Association of dopamine D2/3 receptor binding potential measured using PET and [11C]-(+)-PHNO with post-mortem DRD2/3 gene expression in the human brain.

Open access post-mortem transcriptome atlases such as the Allen Human Brain Atlas (AHBA) can inform us about mRNA expression of numerous proteins of interest across the whole brain, while in vivo protein binding in the human brain can be quantified by means of neuroreceptor positron emission tomography (PET). By combining both modalities, the association between regional gene expression and receptor distribution in the living brain can be approximated. Here, we compare the characteristics of D2 and D3 dopamine receptor distribution by applying the dopamine D2/3 receptor agonist radioligand [11C]-(+)-PHNO and human gene expression data. Since [11C]-(+)-PHNO has a higher affinity for D3 compared to D2 receptors, we hypothesized that there is a stronger relationship between D2/3 non-displaceable binding potentials (BPND) and D3 mRNA expression. To investigate the relationship between D2/3 BPND and mRNA expression of DRD2 and DRD3 we performed [11C]-(+)-PHNO PET scans in 27 healthy subjects (12 females) and extracted gene expression data from the AHBA. We also calculated D2/D3 mRNA expression ratios to imitate the mixed D2/3 signal of [11C]-(+)-PHNO. In accordance with our a priori hypothesis, a strong correlation between [11C]-(+)-PHNO and DRD3 expression was found. However, there was no significant correlation with DRD2 expression. Calculated D2/D3 mRNA expression ratios also showed a positive correlation with [11C]-(+)-PHNO binding, reflecting the mixed D2/3 signal of the radioligand. Our study supports the usefulness of combining gene expression data from open access brain atlases with in vivo imaging data in order to gain more detailed knowledge on neurotransmitter signaling.

Are reprogrammed cells a useful tool for studying dopamine dysfunction in psychotic disorders? A review of the current evidence.

Since 2006, reprogrammed cells have increasingly been used as a biomedical research technique in addition to neuro-psychiatric methods. These rapidly evolving techniques allow for the generation of neuronal sub-populations, and have sparked interest not only in monogenetic neuro-psychiatric diseases, but also in poly-genetic and poly-aetiological disorders such as schizophrenia (SCZ) and bipolar disorder (BPD). This review provides a summary of 19 publications on reprogrammed adult somatic cells derived from patients with SCZ, and five publications using this technique in patients with BPD. As both disorders are complex and heterogeneous, there is a plurality of hypotheses to be tested in vitro. In SCZ, data on alterations of dopaminergic transmission in vitro are sparse, despite the great explanatory power of the so-called DA hypothesis of SCZ. Some findings correspond to perturbations of cell energy metabolism, and observations in reprogrammed cells suggest neuro-developmental alterations. Some studies also report on the efficacy of medicinal compounds to revert alterations observed in cellular models. However, due to the paucity of replication studies, no comprehensive conclusions can be drawn from studies using reprogrammed cells at the present time. In the future, findings from cell culture methods need to be integrated with clinical, epidemiological, pharmacological and imaging data in order to generate a more comprehensive picture of SCZ and BPD.

Making Sense of: Sensitization in Schizophrenia.

Sensitization is defined as a process whereby repeated intermittent exposure to a given stimulus results in an enhanced response at subsequent exposures. Next to robust findings of an increased dopamine synthesis capacity in schizophrenia, empirical data and neuroimaging studies support the notion that the mesolimbic dopamine system of patients with schizophrenia is more reactive compared with healthy controls. These studies led to the conceptualization of schizophrenia as a state of endogenous sensitization, as stronger behavioral response and increased dopamine release after amphetamine administration or exposure to stress have been observed in patients with schizophrenia. These findings have also been integrated into the neurodevelopmental model of the disorder, which assumes that vulnerable neuronal circuits undergo progressive changes during puberty and young adulthood that lead to manifest psychosis. Rodent and human studies have made an attempt to identify the exact mechanisms of sensitization of the dopaminergic system and its association with psychosis. Doing so, several epigenetic and molecular alterations associated with dopamine release, neuroplasticity, and cellular energy metabolism have been discovered. Future research aims at targeting these key proteins associated with sensitization in schizophrenia to enhance the knowledge of the pathophysiology of the illness and pave the way for an improved treatment or even prevention of this severe psychiatric disorder.

Administration of ketamine for unipolar and bipolar depression.

