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issn:0893-133
1.  Fragile X: Translation in Action 
Fragile X is a synapsopathy—a disorder of synaptic function and plasticity. Recent studies using mouse models of the disease suggest that the critical defect is altered regulation of synaptic protein synthesis. Various strategies to restore balanced synaptic protein synthesis have been remarkably successful in correcting widely varied mutant phenotypes in mice. Insights gained by the study of synaptic plasticity in animal models of fragile X have suggested novel therapeutic approaches, not only for human fragile X but also for autism and mental retardation of unknown etiology.
doi:10.1038/sj.npp.1301610
PMCID: PMC4327813  PMID: 17940551
2.  [No title available] 
PMCID: PMC4057932  PMID: 24622470
3.  Altered 5-HT2A Receptor Binding after Recovery from Bulimia-Type Anorexia Nervosa: Relationships to Harm Avoidance and Drive for Thinness 
Several lines of evidence suggest that a disturbance of serotonin neuronal pathways may contribute to the pathogenesis of anorexia nervosa (AN) and bulimia nervosa (BN). This study applied positron emission tomography (PET) to investigate the brain serotonin 2A (5-HT2A) receptor, which could contribute to disturbances of appetite and behavior in AN and BN. To avoid the confounding effects of malnutrition, we studied 10 women recovered from bulimia-type AN (REC AN–BN, >1 year normal weight, regular menstrual cycles, no binging, or purging) compared with 16 healthy control women (CW) using PET imaging and a specific 5-HT2A receptor antagonist, [18F]altanserin. REC AN–BN women had significantly reduced [18F]altanserin binding potential relative to CW in the left subgenual cingulate, the left parietal cortex, and the right occipital cortex. [18F]altanserin binding potential was positively related to harm avoidance and negatively related to novelty seeking in cingulate and temporal regions only in REC AN–BN subjects. In addition, REC AN–BN had negative relationships between [18F]altanserin binding potential and drive for thinness in several cortical regions. In conclusion, this study extends research suggesting that altered 5-HT neuronal system activity persists after recovery from bulimia-type AN, particularly in subgenual cingulate regions. Altered 5-HT neurotransmission after recovery also supports the possibility that this may be a trait-related disturbance that contributes to the pathophysiology of eating disorders. It is possible that subgenual cingulate findings are not specific for AN–BN, but may be related to the high incidence of lifetime major depressive disorder diagnosis in these subjects.
doi:10.1038/sj.npp.1300430
PMCID: PMC4301578  PMID: 15054474
anorexia nervosa; bulimia nervosa; serotonin; receptor; cingulate cortex; positron emission tomography
4.  Nicotine Effect on Prepulse Inhibition and Prepulse Facilitation in Schizophrenia Patients 
Acoustic prepulse inhibition (PPI) is considered an important biomarker in animal studies of psychosis and a number of psychiatric conditions. Nicotine has been shown to improve acoustic PPI in some animal strains and in humans. However, there is little data on effects of nicotine on acoustic PPI in schizophrenia patients using a double-blind, placebo-controlled study design. The primary aim of the current study was to test the effect of nicotine nasal spray on acoustic PPI in schizophrenia patients. The secondary aim was to test nicotine effect on prepulse facilitation (PPF). The study included 18 schizophrenia patient smokers and 12 healthy control smokers, tested in a double-blind, placebo-controlled, crossover, randomized design immediately after nicotine or saline placebo nasal sprays. PPI was tested using 120 ms prepulse–pulse interval. PPF was tested using 4500 ms prepulse–pulse interval. The results showed a significant main effect of drug on PPI in that nicotine improved PPI compared to placebo (p=0.008) with no drug by diagnosis interaction (p=0.90). Improvement in PPI in response to nicotine was significantly correlated with the baseline severity of clinical symptoms (r=0.59, p=0.02) in patients. There was no significant drug or drug by diagnosis interaction for the 4500 ms prepulse–pulse interval condition. However, nicotine improved inhibition in a subgroup of subjects exhibiting PPF (p=0.002). In conclusion, the findings confirmed that nicotine transiently improves acoustic PPI in schizophrenia patients. Additionally, schizophrenia patients with more clinical symptoms may have benefited more from nicotinic effect on PPI.
