Dopamine Response Research Articles

Cortical visual processing evokes short-latency reward-predicting cue responses in primate midbrain dopamine neurons

After classical conditioning dopamine (DA) neurons exhibit short latency responses to reward-predicting visual cues. At least two possible projections could induce such DA responses; the cortical and subcortical visual pathways. Our recent study has shown that after a lesion of the striate cortex (V1), the superior colliculus (SC), a critical node of the subcortical visual pathway, can mediate short latency cue responses in the DA neurons of macaque monkeys. An obvious question then is does the cortical pathway have a similar capacity? Using the monkeys with a unilateral V1 lesion that took part in the preceding study, we recorded DA activity while they were performing the same classical conditioning task. However, in this study conditioned visual stimuli were presented to the intact visual field, and the effects of ipsilateral SC inactivation were examined. We found that after the SC was inactivated by injections of muscimol both conditioned behavioral responding and reward-predicting, short latency (~100 ms) cue-elicited DA neuronal responses were unaffected These results indicate that the intact cortical visual pathway can also mediate short latency cue elicited responses in DA neurons in the absence of a normally functioning subcortical visual system.

Association of pleasant sensations at cigarette smoking initiation with subsequent tobacco product use among U.S. adolescents

Approximately 20% of high school students and 7% of middle school students in the United States used tobacco products in 2016. One factor that may contribute to tobacco use is pleasant sensations – typically characterized as physiological reinforcement such as a dopamine response, or as social reinforcement such as social acceptance. In the present study, the Wave 1 (2013–2014) of the Population Assessment of Tobacco and Health (PATH) Study was analyzed to examine the influence of pleasant sensations at cigarette smoking initiation on current use of other tobacco products among adolescents. While those who reported higher unpleasant sensations at cigarette smoking initiation were less likely to report current use of any tobacco product(s) (Odds Ratio [OR] = 0.70), those who reported higher pleasant sensations at cigarette initiation were more likely to report current use of any tobacco product(s) (OR = 2.12) – including: cigarettes (OR = 2.09), cigars (OR = 1.58), hookah (OR = 1.37), and e-cigarettes (OR = 1.37). Based on these findings, interventions for smoking education and further surveillance may benefit adolescents who report higher pleasant sensations at cigarette smoking initiation.

Real-Time Accumbal Dopamine Response to Negative Stimuli: Effects of Ethanol.

Activity in the mesolimbic dopamine (DA) pathway is known to have a role in reward processing and related behaviors. The mesolimbic DA response to reward has been well-examined, while the response to aversive or negative stimuli has been studied to a lesser extent and produced inconclusive results. However, a brief increase in the DA concentration in terminals during nociceptive activation has become an established but not well-characterized phenomenon. Consequently, the interpretation of the significance of this neurochemical response is still elusive. The present study was designed to further explore these increases in subsecond DA dynamics triggered by negative stimuli using voltammetry in anesthetized rats. Our experiments revealed that repeated exposure to a tail pinch resulted in more efficacious DA release in rat nucleus accumbens. This fact may suggest a protective nature of immediate DA efflux. Furthermore, a sensitized DA response to a neutral stimulus, such as a touch, was discovered following several noxious pinches, while a touch applied before these pinches did not trigger DA release. Finally, it was found that the pinch-evoked DA efflux was significantly decreased by ethanol acutely administrated at an analgesic dose. Taken together, these results support the hypothesis that subsecond DA release in the nucleus accumbens may serve as an endogenous antinociceptive signal.

Selective response of dopamine on 3-thienylphosphonic acid modified gold electrode with high antifouling capability and long-term stability

In this work, an Au electrode modified with self-assembled monolayers (SAMs) of 3-thienylphosphonic acid (TPA) was used as a novel functional interface to selectively sense dopamine (DA) in the presence of excess ascorbic acid (AA). Ellipsometry, X-ray photoelectron spectroscopic (XPS) and electrochemical measurements proved the immobilization of TPA on the gold surface. Interestingly, the Au electrode modified with TPA substantially improved the antifouling and renewal capabilities towards the oxidation of dopamine (DA) after 15 days of storage in undeoxygenated phosphate buffer solution (PBS pH 7.4). Moreover, the TPA-SAMs modified Au electrode could afford a selective electrochemical response for the DA oxidation in the presence of ascorbic acid (AA). Based on this result, a high sensitive detection limit of 2.0 × 10−7 M for DA could be obtained in the presence of high concentration of AA.