OBJECTIVE: Clinical trials demonstrated that ketamine exhibits rapid antidepressant efficacy when administered in subanaesthetic dosages. We reviewed currently available literature investigating efficacy, response rates and safety profile. METHODS: Twelve studies investigating unipolar, seven on bipolar depression were included after search in medline, scopus and web of science. RESULTS: Randomized, placebo-controlled or open-label trials reported antidepressant response rates after 24 h on primary outcome measures at 61%. The average reduction of Hamilton Depression Rating Scale (HAM-D) was 10.9 points, Beck Depression Inventory (BDI) 15.7 points and Montgomery-Asberg Depression Rating Scale (MADRS) 20.8 points. Ketamine was always superior to placebo. Most common side effects were dizziness, blurred vision, restlessness, nausea/vomiting and headache, which were all reversible. Relapse rates ranged between 60% and 92%. To provide best practice-based information to patients, a consent-form for application and modification in local language is included. CONCLUSIONS: Ketamine constitutes a novel, rapid and efficacious treatment option for patients suffering from treatment resistant depression and exhibits rapid and significant anti-suicidal effects. New administration routes might serve as alternative to intravenous regimes for potential usage in outpatient settings. However, long-term side effects are not known and short duration of antidepressant response need ways to prolong ketamine's efficacy.

Neural Hyperresponsivity During the Anticipation of Tangible Social and Nonsocial Rewards in Autism Spectrum Disorder: A Concurrent Neuroimaging and Facial Electromyography Study.

BACKGROUND: Atypical anticipation of social reward has been shown to lie at the core of the social challenges faced by individuals with autism spectrum disorder (ASD). However, previous research has yielded inconsistent results and has often overlooked crucial characteristics of stimuli. Here, we investigated ASD reward processing using social and nonsocial tangible stimuli, carefully matched on several key dimensions. METHODS: We examined the anticipation and consumption of social (interpersonal touch) and nonsocial (flavored milk) rewards in 25 high-functioning individuals with ASD and 25 neurotypical adult individuals. In addition to subjective ratings of wanting and liking, we measured physical energetic expenditure to obtain the rewards, brain activity with neuroimaging, and facial reactions through electromyography on a trial-by-trial basis. RESULTS: Participants with ASD did not exhibit reduced motivation for social or nonsocial rewards; their subjective ratings, motivated efforts, and facial reactions were comparable to those of neurotypical participants. However, anticipation of higher-value rewards increased neural activation in lateral parietal cortices, sensorimotor regions, and the orbitofrontal cortex. Moreover, participants with ASD exhibited hyperconnectivity between frontal medial regions and occipital regions and the thalamus. CONCLUSIONS: Individuals with ASD who experienced rewards with tangible characteristics, whether social or nonsocial, displayed typical subjective and objective motivational and hedonic responses. Notably, the observed hyperactivations in sensory and attentional nodes during anticipation suggest atypical sensory overprocessing of forthcoming rewards rather than decreased reward value. While these atypicalities may not have manifested in observable behavior here, they could impact real-life social interactions that require nuanced predictions, potentially leading to the misperception of reduced interest in rewarding social stimuli in ASD.

Facial mimicry is not modulated by dopamine D2/3 and opioid receptor antagonism.

RATIONALE: According to theories of embodied cognition, facial mimicry - the spontaneous, low-intensity imitation of a perceived emotional facial expression - is first an automatic motor response, whose accompanying proprioceptive feedback contributes to emotion recognition. Alternative theoretical accounts, however, view facial mimicry as an emotional response to a rewarding stimulus, and/or an affiliative signal, and thus reject the view of an automatic motor copy. OBJECTIVES: To contribute to this debate and further investigate the neural basis of facial mimicry, as well as its relation to reward processing, we measured facial reactions to dynamic happy and angry faces after pharmacologically manipulating the opioid and dopamine systems - respectively, thought to subserve 'liking' and 'wanting' of rewards. METHODS: In a placebo-controlled, double-blind experiment, 130 volunteers received in a between-subjects design 50 mg of the opioidergic antagonist naltrexone, 400 mg of the dopaminergic antagonist amisulpride, or placebo. RESULTS: Clear occurrence of facial mimicry, measured 4 h after drug intake with electromyography (EMG) of the zygomaticus major and corrugator supercilii muscles, was found. However, facial mimicry was not affected by either compound, as shown with both frequentist statistics, and a Bayesian asymptotic regression model. CONCLUSIONS: This null finding does not support the hypothesis that facial mimicry (of happiness) reflects an emotional response to a rewarding stimulus, leaving open the possibility of facial mimicry being an automatic motor copy. The results are relevant to the discussion about the psychological nature and the neural basis of facial mimicry, although they should be considered preliminary, given the challenges of interpreting null findings when targeting a novel effect of unknown size.