doi:10.1038/sj.npp.1301601
PMCID: PMC4241357  PMID: 17957213
PPI; facilitation; schizophrenia; attention; inhibition; nicotine
5.  Focal Electrically Administered Seizure Therapy (FEAST): A novel form of ECT illustrates the roles of current directionality, polarity, and electrode configuration in seizure induction 
Electroconvulsive therapy (ECT) is a mainstay in the treatment of severe, medication resistant depression. The antidepressant efficacy and cognitive side effects of ECT are influenced by the position of the electrodes on the head and by the degree to which the electrical stimulus exceeds the threshold for seizure induction. However, surprisingly little is known about the effects of other key electrical parameters such as current directionality, polarity, and electrode configuration. Understanding these relationships may inform the optimization of therapeutic interventions to improve their risk/benefit ratio. To elucidate these relationships, we evaluated a novel form of ECT (focal electrically administered seizure therapy, FEAST) that combines unidirectional stimulation, control of polarity, and an asymmetrical electrode configuration, and contrasted it with conventional ECT in a nonhuman primate model. Rhesus monkeys had their seizure thresholds determined on separate days with ECT conditions that crossed the factors of current directionality (unidirectional or bidirectional), electrode configuration (standard bilateral or FEAST (small anterior and large posterior electrode)), and polarity (assignment of anode and cathode in unidirectional stimulation). Ictal expression and post-ictal suppression were quantified via scalp EEG. Findings were replicated and extended in a second experiment with the same subjects. Seizures were induced in each of 75 trials, including 42 FEAST procedures. Seizure thresholds were lower with unidirectional than with bidirectional stimulation (p<0.0001), and lower in FEAST than in bilateral ECS (p=0.0294). Ictal power was greatest in posterior-anode unidirectional FEAST, and post-ictal suppression was strongest in anterior-anode FEAST (p=0.0008 and p=0.0024, respectively). EEG power was higher in the stimulated hemisphere in posterior-anode FEAST (p=0.0246), consistent with the anode being the site of strongest activation. These findings suggest that current directionality, polarity, and electrode configuration influence the efficiency of seizure induction with ECT. Unidirectional stimulation and novel electrode configurations such as FEAST are two approaches to lowering seizure threshold. Furthermore, the impact of FEAST on ictal and post-ictal expression appeared to be polarity-dependent. Future studies may examine whether these differences in seizure threshold and expression have clinical significance for patients receiving ECT.
doi:10.1038/npp.2009.12
PMCID: PMC4226514  PMID: 19225453
electroconvulsive; bilateral; ECT; FEAST; unidirectional; seizure threshold; ictal; EEG; electric field; anode; cathode; anodal; cathodal; polarity
6.  Evidence for a role of transporter-mediated currents in the depletion of brain serotonin induced by serotonin transporter substrates 
Serotonin (5-HT) transporter (SERT) substrates like fenfluramine and 3,4-methylenedioxymethamphetamine cause long-term depletion of brain 5-HT, while certain other substrates do not. The 5-HT deficits produced by SERT substrates are dependent upon transporter proteins, but the exact mechanisms responsible are unclear. Here, we compared the pharmacology of several SERT substrates: fenfluramine, d-fenfluramine, 1-(m-chlorophenyl)piperazine (mCPP) and 1-(m-trifluoromethylphenyl)piperainze (TFMPP), to establish relationships between acute drug mechanisms and the propensity for long-term 5-HT depletions. In vivo microdialysis was carried out in rat nucleus accumbens to examine acute 5-HT release and long-term depletion in the same subjects. In vitro assays were performed to measure efflux of [3H]5-HT in rat brain synaptosomes and transporter-mediated ionic currents in SERT-expressing Xenopus oocytes. When administered repeatedly to rats (6 mg/kg, i.p., 4 doses), all drugs produce large sustained elevations in extracellular 5-HT (>5-fold) with minimal effects on dopamine. Importantly, two weeks after dosing, only rats exposed to fenfluramine and d-fenfluramine display depletion of brain 5-HT. All test drugs evoke fluoxetine-sensitive efflux of [3H]5-HT from synaptosomes, but d-fenfluramine and its bioactive metabolite d-norfenfluramine induce significantly greater SERT-mediated currents than phenylpiperazines. Our data confirm that drug-induced 5-HT release probably does not mediate 5-HT depletion. However, the magnitude of transporter-mediated inward current may be a critical factor in the cascade of events leading to 5-HT deficits. This hypothesis warrants further study, especially given the growing popularity of designer drugs that target SERT.
doi:10.1038/npp.2013.331
PMCID: PMC3988539  PMID: 24287719
serotonin (5-HT) release; 5-HT depletion; 5-HT transporter (SERT); SERT substrate; SERT-mediated current
7.  Combined White Matter Imaging Suggests Myelination Defects in Visual Processing Regions in Schizophrenia 
Neuropsychopharmacology  2013;38(9):1808-1815.
