensin IV and angiotensin-(1–7). Some years ago, we and others discovered that the Mas proto-oncogene encodes a G protein-coupled receptor being essential for angiotensin-(1–7) signaling. Mas is not only expressed in the periphery but also within the brain, e.g. in the dentate gyrus (DG) and the piriform cortex (PC). Since the DG is capable of adult neurogenesis, we examined the impact of a deletion of Mas upon adult neurogenesis. Deletion of Mas did not alter cell proliferation in the adult DG (as monitored with phosphohistone H3) and did not alter cell death (as monitored with activated Caspase 3). However, Mas deficiency resulted in an increase in the number of doublecortin (DCX) positive cells, indicating that lack of Mas increases the number of this cell population. Concerning the PC, it is discussed whether adult neurogenesis occurs under physiological conditions in this area. We could demonstrate that Mas deficiency has an impact on cell division and on the population of DCX-positive cells within the PC. Since Mas is not expressed before birth within the brain, our data may suggest that adult hippocampal neurogenesis and neurogenesis occurring during prenatal development share several common mechanisms, but are, at least in part, differentially regulated. Moreover, since deficiency for Mas increases the numbers of DCX-positive young neurons, blockage of Mas might be beneficial in stimulating neurogenesis in adults.
Keywords: Abercrombie's; Doublecortin; Hippocampus; Immunohistochemistry; Knockout; Mice;

Concomitant manipulation of murine NMDA- and AMPA-receptors to produce pro-cognitive drug effects in mice by Julie Vignisse; Harry W.M. Steinbusch; Vladimir Grigoriev; Alexei Bolkunov; Alexey Proshin; Lucien Bettendorff; Sergey Bachurin; Tatyana Strekalova (309-320).
Bifunctional drug therapy targeting distinct receptor signalling systems can generate increased efficacy at lower concentrations compared to monofunctional therapy. Non-competitive blockade of the NMDA receptors or the potentiation of AMPA receptors is well documented to result in memory enhancement. Here, we compared the efficacy of the low-affinity NMDA receptor blocker memantine or the positive modulator of AMPA receptor QXX (in C57BL/6 J at 1 or 5 mg/kg, ip) with new derivatives of isothiourea (0.5–1 mg/kg, ip) that have bifunctional efficacy. Low-affinity NMDA blockade by these derivatives was achieved by introducing greater flexibility into the molecule, and AMPA receptor stimulation was produced by a sulfamide-containing derivative of isothiourea. Contextual learning was examined in a step-down avoidance task and extinction of contextual memory was studied in a fear-conditioning paradigm. Memantine enhanced contextual learning while QXX facilitated memory extinction; both drugs were effective at 5 mg/kg. The new derivative IPAC-5 elevated memory scores in both tasks at the dose 0.5 mg/kg and exhibited the lowest IC50 values of NMDA receptor blockade and highest potency of AMPA receptor stimulation. Thus, among the new drugs tested, IPAC-5 replicated the properties of memantine and QXX in one administration with increased potency. Our data suggest that a concomitant manipulation of NMDA- and AMPA-receptors results in pro-cognitive effects and supports the concept bifunctional drug therapy as a promising strategy to replace monofunctional therapies with greater efficacy and improved compliance.
Keywords: Low-affinity NMDA receptor blockade; Positive modulation of AMPA receptor; Multi-target mechanism; Mouse;

Characterization of electrically evoked field potentials in the medial prefrontal cortex and orbitofrontal cortex of the rat: Modulation by monoamines by Joanne Wallace; Rosanna K. Jackson; Tanya L. Shotton; Ishaana Munjal; Richard McQuade; Sarah E. Gartside (321-332).
Medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC) play critical roles in cognition and behavioural control. Glutamatergic, GABAergic, and monoaminergic dysfunction in the prefrontal cortex has been hypothesised to underlie symptoms in neuropsychiatric disorders. Here we characterised electrically-evoked field potentials in the mPFC and OFC. Electrical stimulation evoked field potentials in layer V/VI of the mPFC and layer V of the OFC. The earliest component (approximately 2 ms latency) was insensitive to glutamate receptor blockade and was presumed to be presynaptic. Later components were blocked by 6,7-dinitroquinoxaline-2,3-dione (DNQX (20 µM)) and were assumed to reflect monosynaptic (latency 4–6 ms) and polysynaptic activity (latency 6–40 ms) mediated by glutamate via AMPA/kainate receptor. In the mPFC, but not the OFC, the monosynaptic component was also partly blocked by 2-amino-5-phosphonopentanoic acid (AP-5 (50–100 µM)) indicating the involvement of NMDA receptors. Bicuculline (3–10 µM) enhanced the monosynaptic component suggesting electrically-evoked and/or glutamate induced GABA release inhibits the monosynaptic component via GABAA receptor activation. There were complex effects of bicuculline on polysynaptic components. In the mPFC both the mono- and polysynaptic components were attenuated by 5-HT (10–100 µM) and NA (30 and 60 µM) and the monosynaptic component was attenuated by DA (100 µM). In the OFC the mono- and polysynaptic components were also attenuated by 5-HT (100 µM), NA (10–100 µM) but DA (10–100 µM) had no effect. We propose that these pharmacologically characterised electrically-evoked field potentials in the mPFC and OFC are useful models for the study of prefrontal cortical physiology and pathophysiology.
Keywords: Glutamate; GABA; 5-HT; Noradrenaline; Dopamine;