Navigating the complex landscape of benzodiazepine- and Z-drug diversity: insights from comprehensive FDA adverse event reporting system analysis and beyond.

Introduction: Medications which target benzodiazepine (BZD) binding sites of GABAA receptors (GABAARs) have been in widespread use since the nineteen-sixties. They carry labels as anxiolytics, hypnotics or antiepileptics. All benzodiazepines and several nonbenzodiazepine Z-drugs share high affinity binding sites on certain subtypes of GABAA receptors, from which they can be displaced by the clinically used antagonist flumazenil. Additional binding sites exist and overlap in part with sites used by some general anaesthetics and barbiturates. Despite substantial preclinical efforts, it remains unclear which receptor subtypes and ligand features mediate individual drug effects. There is a paucity of literature comparing clinically observed adverse effect liabilities across substances in methodologically coherent ways. Methods: In order to examine heterogeneity in clinical outcome, we screened the publicly available U.S. FDA adverse event reporting system (FAERS) database for reports of individual compounds and analyzed them for each sex individually with the use of disproportionality analysis. The complementary use of physico-chemical descriptors provides a molecular basis for the analysis of clinical observations of wanted and unwanted drug effects. Results and Discussion: We found a multifaceted FAERS picture, and suggest that more thorough clinical and pharmacoepidemiologic investigations of the heterogenous side effect profiles for benzodiazepines and Z-drugs are needed. This may lead to more differentiated safety profiles and prescription practice for particular compounds, which in turn could potentially ease side effect burden in everyday clinical practice considerably. From both preclinical literature and pharmacovigilance data, there is converging evidence that this very large class of psychoactive molecules displays a broad range of distinctive unwanted effect profiles - too broad to be explained by the four canonical, so-called "diazepam-sensitive high-affinity interaction sites". The substance-specific signatures of compound effects may partly be mediated by phenomena such as occupancy of additional binding sites, and/or synergistic interactions with endogenous substances like steroids and endocannabinoids. These in turn drive the wanted and unwanted effects and sex differences of individual compounds.

Case report: Interstitial pneumonitis after initiation of lamotrigine.

The second-generation anticonvulsant lamotrigine is widely used in the psychiatric field as a mood stabilizer or antidepressant augmentation therapy. Although particularly older anticonvulsants are known for their potential to cause hypersensitivity syndromes, newer antiepileptic drugs do hold a certain risk as well. Presenting a case of a 32-year-old male inpatient of African ethnicity suffering from a primary severe depressive episode in the course of a recurrent major depressive disorder, we report the occurrence of a rapid-onset drug-induced pneumonitis. Herewith, the interstitial pneumonitis occurred after the initiation of 25 mg lamotrigine as an augmentation therapy. Except for the clear temporal correlation between the administration of lamotrigine and the onset of pneumonitis, we did not reveal any further potentially causal diagnostic hints. Importantly, no relevant genetic variations of metabolizing enzymes or drug interactions resulting in lamotrigine overdosage as a potential cause of toxicity were identified. Our experience with a potentially life-threatening adverse drug reaction shortly after the initiation of the largely well-tolerated lamotrigine suggests a potential side effect under the second-generation anticonvulsant although similar adverse events are deemed to be very rare.

Effects of dopamine D2/3 and opioid receptor antagonism on the trade-off between model-based and model-free behaviour in healthy volunteers.

Human behaviour requires flexible arbitration between actions we do out of habit and actions that are directed towards a specific goal. Drugs that target opioid and dopamine receptors are notorious for inducing maladaptive habitual drug consumption; yet, how the opioidergic and dopaminergic neurotransmitter systems contribute to the arbitration between habitual and goal-directed behaviour is poorly understood. By combining pharmacological challenges with a well-established decision-making task and a novel computational model, we show that the administration of the dopamine D2/3 receptor antagonist amisulpride led to an increase in goal-directed or 'model-based' relative to habitual or 'model-free' behaviour, whereas the non-selective opioid receptor antagonist naltrexone had no appreciable effect. The effect of amisulpride on model-based/model-free behaviour did not scale with drug serum levels in the blood. Furthermore, participants with higher amisulpride serum levels showed higher explorative behaviour. These findings highlight the distinct functional contributions of dopamine and opioid receptors to goal-directed and habitual behaviour and support the notion that even small doses of amisulpride promote flexible application of cognitive control.