Diverse pathological changes occur in the white matter (WM) of patients with schizophrenia. Various microstructural alterations including a reduction in axonal number or diameter, reduced myelination, or poor coherence of fibers could account for these changes. Abnormal integrity of macromolecules such as myelin (‘dysmyelination') can be studied by applying multiple modalities of WM imaging such as diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI) in parallel. Using ultra-high field (7 Tesla) MTI in 17 clinically stable patients with schizophrenia and 20 controls, we evaluated the voxelwise distribution of macromolecular WM abnormalities. Patients had a significant reduction in magnetization transfer ratio (MTR) in WM adjacent to visual processing regions and inferior temporal cortex (Cohen's d=1.54). Among the regions showing MTR reduction, a concurrent reduction in fractional anisotropy (FA) occurs proximal to the lingual gyrus. Multiple regression analysis revealed that the degree of FA reduction in the putatively ‘dysmyelinated' regions in patients predicted impaired processing speed (PS; β=0.74; P=0.003), a core cognitive dysfunction in schizophrenia. In controls, MTR/FA in the occipito-temporal regions were not associated with PS. Our findings suggest that dysmyelination in visual processing regions is present in patients with schizophrenia with greatest cognitive and functional impairment. Combined DTI/MTI deficits in the occipito-temporal region may be an important variable when considering potential treatment targets for improving cognitive function in schizophrenia.
doi:10.1038/npp.2013.80
PMCID: PMC3712891  PMID: 23558741
Biological Psychiatry; Schizophrenia; Antipsychotics; Imaging; Clinical or Preclinical; Cognition; myelination; processing speed; visual processing; magnetization transfer; ultra-high field MRI; myelination; magnetization transfer; visual processing; occipital; schizophrenia
8.  Dopamine Modulates Reward-Related Vigor 
Neuropsychopharmacology  2013;38(8):1495-1503.
Subjects routinely control the vigor with which they emit motoric responses. However, the bulk of formal treatments of decision-making ignores this dimension of choice. A recent theoretical study suggested that action vigor should be influenced by experienced average reward rate and that this rate is encoded by tonic dopamine in the brain. We previously examined how average reward rate modulates vigor as exemplified by response times and found a measure of agreement with the first suggestion. In the current study, we examined the second suggestion, namely the potential influence of dopamine signaling on vigor. Ninety healthy subjects participated in a double-blind experiment in which they received one of the following: placebo, L-DOPA (which increases dopamine levels in the brain), or citalopram (which has a selective, if complex, effect on serotonin levels). Subjects performed multiple trials of a rewarded odd-ball discrimination task in which we varied the potential reward over time in order to exercise the putative link between vigor and average reward rate. Replicating our previous findings, we found that a significant fraction of the variance in subjects' responses could be explained by our experimentally manipulated changes in average reward rate. Crucially, this relationship was significantly stronger under L-Dopa than under Placebo, suggesting that the impact of average reward levels on action vigor is indeed subject to a dopaminergic influence.
doi:10.1038/npp.2013.48
PMCID: PMC3682144  PMID: 23419875
dopamine; psychopharmacology; Cognition; vigor; reward learning; reinforcement learning; behavioral science; Cognition; dopamine; normative; psychopharmacology; reinforcement learning; reward learning; vigor
9.  Self-Administered Heroin and Cocaine Combinations in the Rat: Additive Reinforcing Effects—Supra-Additive Effects on Nucleus Accumbens Extracellular Dopamine 
The concurrent use of cocaine and opiate combinations (speedball) has increased since the 1970s and now represents a growing subset of intravenous drug abusers. An isobolographic analysis was applied to the ascending limb of the dose–effect curves for rat self-administration of cocaine, heroin, and their combination to determine the nature of the interaction. The addition of heroin to cocaine shifted the dose–effect curve for self-administration to the left, and the modulation in reinforcing efficacy of the combination of cocaine and heroin was found to be additive. A second experiment used microdialysis to determine the effects of this drug combination on nucleus accumbens (NAc) extracellular levels of dopamine ([DA]e) in rats self-administering low doses of cocaine, heroin, or cocaine/ heroin combinations. These doses of cocaine and cocaine/heroin combinations significantly increased NAc [DA]e, while heroin alone did not. The ratio of the % baseline of [DA]e (or the dialysate concentrations of DA) to cocaine in the dialysate was higher during self-administration of cocaine/heroin combinations than with cocaine alone. These data indicate that although the interaction between cocaine and heroin in maintaining self-administration is additive, a potentiation of NAc dopaminergic neurotransmission is present, suggesting that NAc [DA]e may not be a direct measure of reinforcing efficacy and/or it is not central to the mediation of the self-administration of this drug combination.
doi:10.1038/sj.npp.1300786
PMCID: PMC4048550  PMID: 15956989
dopamine; microdialysis; speedball; cocaine; heroin; self-administration
10.  Stress-induced potentiation of cocaine reward: a role for CRFR1 and CREB 
Both clinical and preclinical research have shown that stress can potentiate drug use, however the underlying mechanisms of this interaction are unknown. Previously, we have shown that a single exposure to forced swim (FS) reinstates extinguished conditioned place preference (CPP) to cocaine and that cAMP response element binding protein (CREB) is necessary for this response. CREB can be activated by corticotropin releasing factor (CRF) receptor type 1 (CRFR1) binding, which mediates neuroendocrine and behavioral responses to stress as well as to drugs of abuse. The present experiments investigate whether changes in cocaine reward elicited by previous exposure to stress are mediated by CREB and/or CRFR1. Chronic exposure to FS in advance of conditioning enhances the acquisition of cocaine CPP in wildtype mice but this is blocked in CREB deficient mice. In addition, pretreatment with the CRFR1 antagonist, antalarmin, prior to FS exposure blocks the enhancement of stress induced acquisition of cocaine CPP. Furthermore, FS induced increase in phosphorylated CREB (pCREB), specifically in the nucleus accumbens (NAc) and the lateral septum (LS) is also blocked by antalarmin. Taken together, these studies suggest that both CREB and CRFR1 activation are necessary for stress-induced potentiation of drug reward.