Chronic Social Isolation Stress during Peri-Adolescence Alters Presynaptic Dopamine Terminal Dynamics via Augmentation in Accumbal Dopamine Availability.

Chronic peri-adolescent stress in humans increases risk to develop a substance use disorder during adulthood. Rats reared in social isolation during peri-adolescence (aSI; 1 rat/cage) period show greater ethanol and cocaine intake compared to group housed (aGH; 4 rats/cage) rats. In addition, aSI rats have a heightened dopamine response in the nucleus accumbens (NAc) to rewarding and aversive stimuli. Furthermore, single pulse electrical stimulation in slices containing NAc core elicits greater dopamine release in aSI rats. Here, we further investigated dopamine release kinetics and machinery following aSI. Dopamine release, across a wide range of stimulation intensities and frequencies, was significantly greater in aSI rats. Interestingly, subthreshold intensity stimulations also resulted in measurable dopamine release in accumbal slices from aSI but not aGH rats. Extracellular [Ca2+] manipulations revealed augmented calcium sensitivity of dopamine release in aSI rats. The readily releasable pools of dopamine, examined by bath application of Ro-04-1284/000, a vesicular monoamine transporter 2 (VMAT2) inhibitor, were depleted faster in aGH rats. Western blot analysis of release machinery proteins (VMAT2, Synaptogyrin-3, Syntaxin-1, and Munc13-3) showed no difference between the two groups. Tyrosine hydroxylase (TH) protein expression levels, however, were elevated in aSI rats. The greater dopamine release could potentially be explained by higher levels of TH, the rate-limiting step for dopamine synthesis. This augmented responsivity of the dopamine system and heightened dopamine availability post-aSI may lead to an increased risk of addiction vulnerability.

Deletion of the type 2 metabotropic glutamate receptor increases heroin abuse vulnerability in transgenic rats.

Opioid abuse is a rapidly growing public health crisis in the USA. Despite extensive research in the past decades, little is known about the etiology of opioid addiction or the neurobiological risk factors that increase vulnerability to opioid use and abuse. Recent studies suggest that the type 2 metabotropic glutamate receptor (mGluR2) is critically involved in substance abuse and addiction. In the present study, we evaluated whether low-mGluR2 expression may represent a risk factor for the development of opioid abuse and addiction using transgenic mGluR2-knockout (mGluR2-KO) rats. Compared to wild-type controls, mGluR2-KO rats exhibited higher nucleus accumbens (NAc) dopamine (DA) and locomotor responses to heroin, higher heroin self-administration and heroin intake, more potent morphine-induced analgesia and more severe naloxone-precipitated withdrawal symptoms. In contrast, mGluR2-KO rats displayed lower motivation for heroin self-administration under high price progressive-ratio (PR) reinforcement conditions. Taken together, these findings suggest that mGluR2 may play an inhibitory role in opioid action, such that deletion of this receptor results in an increase in brain DA responses to heroin and in acute opioid reward and analgesia. Low-mGluR2 expression in the brain may therefore be a risk factor for the initial development of opioid abuse and addiction.

P11 in Cholinergic Interneurons of the Nucleus Accumbens Is Essential for Dopamine Responses to Rewarding Stimuli

A recent study showed that p11 expressed in cholinergic interneurons (CINs) of the nucleus accumbens (NAc) is a key regulator of depression-like behaviors. Dopaminergic neurons projecting to the NAc are responsible for reward-related behaviors, and their function is impaired in depression. The present study investigated the role of p11 in NAc CINs in dopamine responses to rewarding stimuli. The extracellular dopamine and acetylcholine (ACh) levels in the NAc were determined in freely moving male mice using in vivo microdialysis. Rewarding stimuli (cocaine, palatable food, and female mouse encounter) induced an increase in dopamine efflux in the NAc of wild-type (WT) mice. The dopamine responses were attenuated (cocaine) or abolished (food and female mouse encounter) in constitutive p11 knock-out (KO) mice. The dopamine response to cocaine was accompanied by an increase in ACh NAc efflux, whereas the attenuated dopamine response to cocaine in p11 KO mice was restored by activation of nicotinic or muscarinic ACh receptors in the NAc. Dopamine responses to rewarding stimuli and ACh release in the NAc were attenuated in mice with deletion of p11 from cholinergic neurons (ChAT-p11 cKO mice), whereas gene delivery of p11 to CINs restored the dopamine responses. Furthermore, chemogenetic studies revealed that p11 is required for activation of CINs in response to rewarding stimuli. Thus, p11 in NAc CINs plays a critical role in activating these neurons to mediate dopamine responses to rewarding stimuli. The dysregulation of mesolimbic dopamine system by dysfunction of p11 in NAc CINs may be involved in pathogenesis of depressive states.