Tricyclic antipsychotics and antidepressants can inhibit α5-containing GABAA receptors by two distinct mechanisms.

BACKGROUND AND PURPOSE: Many psychotherapeutic drugs, including clozapine, display polypharmacology and act on GABAA receptors. Patients with schizophrenia show alterations in function, structure and molecular composition of the hippocampus, and a recent study demonstrated aberrant levels of hippocampal α5 subunit-containing GABAA receptors. The purpose of this study is to investigate the effects of tricyclic compounds on α5 subunit-containing receptor subtypes. EXPERIMENTAL APPROACH: Functional studies of effects by seven antipsychotic and antidepressant medications were performed in several GABAA receptor subtypes by two-electrode voltage-clamp electrophysiology using Xenopus laevis oocytes. Computational structural analysis was employed to design mutated constructs of the α5 subunit, probing a novel binding site. Radioligand displacement data complemented the functional and mutational findings. KEY RESULTS: The antipsychotic drugs clozapine and chlorpromazine exerted functional inhibition on multiple GABAA receptor subtypes, including those containing α5-subunits. Based on a chlorpromazine binding site observed in a GABA-gated bacterial homologue, we identified a novel site in α5 GABAA receptor subunits and demonstrate differential usage of this and the orthosteric sites by these ligands. CONCLUSION AND IMPLICATIONS: Despite high molecular and functional similarities among the tested ligands, they reduce GABA currents by differential usage of allosteric and orthosteric sites. The chlorpromazine site we describe here is a new potential target for optimizing antipsychotic medications with beneficial polypharmacology. Further studies in defined subtypes are needed to substantiate mechanistic links between the therapeutic effects of clozapine and its action on certain GABAA receptor subtypes.

Lithium in drinking water and suicide mortality.

BACKGROUND: There is some evidence that natural levels of lithium in drinking water may have a protective effect on suicide mortality. AIMS: To evaluate the association between local lithium levels in drinking water and suicide mortality at district level in Austria. METHOD: A nationwide sample of 6460 lithium measurements was examined for association with suicide rates per 100,000 population and suicide standardised mortality ratios across all 99 Austrian districts. Multivariate regression models were adjusted for well-known socioeconomic factors known to influence suicide mortality in Austria (population density, per capita income, proportion of Roman Catholics, as well as the availability of mental health service providers). Sensitivity analyses and weighted least squares regression were used to challenge the robustness of the results. RESULTS: The overall suicide rate (R(2) = 0.15, ß = -0.39, t = -4.14, P = 0.000073) as well as the suicide mortality ratio (R(2) = 0.17, ß = -0.41, t = -4.38, P = 0.000030) were inversely associated with lithium levels in drinking water and remained significant after sensitivity analyses and adjustment for socioeconomic factors. CONCLUSIONS: In replicating and extending previous results, this study provides strong evidence that geographic regions with higher natural lithium concentrations in drinking water are associated with lower suicide mortality rates.

Imaging the effects of genetic polymorphisms on radioligand binding in the living human brain: A review on genetic neuroreceptor imaging of monoaminergic systems in psychiatry.

Imaging genetics is a research field that describes the impact of genetic risk variants on brain structure and function. While magnetic resonance based imaging techniques are able to provide complex information on a system level, positron emission tomography (PET) and single photon emission computer tomography (SPECT) allow for determination of distribution and density of single receptor molecules in the human brain. Major psychiatric disorders are highly heritable, and have been associated with a dysregulation in brain dopamine and serotonin systems. Understanding the role of genetic polymorphisms within these neurotransmitter systems on brain phenotype is essential. This review tries to cover the literature on the impact of gene variants implicated in psychiatric disorders on serotonin, dopamine, and MAO-A radioligand binding in living humans. The majority of PET and SPECT studies investigated the role of polymorphisms within genes coding for the serotonin and dopamine transporters, the serotonin 1A receptor, and the dopamine D2 receptor on G protein coupled receptors or transporter proteins critically involved in serotonin or dopamine neurotransmission. Other studies investigated the impact of variants in genes for monoamine oxidase-A (MAO-A) or brain derived neurotrophic factor on monoamine transporters, receptors, or MAO-A activity. Two main findings in healthy subjects emerge from the current literature: one is an increased binding of the selective ligand [(11)C]DASB to serotonin transporters in subjects homozygous for the triallelic 5-HTTLPR LA allele. The other one is decreased binding of the radioligand [(11)C]raclopride to dopamine D2 receptors in D2 Taq1 A1 allele carriers. Other findings reported are highly interesting but require independent replication.