doi:10.1038/npp.2009.91
PMCID: PMC4034179  PMID: 19675537
CREB; CRFR1; cocaine; forced swim stress; CPP
11.  Evidence for a Role of Transporter-Mediated Currents in the Depletion of Brain Serotonin Induced by Serotonin Transporter Substrates 
Neuropsychopharmacology  2014;39(6):1355-1365.
Serotonin (5-HT) transporter (SERT) substrates like fenfluramine and 3,4-methylenedioxymethamphetamine cause long-term depletion of brain 5-HT, while certain other substrates do not. The 5-HT deficits produced by SERT substrates are dependent upon transporter proteins, but the exact mechanisms responsible are unclear. Here, we compared the pharmacology of several SERT substrates: fenfluramine, d-fenfluramine, 1-(m-chlorophenyl)piperazine (mCPP) and 1-(m-trifluoromethylphenyl)piperainze (TFMPP), to establish relationships between acute drug mechanisms and the propensity for long-term 5-HT depletions. In vivo microdialysis was carried out in rat nucleus accumbens to examine acute 5-HT release and long-term depletion in the same subjects. In vitro assays were performed to measure efflux of [3H]5-HT in rat brain synaptosomes and transporter-mediated ionic currents in SERT-expressing Xenopus oocytes. When administered repeatedly to rats (6 mg/kg, i.p., four doses), all drugs produce large sustained elevations in extracellular 5-HT (>5-fold) with minimal effects on dopamine. Importantly, 2 weeks after dosing, only rats exposed to fenfluramine and d-fenfluramine display depletion of brain 5-HT. All test drugs evoke fluoxetine-sensitive efflux of [3H]5-HT from synaptosomes, but d-fenfluramine and its bioactive metabolite d-norfenfluramine induce significantly greater SERT-mediated currents than phenylpiperazines. Our data confirm that drug-induced 5-HT release probably does not mediate 5-HT depletion. However, the magnitude of transporter-mediated inward current may be a critical factor in the cascade of events leading to 5-HT deficits. This hypothesis warrants further study, especially given the growing popularity of designer drugs that target SERT.
doi:10.1038/npp.2013.331
PMCID: PMC3988539  PMID: 24287719
5-HT depletion; neurotransmitters; psychopharmacology; psychostimulants; serotonin; serotonin (5-HT) release; serotonin (5-HT) transporter; SERT substrate; SERT-mediated current; toxicity; serotonin (5-HT) release; 5-HT depletion; 5-HT transporter (SERT); SERT substrate; SERT-mediated current
12.  The role of the nucleus accumbens shell in the mediation of the reinforcing properties of a safety signal in free-operant avoidance: Dopamine-dependent inhibitory effects of d-amphetamine 
Safety signals (SS) have been shown to reinforce instrumental avoidance behaviour due to their ability to signal the absence of an aversive event; however, little is known of their neural mediation. The present study investigated whether infusions of d-amphetamine in the nucleus accumbens (Nac), previously shown to potentiate responding for appetitive conditioned reinforcers (CRf), also regulate avoidance responding for a SS. Rats were trained on a free-operant task in which lever-press responses avoided shock and were reinforced with an auditory SS. Rats were then cannulated in the Nac core (NacC) or shell (NacS) and infused with d-amphetamine and, in separate NacS groups, other drugs, prior to extinction sessions with the SS present or absent following responding. Selective effects of d-amphetamine were found in the NacS, but not in the NacC when the SS was present in the session. A significant increase in response rate during the presentation of the SS reflected a disruption of its fear-inhibiting properties. In parallel, a decrease in avoidance response rate reflected the reduced influence of the SS as a CRf. Inactivation of the NacS reduced avoidance responding only when the SS was present in the session whereas, the D1-D2 DA receptor antagonist alpha-flupenthixol reduced responding both prior to and during the SS regardless of the presence of the SS. Atomoxetine (ATO), a selective noradrenaline re-uptake inhibitor, had no effect on responding. These results indicate a role for the NacS in the mediation of the conditioned reinforcing properties of a SS. These effects appear to be modulated by dopaminergic mechanisms but seem distinct from those previously reported with food-related CRfs.