Mode of Sucrose Delivery Alters Reward-Related Phasic Dopamine Signals in Nucleus Accumbens.

In studies of appetitive Pavlovian conditioning, rewards are often delivered to subjects in a manner that confounds several processes. For example, delivery of a sugar pellet to a rodent requires movement to collect the pellet and is associated with sensory stimuli such as the sight and sound of the pellet arrival. Thus, any neurochemical events occurring in proximity to the reward may be related to multiple coincident phenomena. We used fast-scan cyclic voltammetry in rats to compare nucleus accumbens dopamine responses to two different modes of delivery: sucrose pellets, which require goal-directed action for their collection and are associated with sensory stimuli, and intraoral infusions of sucrose, which are passively received and not associated with external stimuli. We found that when rewards were unpredicted, both pellets and infusions evoked similar dopamine release. However, when rewards were predicted by distinct cues, greater dopamine release was evoked by pellet cues than infusion cues. Thus, dopamine responses to pellets, infusions as well as predictive cues suggest a nuanced role for dopamine in both reward seeking and reward evaluation.

Genetic deletion of the dopamine D3 receptor increases vulnerability to heroin in mice

Despite extensive research, the neurobiological risk factors that convey vulnerability to opioid abuse are still unknown. Recent studies suggest that the dopamine D3 receptor (D3R) is involved in opioid self-administration, but it remains unclear whether altered D3R availability is a risk factor for the development of opioid abuse and addiction. Here we used dopamine D3 receptor-knockout (D3-KO) mice to investigate the role of this receptor in the different phases of opioid addiction. D3-KO mice learned to self-administer heroin faster and took more heroin than wild-type mice during acquisition and maintenance of self-administration. D3R-KO mice also displayed higher motivation to work to obtain heroin reward during self-administration under progressive-ratio reinforcement, as well as elevated heroin-seeking during extinction and reinstatement testing. In addition, deletion of the D3R induced higher baseline levels of extracellular dopamine (DA) in the nucleus accumbens (NAc), higher basal levels of locomotion, and reduced NAc DA and locomotor responses to lower doses of heroin. These findings suggest that the D3R is critically involved in regulatory processes that normally limit opioid intake via DA-related mechanisms. Deletion of D3R augments opioid-taking and opioid-seeking behaviors. Therefore, low D3R availability in the brain may represent a risk factor for the development of opioid abuse and addiction.

Transcriptomic signatures of schizophrenia revealed by dopamine perturbation in an ex vivo model

The dopaminergic hypothesis of schizophrenia (SZ) postulates that dopaminergic over activity causes psychosis, a central feature of SZ, based on the observation that blocking dopamine (DA) improves psychotic symptoms. DA is known to have both receptor- and non-receptor-mediated effects, including oxidative mechanisms that lead to apoptosis. The role of DA-mediated oxidative processes in SZ has been little studied. Here, we have used a cell perturbation approach and measured transcriptomic profiles by RNAseq to study the effect of DA exposure on transcription in B-cell transformed lymphoblastoid cell lines (LCLs) from 514 SZ cases and 690 controls. We found that DA had widespread effects on both cell growth and gene expression in LCLs. Overall, 1455 genes showed statistically significant differential DA response in SZ cases and controls. This set of differentially expressed genes is enriched for brain expression and for functions related to immune processes and apoptosis, suggesting that DA may play a role in SZ pathogenesis through modulating those systems. Moreover, we observed a non-significant enrichment of genes near genome-wide significant SZ loci and with genes spanned by SZ-associated copy number variants (CNVs), which suggests convergent pathogenic mechanisms detected by both genetic association and gene expression. The study suggests a novel role of DA in the biological processes of immune and apoptosis that may be relevant to SZ pathogenesis. Furthermore, our results show the utility of pathophysiologically relevant perturbation experiments to investigate the biology of complex mental disorders.