Dopaminergic and opioidergic regulation during anticipation and consumption of social and nonsocial rewards.

The observation of animal orofacial and behavioral reactions has played a fundamental role in research on reward but is seldom assessed in humans. Healthy volunteers (N = 131) received 400 mg of the dopaminergic antagonist amisulpride, 50 mg of the opioidergic antagonist naltrexone, or placebo. Subjective ratings, physical effort, and facial reactions to matched primary social (affective touch) and nonsocial (food) rewards were assessed. Both drugs resulted in lower physical effort and greater negative facial reactions during reward anticipation, especially of food rewards. Only opioidergic manipulation through naltrexone led to a reduction in positive facial reactions to liked rewards during reward consumption. Subjective ratings of wanting and liking were not modulated by either drug. Results suggest that facial reactions during anticipated and experienced pleasure rely on partly different neurochemical systems, and also that the neurochemical bases for food and touch rewards are not identical.

Studies in rats and other species have shown that two chemical messengers in the brain regulate how much an animal desires a reward, and how pleasant receiving the reward is. In this context, chemicals called opioids control both wanting and enjoying a reward, whereas a chemical called dopamine only regulates how much an animal desires it. However, since these results were obtained from research performed on animals, further studies are needed to determine if these chemicals play the same roles in the human brain. Korb et al. show that the same brain chemicals that control reward anticipation and pleasure in rats are also at work in humans. In the experiment, 131 healthy volunteers received either a drug that blocks opioid signaling in the brain, a drug that blocks dopamine signaling, or a placebo, a pill with no effect. Then, participants were given, on several occasions, either sweet milk with chocolate or a gentle caress on the forearm. Participants rated how much they wanted each of the rewards before receiving it, and how much they liked it after experiencing it. To measure their implicit wanting of the reward, participants also pressed a force-measuring device to increase their chances of receiving the reward. Additionally, small electrodes measured the movement of the volunteer's smiling or frowning muscles to detect changes in facial expressions of pleasure. Volunteers taking either drug pressed on the device less hard than the participants taking the placebo, suggesting they did not want the rewards as much, and they frowned more as they anticipated the reward, indicating less anticipatory pleasure. However, only the volunteers taking the opioid-blocking drug smiled less when they received a reward, indicating that these participants did not get as much pleasure as others out of receiving it. These differences were most pronounced when volunteers looked at or received the sweet milk with chocolate. This experiment helps to shed light on the chemicals in the human brain that are involved in reward-seeking behaviors. In the future, the results may be useful for developing better treatments for addictions.

On the relationship of first-episode psychosis to the amphetamine-sensitized state: a dopamine D2/3 receptor agonist radioligand study.

Schizophrenia is characterized by increased behavioral and neurochemical responses to dopamine-releasing drugs. This prompted the hypothesis of psychosis as a state of "endogenous" sensitization of the dopamine system although the exact basis of dopaminergic disturbances and the possible role of prefrontal cortical regulation have remained uncertain. To show that patients with first-episode psychosis release more dopamine upon amphetamine-stimulation than healthy volunteers, and to reveal for the first time that prospective sensitization induced by repeated amphetamine exposure increases dopamine-release in stimulant-naïve healthy volunteers to levels observed in patients, we collected data on amphetamine-induced dopamine release using the dopamine D2/3 receptor agonist radioligand [11C]-(+)-PHNO and positron emission tomography. Healthy volunteers (n = 28, 14 female) underwent a baseline and then a post-amphetamine scan before and after a mildly sensitizing regimen of repeated oral amphetamine. Unmedicated patients with first-episode psychosis (n = 21; 6 female) underwent a single pair of baseline and then post-amphetamine scans. Furthermore, T1 weighted magnetic resonance imaging of the prefrontal cortex was performed. Patients with first-episode psychosis showed larger release of dopamine compared to healthy volunteers. After sensitization of healthy volunteers their dopamine release was significantly amplified and no longer different from that seen in patients. Healthy volunteers showed a negative correlation between prefrontal cortical volume and dopamine release. There was no such relationship after sensitization or in patients. Our data in patients with untreated first-episode psychosis confirm the "endogenous sensitization" hypothesis and support the notion of impaired prefrontal control of the dopamine system in schizophrenia.