doi:10.1038/npp.2013.337
PMCID: PMC3988545  PMID: 24336447
avoidance; dopamine; safety signals; psychostimulants; neuropharmacology; behavioural science
13.  Increased Leptin Permeation across the Blood–Brain Barrier after Chronic Alcohol Ingestion 
Leptin, a polypeptide mainly produced in the periphery, crosses the blood–brain barrier (BBB) by receptor-mediated transport to exert multiple central nervous system actions including decreased food intake. The reciprocal interactions between leptin transport and alcohol drinking are not clear. In this study, we tested whether alcohol increases leptin entry into brain and, if this occurs, whether it is a consequence of a generalized increase in the permeability of the BBB. BBB permeability to albumin, the increased permeation of which indicates BBB disruption, as well as to leptin was measured after alcohol ingestion. CD1 and B6 mice ingested a 5% liquid alcohol diet or its isocaloric control for 2 weeks. Alcohol ingestion resulted in increased blood-alcohol levels, decreased blood-leptin concentrations, and increased permeation of radioactively labeled leptin across the BBB as shown by in situ perfusion. Although the increased influx of the vascular marker albumin into brain showed partial disruption of the BBB, the influx of 125I-leptin still could be suppressed by excess unlabeled leptin, indicating persistence of its saturable transport system. When given a choice of either alcohol or control diet, even the alcohol-preferring B6 mice showed a significantly greater preference for the control liquid diet, and there was no evidence of BBB disruption or alterated leptin transport. Furthermore, acute alcohol intoxication induced by intraperitoneal injection of 20% alcohol did not result in BBB disruption or increased leptin permeation 4 h later. Thus, partial disruption of the BBB and increased permeation of leptin in both CD1 and B6 mice were only induced by chronic alcohol ingestion. The results showing increased leptin permeation across the BBB lead to the speculation that leptin may serve as a homeostatic feeding signal in these mice.
doi:10.1038/sj.npp.1301452
PMCID: PMC3939624  PMID: 17487223
alcohol; blood–brain barrier; leptin; transport system; preference; feeding
14.  APOE E4 Carriers Show Prospective Memory Enhancement Under Nicotine, and Evidence for Specialisation Within Medial BA10 
Neuropsychopharmacology  2012;38(4):655-663.
There is evidence to suggest that the APOE ɛ4 allele (which confers an increased risk of developing dementia) might be associated with cognitive advantages earlier in life. Further, nicotine might selectively benefit ɛ4 carriers. We used fMRI to explore performance on a prospective memory (PM) task in young adults (age 18–30) with and without nicotine using a within-subjects design. Participants performed an ongoing task while retaining a PM instruction to respond to specific stimuli embedded in the task. Nicotine effects varied according to APOE status. Reaction times to the PM cue were improved under nicotine in ɛ4 carriers, but not in ɛ3 carriers. In an event-related analysis, extrastriate responses to PM trials were enhanced by nicotine only in ɛ4 carriers. These differences in early visual processing may contribute to the behavioral findings. Activity in medial BA10 (previously implicated in PM) differentiated ɛ4 from ɛ3 carriers. One BA10 subregion showed greater deactivation in ɛ4 carriers during PM trials. Activity in other BA10 subregions was modulated by PM reaction time, pointing to region-specific effects within medial BA10. In addition, activity in right hippocampal formation was only seen in ɛ4 carriers receiving nicotine. These results demonstrate that cognitive enhancement by nicotine can selectively benefit APOE ɛ4 carriers, and point to genotype-specific differences in neural activity during PM. In addition, these results show that the role of medial BA10 in PM likely involves varying contributions from functionally specific subregions.
doi:10.1038/npp.2012.230
PMCID: PMC3572462  PMID: 23232444
Alzheimer's Disease; APOE; Imaging; Clinical or Preclinical; Learning & Memory; Nicotine; Prospective memory; Psychopharmacology; Alzheimer's disease; psychopharmacology; imaging; learning and memory; nicotine; APOE
15.  Behavioral and Neurochemical Changes Induced by Oxycodone Differ Between Adolescent and Adult Mice 
Nonmedical use of the prescription opioid analgesic oxycodone is a major problem in the United States, particularly among adolescents and young adults. This study characterized self-administration of oxycodone by adolescent and adult mice, and how this affects striatal dopamine levels. Male C57BL/6J mice (4 or 10 weeks old) were allowed to acquire oxycodone self-administration (0.25 mg/kg per infusion) for 9 days, and then tested with varying doses of oxycodone (0, 0.125, 0.25, 0.5, and 0.75 mg/kg per infusion). On completion of the self-administration study, a guide cannula was implanted into the striatum of these mice. Six days later, microdialysis was conducted on the freely moving mouse. After collection of baseline samples, oxycodone was administered i.p. (1.25, 2.5, and 5.0 mg/kg) and samples were collected for 1 h after each dose. Adult mice self-administered significantly more oxycodone across the doses tested. After 1 week, basal striatal dopamine levels were lower in mice of both ages that had self-administered oxycodone than in yoked saline controls. Oxycodone challenge increased striatal dopamine levels in a dose-dependent manner in both age groups. Of interest, the lowest dose of oxycodone led to increased striatal dopamine levels in the mice that had self-administered oxycodone during adolescence but not those that self-administered it as adults. The lower number of infusions of oxycodone self-administered by adolescent mice, and their later increased striatal dopamine in response to the lowest dose of oxycodone (not found in adults), suggest differential sensitivity to the reinforcing and neurobiological effects of oxycodone in the younger mice.