Effects of exposure to 5-MeO-DIPT during adolescence on brain neurotransmission and neurotoxicity in adult rats

PurposeTryptamine hallucinogen 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) is a serotonin transporter inhibitor with high affinity for serotonin 5-HT1A and 5-HT2A/C receptors. We showed previously that 5-MeO-DIPT in a single dose increased neurotransmitter release in brain regions of rats and elicited single- and double-strand DNA breaks. Herein we investigated the effects of repeated-intermittent 5-MeO-DIPT administration in adolescence on dopamine (DA), serotonin (5-HT) and glutamate release in brain regions of adult rats. Furthermore, we examined caspase-3 activity, oxidative DNA damage, the Gpx3, Sod1, Ht1a and Ht2a mRNA expression levels, and cell viability.MethodsNeurotransmitter release was measured by microdialysis in freely moving animals. Caspase-3 activity was assessed colorimetrically, and oxidative DNA damage with the comet assay, while the Gpx3, Sod1, Ht1a and Ht2a mRNA expression levels were assessed by real-time polymerase chain reaction. Cell viability was studied in SH-SY5Y and Hep G2 cells by the MTT test.ResultsWe observed changed responses of DA, 5-HT and glutamate neurons to a challenge dose of 5-MeO-DIPT when animals were treated repeatedly in adolescence with this hallucinogen. The basal extracellular levels of DA and 5-HT were decreased in the striatum and nucleus accumbens, while glutamate level was increased in the nucleus accumbens and frontal cortex. The damage of cortical DNA, increased Gpx3 and Sod1 mRNA expression and affected caspase-3 activity were also observed. Furthermore, decreased Ht1a and Ht2a mRNA expression in the frontal cortex and marked cytotoxicity of 5-MeO-DIPT were found.ConclusionsThese results suggest that 5-MeO-DIPT given repeatedly during adolescence affects brain neurotransmission and shows neurotoxic potential observed in adult animals.

The Beta-Arrestin-Biased Dopamine D2 Receptor Ligand, UNC9994, Is a Partial Agonist at G-Protein-Mediated Potassium Channel Activation.

BackgroundPrevious evidence suggests that UNC9994 is a beta-arrestin2-selective agonist at the dopamine D2 receptor, lacking ability both to activate and antagonize G protein-dependent signaling. However, this has only been reported by one laboratory using a single assay.MethodsWe used G protein-coupled inward rectifier potassium channel activation in Xenopus oocytes to investigate UNC9994-induced modulation of G protein-dependent signaling at dopamine D2 receptor and dopamine D3 receptor.ResultsAt dopamine D2 receptor, UNC9994 induced G protein-coupled inward rectifier potassium channel currents that were 15% of the maximal response to dopamine, with an EC50 of 185 nM. At dopamine D3 receptor, the ligand elicited 89% of the maximal dopamine response with an EC50 of 62 nM. Pertussis toxin abolished G protein-coupled inward rectifier potassium channel activation. Furthermore, UNC9994 antagonized dopamine-induced G protein-coupled inward rectifier potassium channel activation at dopamine D2 receptor.ConclusionsUNC9994 modulates G protein-coupled inward rectifier potassium channel channel activation via pertussis toxin-sensitive G proteins at dopamine D2 receptor and dopamine D3 receptor. These findings may have implications for the interpretation of data obtained with this ligand.

Carbon Paste Electrode Modified with ZrO2 Nanoparticles and Ionic Liquid for Sensing of Dopamine in the Presence of Uric Acid

A novel carbon paste electrode modified with ZrO2 nanoparticles and an ionic liquid (n-hexyl-3- methylimidazolium hexafluorophosphate) was fabricated. The electrochemical study of the modified electrode, as well as its efficiency for simultaneous voltammetric oxidation of dopamine and uric acid is described. The electrode was also employed to study the electrochemical oxidation of dopamine and uric acid, using cyclic voltammetry, chronoamperometry and square wave voltammetry as diagnostic techniques. Square wave voltammetry exhibits linear dynamic range from 1.0 × 10−6 to 9.0 × 10−4 M for dopamine. Also, square wave voltammetry exhibits linear dynamic range from 9.0 × 10−6–1.0 × 10−3 M for uric acid. The modified electrode displayed strong function for resolving the overlapping voltammetric responses of dopamine and uric acid into two well-defined voltammetric peaks. In the mixture containing dopamine and uric acid, the two compounds can be well separated from each other with potential difference of 155 mV, which is large enough to determine dopamine and uric acid individually and simultaneously. Finally, the modified electrode was used for determination of dopamine and uric acid in real samples.