Toward the Optimization of (+)-[11C]PHNO Synthesis: Time Reduction and Process Validation.

(+)-[11C]PHNO, a dopamine D2/3 receptor agonistic radiotracer, is applied for investigating the dopaminergic system via positron emission tomography (PET). An improved understanding of neuropsychiatric disorders associated with dysfunctions in the dopamine system and the underlying mechanism is a necessity in order to promote the development of new potential therapeutic drugs. In contrast to other broadly applied 11C-radiopharmaceuticals, the production of this radiotracer requires a challenging four-step radiosynthesis involving harsh reaction conditions and reactants as well as an inert atmosphere. Consequently, the production is prone to errors and troubleshooting after failed radiosyntheses remains time consuming. Hence, we aimed to optimize the radiosynthesis of (+)-[11C]PHNO for achieving better activity yields without loss of product quality. Therefore, we synthesized (+)-[11C]PHNO and omitted all heating and cooling steps leading to higher activity yields. As a result, radiosynthesis fully conducted at room temperature led to a time-reduced production procedure that saves about 5 min, which is an appreciable decay-prevention of around 15% of the activity yield. Additionally, we established a troubleshooting protocol by investigating reaction intermediates, byproducts, and impurities. Indeed, partial runs enabled the assignment of byproducts to their associated error source. Finally, we were able to generate a decision tree facilitating error detection in (+)-[11C]PHNO radiosynthesis.

First human evidence of d-amphetamine induced displacement of a D2/3 agonist radioligand: A [11C]-(+)-PHNO positron emission tomography study.

Imaging the competition between D(2/3) radioligands and endogenous dopamine is so far the only way to measure dopamine release in the living human brain. The dopamine D(2) receptor exists in a high (D(2)(high)) and a low-affinity state for dopamine. Under physiological conditions, dopamine is expected to bind to D(2)(high) only. [(11)C]-(+)-4-propyl-9-hydroxynaphthoxazine ((+)-PHNO) is the first D(2/3) agonist radioligand for positron emission tomography (PET) imaging in humans. Since [(11)C]-(+)-PHNO is expected to bind preferentially to D(2)(high), it should be particularly vulnerable to competition with endogenous dopamine. Nine healthy subjects participated in two PET scans, one after administration of d-amphetamine and one after placebo. [(11)C]-(+)-PHNO PET test re-test variability was determined in 11 healthy subjects. Binding potentials (BPs) were calculated for caudate, putamen, ventral striatum, and globus pallidus. d-Amphetamine led to a significant decrease of [(11)C]-(+)-PHNO BPs in caudate (-13.2%), putamen (-20.8%), and ventral striatum (-24.9%), but not in globus pallidus (-6.5%). d-Amphetamine-induced displacement correlated with serum d-amphetamine levels in all regions but caudate. This is the first report on competition between endogenous dopamine and a D(2/3) agonist radioligand in humans. [(11)C]-(+)-PHNO PET might be a superior measure for release of endogenous dopamine than PET employing conventional D(2/3) antagonist radioligands.

The formation of abnormal associations in schizophrenia: neural and behavioral evidence.

It is hypothesized that due to an abnormal functioning of the reward system patients with schizophrenia form context-inappropriate associations. It has been shown that the dopamine target regions, especially the ventral striatum, are critical in the formation of reward associations. We wanted to examine how the ventral striatum responds as patients learn reward-related associations and how this neural response is linked to objective and subjective behavioral measures. Functional magnetic resonance imaging (fMRI) Blood oxygen level dependent (BOLD) responses were examined using aversive Pavlovian learning in 13 medicated patients with schizophrenia and 13 matched healthy controls. Colored circles served as conditioned stimulus (CS+) while a loud, individually adjusted, noise served as the unconditioned stimulus. Circles of another color served as neutral comparators (CS-). Subjective indices were assessed by a post-scan self-report, and galvanic skin responses (GSR) were used as objective measures of associative learning. fMRI data were analyzed using a random effects model in SPM2. Patients showed inappropriately strong activations in the ventral striatum in response to the neutral stimulus (CS-) as compared to the healthy controls. Consistent with this neural evidence of aberrant learning, patients also showed evidence of abnormal learning by self-report and as indexed by GSR. The main finding here is that patients with schizophrenia, when exposed to neutral stimuli in a threatening situation, show an abnormal pattern of learning. The aberrant activations and response are consistent with the idea that patients aberrantly assign motivational salience to neutral stimuli, and this process may be one of the aberrations that predisposes them to psychosis.