doi:10.1038/npp.2008.134
PMCID: PMC3926215  PMID: 18784649
self-administration; adolescent; adult; mice; oxycodone; microdialysis
17.  Nature or Nurture? Determining the Heritability of Human Striatal Dopamine Function: an [18F]-DOPA PET Study 
Neuropsychopharmacology  2012;38(3):485-491.
Striatal dopamine function is important for normal personality, cognitive processes and behavior, and abnormalities are linked to a number of neuropsychiatric disorders. However, no studies have examined the relative influence of genetic inheritance and environmental factors in determining striatal dopamine function. Using [18F]-DOPA positron emission tomography (PET), we sought to determine the heritability of presynaptic striatal dopamine function by comparing variability in uptake values in same sex monozygotic (MZ) twins to dizygotic (DZ) twins. Nine MZ and 10 DZ twin pairs underwent high-resolution [18F]-DOPA PET to assess presynaptic striatal dopamine function. Uptake values for the overall striatum and functional striatal subdivisions were determined by a Patlak analysis using a cerebellar reference region. Heritability, shared environmental effects and non-shared individual-specific effects were estimated using a region of interest (ROI) analysis and a confirmatory parametric analysis. Overall striatal heritability estimates from the ROI and parametric analyses were 0.44 and 0.33, respectively. We found a distinction between striatal heritability in the functional subdivisions, with the greatest heritability estimates occurring in the sensorimotor striatum and the greatest effect of individual-specific environmental factors in the limbic striatum. Our results indicate that variation in overall presynaptic striatal dopamine function is determined by a combination of genetic factors and individual-specific environmental factors, with familial environmental effects having no effect. These findings underline the importance of individual-specific environmental factors for striatal dopaminergic function, particularly in the limbic striatum, with implications for understanding neuropsychiatric disorders such as schizophrenia and addictions.
doi:10.1038/npp.2012.207
PMCID: PMC3547199  PMID: 23093224
twin; PET; dopamine; heritability; [18F]-DOPA; environment; [18F]-DOPA; Dopamine; Environment; Heritability; Imaging; Clinical or Preclinical; Neurochemistry; PET; Psychiatry & Behavioral Sciences; Striatum; Twin
18.  Combined white matter imaging suggests myelination defects in visual processing regions in schizophrenia 
Diverse pathological changes occur in the white matter (WM) in patients with schizophrenia. Various microstructural alterations including a reduction in axonal number or diameter, reduced myelination or poor coherence of fibers could account for these changes. Abnormal integrity of macromolecules such as myelin (‘dysmyelination’) can be studied by applying multiple modalities of WM imaging such as diffusion tensor (DTI) and magnetization transfer imaging (MTI) in parallel. Using ultra-high field (7 Tesla) MTI in 17 clinically stable patients with schizophrenia and 20 controls, we evaluated the voxel-wise distribution of macromolecular WM abnormalities. Patients had a significant reduction in magnetization transfer ratio (MTR) in WM adjacent to visual processing regions and inferior temporal cortex (Cohen’s d=1.54). Among the regions showing MTR reduction, a concurrent reduction in fractional anisotropy occurs proximal to the lingual gyrus. Multiple regression analysis revealed that the degree of Fractional Anisotropy (FA) reduction in the putatively ‘dysmyelinated’ regions in patients predicted impaired processing speed (β=0.74;p=0.003), a core cognitive dysfunction in schizophrenia. In controls, MTR/FA in the occipito-temporal regions were not associated with processing speed. Our findings suggest that dysmyelination in visual processing regions is present in patients with schizophrenia with greatest cognitive and functional impairment. Combined DTI/MTI deficits in the occipito-temporal region may be an important variable when considering potential treatment targets for improving cognitive function in schizophrenia.