Challenges to Body Fluid Homeostasis Differentially Recruit Phasic Dopamine Signaling in a Taste-Selective Manner.

The internal environment of an organism must remain stable to ensure optimal performance and ultimately survival. The generation of motivated behaviors is an adaptive mechanism for defending homeostasis. Although physiological state modulates motivated behaviors, the influence of physiological state on phasic dopamine signaling, an underlying neurobiological substrate of reward-driven behavior, is underexplored. Here, we use sodium depletion and water restriction, manipulations of body fluid homeostasis, to determine the flexibility and specificity of dopamine responses. Changes in dopamine concentration were measured using fast-scan cyclic voltammetry in the nucleus accumbens shell of male rats in response to intraoral infusions of fluids that either satisfied or did not satisfy homeostatic need. Increases in dopamine concentration during intraoral infusions were observed only under conditions of physiological deficit. Furthermore, dopamine increases were selective and limited to those that satisfied the need state of the animal. Thus, dopamine neurons track fluid balance and respond to salt and water stimuli in a state- and taste-dependent manner. Using Fluoro-Gold tracing and immunohistochemistry for c-Fos and Foxp2, a marker of sodium-deprivation responsive neurons, we revealed brainstem populations of neurons that are activated by sodium depletion and project directly to the ventral tegmental area. The identified projections may modulate dopamine neuron excitability and consequently the state-specific dopamine release observed in our experiments. This work illustrates the impact of physiological state on mesolimbic dopamine signaling and a potential circuit by which homeostatic disruptions are communicated to mesolimbic circuitry to drive the selective reinforcement of biologically-required stimuli under conditions of physiological need.SIGNIFICANCE STATEMENT Motivated behaviors arise during physiological need and are highly selective for homeostasis-restoring stimuli. Although phasic dopamine signaling has been shown to contribute to the generation of motivated behaviors, the state and stimulus specificity of phasic dopamine signaling is less clear. These studies use thirst and sodium appetite to show that dopamine neurons dynamically track body fluid homeostasis and respond to water and salt stimuli in a state- and taste-dependent manner. We also identify hindbrain sodium deprivation-responsive neurons that project directly to the ventral tegmental area, where dopamine neuron cell bodies reside. This work demonstrates command of homeostasis over dopamine signaling and proposes a circuit by which physiological need drives motivated behavior by state- and taste-selective recruitment of phasic dopamine signaling.

Poly(glycine)/graphene oxide modified glassy carbon electrode: Preparation, characterization and simultaneous electrochemical determination of dopamine, uric acid, guanine and adenine

A novel poly(glycine) (p-GLY)/graphene oxide (GO) composite based sensor (p-GLY/GO) was successfully prepared on glassy carbon electrode by simple electropolymerization. Electrochemical responses of analytes on p-GLY/GO modified electrode were studied by cyclic voltammetry and differential pulse voltammetry. The results demonstrated that p-GLY/GO modified electrode showed a favorable application for the simultaneous determination of dopamine (DA), uric acid (UA), guanine (GU) and adenine (AD). Owing to the synergistic effect of p-GLY and GO, the oxidation peaks of four analytes separated well from each other, and the potential separations of oxidation peaks of DA-UA, UA-GU and GU-AD were large up to 170, 350 and 300 mV, respectively. As-prepared p-GLY/GO modified electrode offered wide linear responses for DA, UA, GU and AD over the ranges of 0.20–62, 0.10–105, 0.15–48 and 0.090–103 μM with detection limits of 0.011, 0.061, 0.026 and 0.030 μM (S/N = 3), respectively. Moreover, p-GLY/GO modified electrode presented favorable selectivity, stability and reproducibility, which was a promising candidate as an electrochemical sensor for the simultaneous determination of DA, UA, GU and AD.

Cortical stress regulation is disrupted in schizophrenia but not in clinical high risk for psychosis.