doi:10.1038/npp.2013.80
PMCID: PMC3712891  PMID: 23558741
myelination; magnetization transfer; visual processing; occipital; schizophrenia
19.  Contribution of Cystine-Glutamate Antiporters to the Psychotomimetic Effects of Phencyclidine 
Altered glutamate signaling contributes to a myriad of neural disorders, including schizophrenia. While synaptic levels are intensely studied, nonvesicular release mechanisms, including cystine-glutamate exchange, maintain high steady-state glutamate levels in the extrasynaptic space. The existence of extrasynaptic receptors, including metabotropic group II glutamate receptors (mGluR), pose nonvesicular release mechanisms as unrecognized targets capable of contributing to pathological glutamate signaling. We tested the hypothesis that activation of cystine-glutamate antiporters using the cysteine prodrug N-acetylcysteine would blunt psychotomimetic effects in the rodent phencyclidine (PCP) model of schizophrenia. First, we demonstrate that PCP elevates extracellular glutamate in the prefrontal cortex; an effect that is blocked by N-acetylcysteine pretreatment. To determine the relevance of the above finding, we assessed social interaction and found that N-acetylcysteine reverses social withdrawal produced by repeated PCP. In a separate paradigm, acute PCP resulted in working memory deficits assessed using a discrete trial T-maze task, and this effect was also reversed by N-acetylcysteine pretreatment. The capacity of N-acetylcysteine to restore working memory was blocked by infusion of the cystine-glutamate antiporter inhibitor (S)-4-carboxyphenylglycine into the prefrontal cortex or systemic administration of the group II mGluR antagonist LY341495 indicating that the effects of N-acetylcysteine requires cystine-glutamate exchange and group II mGluR activation. Lastly, protein levels from post mortem tissue obtained from schizophrenic patients revealed significant changes in the level of xCT, the active subunit for cystine-glutamate exchange, in the dorsolateral prefrontal cortex. These data advance cystine-glutamate antiporters as novel targets capable of reversing the psychotomimetic effects of PCP.
doi:10.1038/sj.npp.1301532
PMCID: PMC3907109  PMID: 17728701
extrasynaptic; system Xc-; prefrontal cortex; nonvesicular; working memory; xCT
20.  Neurobiological Correlates of the Familial Risk for Stimulant Drug Dependence 
Neuropsychopharmacology  2012;38(1):238-239.
doi:10.1038/npp.2012.183
PMCID: PMC3521985  PMID: 23147481
21.  Baseline-dependent effects of cocaine pre-exposure on impulsivity and D2/3 receptor availability in the rat striatum: Possible relevance to the attention-deficit hyperactivity syndrome 
We have previously shown that impulsivity in rats predicts the emergence of compulsive cocaine seeking and taking, and is coupled to decreased D2/3 receptor availability in the ventral striatum. Since withdrawal from cocaine normalises high impulsivity in rats, we investigated, using positron emission tomography (PET), the effects of response-contingent cocaine administration on D2/3 receptor availability in the striatum. Rats were screened for impulsive behavior on the 5-choice serial reaction time task. After a baseline PET scan with the D2/3 ligand [18F]fallypride, rats were trained to self-administer cocaine for 15 days under a long-access schedule. As a follow up, rats were assessed for impulsivity and underwent a second [18F]fallypride PET scan. At baseline, we found that D2/3 receptor availability was significantly lower in the left, but not right, ventral striatum of high-impulsive rats compared with low-impulsive rats. While the number of self-administered cocaine infusions was not different between the two impulsivity groups, impulsivity selectively decreased in high-impulsive rats withdrawn from cocaine. This effect was accompanied by a significant increase in D2/3 receptor availability in the left, but not right, ventral striatum. We further report that D2/3 receptor availability was inversely related to baseline D2/3 receptor availability in the ventral striatum of high-impulsive rats, as well as to the left and right dorsal striatum of both low-impulsive and high-impulsive rats. These findings indicate that the reduction in impulsivity in high-impulsive rats by prior cocaine exposure may be mediated by a selective correction of deficient D2/3 receptor availability in the ventral striatum. A similar baseline-dependent mechanism may account for the therapeutic effects of stimulant drugs in clinical disorders such as ADHD.
doi:10.1038/npp.2013.44
PMCID: PMC3682140  PMID: 23399948
nucleus accumbens; dopamine; psychostimulants; positron emission tomography; addiction; attention-deficit hyperactivity disorder
22.  Dopamine modulates reward related vigor 
Subjects routinely control the vigor with which they emit motoric responses. However the bulk of formal treatments of decision-making ignores this dimension of choice. A recent theoretical study suggested that action vigor should be influenced by experienced average reward rate, and that this rate is encoded by tonic dopamine in the brain. We previously examined how average reward rate modulates vigor as exemplified by response times, and found a measure of agreement with the first suggestion. In the current study we examined the second suggestion, namely the potential influence of dopamine signaling on vigor. Ninety healthy subjects participated in a double-blind experiment in which they received one of the following: placebo, L-DOPA (which increases dopamine levels in the brain) or citalopram (which has a selective, if complex, effect on serotonin levels). Subjects performed multiple trials of a rewarded odd-ball discrimination task in which we varied the potential reward over time in order to exercise the putative link between vigor and average reward rate. Replicating our prior findings we found a significant fraction of the variance in subjects’ responses could be explained by our experimentally manipulated changes in average reward rate. Crucially, this relationship was significantly stronger under L-Dopa than under Placebo, suggesting the impact of average reward levels on action vigor is indeed subject to a dopaminergic influence.
doi:10.1038/npp.2013.48
PMCID: PMC3682144  PMID: 23419875
Dopamine; Psychopharmacology; Cognition; Behavioral Science; Vigor; Reward Learning; Reinforcement Learning
23.  Abstinence from Chronic Cocaine Self-Administration Alters Striatal Dopamine Systems in Rhesus Monkeys 
Although dysregulation within the dopamine (DA) system is a hallmark feature of chronic cocaine exposure, the question of whether these alterations persist into abstinence remains largely unanswered. Nonhuman primates represent an ideal model in which to assess the effects of abstinence on the DA system following chronic cocaine exposure. In this study, male rhesus monkeys self-administered cocaine (0.3 mg/kg per injection, 30 reinforcers per session) under a fixed-interval 3-min schedule for 100 days followed by either 30 or 90 days abstinence. This duration of cocaine self-administration has been previously shown to decrease DA D2-like receptor densities and increase levels of D1-like receptors and DA transporters (DAT). Responding by control monkeys was maintained by food presentation under an identical protocol and the same abstinence periods. [3H]SCH 23390 binding to DA D1 receptors following 30 days of abstinence was significantly higher in all portions of the striatum, compared to control animals, whereas [3H]raclopride binding to DA D2 receptors was not different between groups. [3H]WIN 35 428 binding to DAT was also significantly higher throughout virtually all portions of the dorsal and ventral striatum following 30 days of abstinence. Following 90 days of abstinence, however, levels of DA D1 receptors and DAT were not different from control values. Although these results indicate that there is eventual recovery of the separate elements of the DA system, they also highlight the dynamic nature of these components during the initial phases of abstinence from chronic cocaine self-administration.
doi:10.1038/npp.2008.135
PMCID: PMC3845090  PMID: 18769473
cocaine; dopamine; autoradiography; abstinence; striatum
24.  The Effects of a Subpsychotic Dose of Ketamine on Recognition and Source Memory for Agency: Implications for Pharmacological Modelling of Core Symptoms of Schizophrenia 
Ketamine is increasingly used to model the cognitive deficits and symptoms of schizophrenia. We investigated the extent to which ketamine administration in healthy volunteers reproduces the deficits in episodic recognition memory and agency source monitoring reported in schizophrenia. Intravenous infusions of placebo or 100 ng/ml ketamine were administered to 12 healthy volunteers in a double-blind, placebo-controlled, randomized, within-subjects study. In response to presented words, the subject or experimenter performed a deep or shallow encoding task, providing a 2(drug) × 2(depth of processing) × 2(agency) factorial design. At test, subjects discriminated old/new words, and recalled the sources (task and agent). Data were analyzed using multinomial modelling to identify item recognition, source memory for agency and task, and guessing biases. Under ketamine, item recognition and cued recall of deeply encoded items were impaired, replicating previous findings. In contrast to schizophrenia, there was a reduced tendency to externalize agency source guessing biases under ketamine. While the recognition memory deficit observed with ketamine is consistent with previous work and with schizophrenia, the changes in source memory differ from those reported in schizophrenic patients. This difference may account for the pattern of psychopathology induced by ketamine.
doi:10.1038/sj.npp.1300846
PMCID: PMC3838935  PMID: 16123767
ketamine; schizophrenia; source memory; multinomial modelling; NMDA
25.  Subdissociative Dose Ketamine Produces a Deficit in Manipulation but not Maintenance of the Contents of Working Memory 
We investigated the effects of subdissociative dose ketamine on executive processes during a working memory task. A total of 11 healthy volunteers participated in a double-blind, placebo-controlled, randomized, within-subjects study. They attended on three occasions, receiving intravenous infusions of placebo, a lower ketamine dose, and a higher ketamine dose. On each occasion, they underwent a series of tasks engaging working memory function in verbal and visuo-spatial domains. Further tasks explored aspects of long-term memory, planning, attention, and perceptual processing. With respect to working memory/executive function, a highly specific pattern of impairment was observed. Impairments were seen only at the higher dose of ketamine and restricted to a subgroup of the verbal working memory tasks: While visuo-spatial working memory showed no evidence of impairment, and while simple maintenance processes during verbal working memory were also unimpaired, higher dose ketamine produced a significant impairment in the manipulation of information within working memory. This process-specific effect of ketamine was reflected in a drug-by-task interaction. The specificity of this ketamine effect suggests that the earliest effect of NMDA receptor blockade is in higher order control of executive function rather than in more basic maintenance processes.
doi:10.1038/sj.npp.1300272
PMCID: PMC3838944  PMID: 12888783
ketamine; schizophrenia; working memory; psychopharmacology; executive

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