While alterations in striatal dopamine in psychosis and stress have been well studied, the role of dopamine in prefrontal cortex is poorly understood. To date, no study has investigated the prefrontocortical dopamine response to stress in the psychosis spectrum, even though the dorsolateral and medial prefrontal cortices are key regions in cognitive and emotional regulation, respectively. The present study uses the high-affinity dopamine D2/3 receptor radiotracer 11C-FLB457 and PET together with a validated psychosocial stress challenge to investigate the dorsolateral and medial prefrontocortical dopamine response to stress in schizophrenia and clinical high risk for psychosis. Forty participants completed two 11C-FLB457 PET scans (14 antipsychotic-free schizophrenia, 14 clinical high risk for psychosis and 12 matched healthy volunteers), one while performing a Sensory Motor Control Task (control) and another while performing the Montreal Imaging Stress Task (stress). Binding potential (BPND) was estimated using Simplified Reference Tissue Model with cerebellar cortex as reference region. Dopamine release was defined as per cent change in BPND between control and stress scans (ΔBPND) using a novel correction for injected mass. Salivary cortisol response (ΔAUCI) was assessed throughout the tasks and its relationship with dopamine release examined. 11C-FLB457 binding at control conditions was significantly different between groups in medial [F(2,37) = 7.98, P = 0.0013] and dorsolateral [F(2,37) = 6.97, P = 0.0027] prefrontal cortex with schizophrenia patients having lower BPND than participants at clinical high risk for psychosis and healthy volunteers, but there was no difference in ΔBPND among groups [dorsolateral prefrontal cortex: F(2,37) = 1.07, P = 0.35; medial prefrontal cortex: F(2,37) = 0.54, P = 0.59]. We report a positive relationship between ΔAUCI and 11C-FLB457 ΔBPND in dorsolateral and medial prefrontal cortex in healthy volunteers (r = 0.72, P = 0.026; r = 0.76, P = 0.014, respectively) and in participants at clinical high risk for psychosis (r = 0.76, P = 0.0075; r = 0.72, P = 0.018, respectively), which was absent in schizophrenia (r = 0.46, P = 1.00; r = 0.19, P = 1.00, respectively). Furthermore, exploratory associations between ΔBPND or ΔAUCI and stress or anxiety measures observed in clinical high risk for psychosis were absent in schizophrenia. These findings provide first direct evidence of a disrupted prefrontocortical dopamine-stress regulation in schizophrenia.

Exposure to conditions of uncertainty promotes the pursuit of amphetamine.

Prior exposure to abused drugs leads to long-lasting neuroadaptations culminating in excessive drug intake. Given the comorbidity between substance use and gambling disorders, surprisingly little is known about the effects of exposure to reinforcement contingencies experienced during games of chance. As it is a central feature of these games, we characterized the effects of exposure to uncertainty on biochemical and behavioral effects normally observed in rats exposed to amphetamine. Rats in different groups were trained to nose-poke for saccharin under certain [fixed-ratio (FR)] or uncertain conditions [variable-ratio (VR)] for 55 1-h sessions. Ratios were escalated on successive sessions and rats maintained on the last ratio (FR/VR 20) for 20-25 days. Two to three weeks later, rats were tested for their locomotor or nucleus accumbens dopamine (NAcc DA) response to amphetamine or self-administration of the drug using a lever press operant. NAcc DA overflow was also assessed in additional rats during the saccharin sessions. Rats exposed to uncertainty subsequently showed a higher locomotor and NAcc DA response to amphetamine and self-administered more drug infusions relative to rats exposed to predictable reinforcement. NAcc DA levels during the saccharin sessions tracked the variance of the scheduled ratios (a measure of uncertainty). VR rats showed escalating DA overflow with increasing ratios. Exposure to uncertainty triggered neuroadaptations similar to those produced by exposure to abused drugs. As these were produced in drug naive rats both during and after exposure to uncertainty, they provide a novel common pathway to drug and behavioral addictions.

Belief state representation in the dopamine system

Learning to predict future outcomes is critical for driving appropriate behaviors. Reinforcement learning (RL) models have successfully accounted for such learning, relying on reward prediction errors (RPEs) signaled by midbrain dopamine neurons. It has been proposed that when sensory data provide only ambiguous information about which state an animal is in, it can predict reward based on a set of probabilities assigned to hypothetical states (called the belief state). Here we examine how dopamine RPEs and subsequent learning are regulated under state uncertainty. Mice are first trained in a task with two potential states defined by different reward amounts. During testing, intermediate-sized rewards are given in rare trials. Dopamine activity is a non-monotonic function of reward size, consistent with RL models operating on belief states. Furthermore, the magnitude of dopamine responses quantitatively predicts changes in behavior. These results establish the critical role of state inference in RL.

Role of N‐Methyl‐D‐Aspartate Receptor (NMDAR) in Co‐morbid Schizophrenia and Substance Abuse

Both schizophrenia (SZ) and substance abuse (SA) exhibit significant heritability. Moreover, N‐methyl‐D‐aspartate receptors (NMDARs) have been implicated in the pathophysiology of both SZ and SA. We hypothesize that the high prevalence of co‐morbid SA in SZ is due to dysfunction of NMDARs caused by shared risk genes. We used transgenic mice with a null mutation of the gene encoding serine racemase (SR), the enzyme that synthesizes the NMDAR co‐agonist D‐serine, to mimic an established genetic risk factor for SZ. We determined the effect of NMDAR hypofunction resulting from the absence of D‐serine on motivated behavior using intracranial self‐stimulation (ICSS) and neurotransmitter release in the nucleus accumbens using in vivo microdialysis. Compared to wild‐type mice (WT), SR−/− mice exhibited similar baseline ICSS thresholds but were less sensitive to the threshold‐lowering (rewarding) and the performance‐elevating (stimulant) effects of cocaine. While basal dopamine (DA) and glutamate release were elevated in the nucleus accumbens of SR−/− mice, cocaine‐induced increases in DA and glutamate release were blunted. γ‐Amino‐butyric acid (GABA) efflux was unaffected in the SR−/− mice. Together, these findings suggest that the impaired NMDAR function and a consequent decrease in sensitivity to cocaine effects on behavior are mediated by blunted DA and glutamate responses normally triggered by the drug. Preliminary data from ongoing behavioral studies in SR−/− and WT mice also show a decreased sensitivity to nicotine's behavioral effects. Projected to humans, NMDAR hypofunction due to mutations in SR or other genes impacting glutamatergic function in SZ may render abused substances less potent and effective, thus requiring higher doses to achieve a hedonic response, resulting in elevated drug exposure and increased dependence/addiction.Support or Funding InformationThis research was supported by NIH grant RO1MH51290‐18 to JTC, DA031231 K01 NIH/NIDA grant to RID, and a NARSAD Young Investigator Award to MDP.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

26.2 CORTICAL STRESS REGULATION IS DISRUPTED IN SCHIZOPHRENIA BUT NOT IN CLINICAL HIGH-RISK FOR PSYCHOSIS

BackgroundWhile striatal dopamine in psychosis and stress has been well studied, the role of dopamine in the prefrontal cortex (PFC) is poorly understood. To date no study has investigated the PFC dopamine response to stress exclusively in schizophrenia or its putative prodrome, even though medial PFC is known as a key area in stress regulation. The present study uses the high-affinity dopamine D2/3 receptor radiotracer [11C]FLB457 and positron emission tomography (PET) together with a validated psychosocial stress challenge to investigate if the PFC dopamine response to stress is dysregulated in schizophrenia and clinical high risk (CHR) for psychosis.MethodsFourteen antipsychotic-free patients with schizophrenia, 14 CHR and 12 matched healthy volunteers underwent two [11C]FLB457 PET scans, one while performing a Sensory Motor Control Task (control) and another while performing the Montreal Imaging Stress Task (stress). PET data were analyzed using the Simplified Reference Tissue Model with non-displaceable binding potential (BPND) as outcome measure. Dopamine release was defined as percent change in BPND between control and stress scan (ΔBPND).ResultsWe observed an increased dopamine release, indexed by ΔBPND, in the medial PFC in schizophrenia patients but not CHR compared to healthy volunteers. Further, associations between stress-induced dopamine release and increase in cortisol levels observed in healthy volunteers and CHR, were absent in schizophrenia, similar to associations with symptoms, distress and anxiety.DiscussionThese findings provide first direct evidence of a disrupted cortical dopamine-stress regulation in schizophrenia.