Dopamine Activity Research Articles

Dopamine D4 receptors in the lateral habenula regulate anxiety-related behaviors in a rat model of Parkinson's disease

Although the output of the lateral habenula (LHb) controls the activity of midbrain dopamine (DA) and 5-hydroxytryptamine (5-HT) containing systems, which are implicated in the pathophysiology of anxiety, it is not clear how activation and blockade of LHb D4 receptors affects anxiety-like behaviors, particularly in Parkinson’s disease related anxiety. In this study, unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc) in rats induced anxiety-like behaviors, which attribute to hyperactivity of LHb neurons and decrease in the level of DA in the medial prefrontal cortex (mPFC), amygdala and ventral hippocampus (vHip) compared to sham-operated rats. Intra-LHb injection of D4 receptor agonist A412997 induced or increased the expression of anxiety-like behaviors, while injection of D4 receptor antagonist L741742 showed anxiolytic effects in sham-operated and the SNc-lesioned rats. However, the doses producing behavioral effects in the lesioned rats were higher than those of sham-operated rats. Intra-LHb injection of A412997 increased firing rate of LHb neurons, and decreased levels of DA and 5-HT in the mPFC, amygdala and vHip; conversely, L741742 decreased firing rate of LHb neurons, and increased levels of DA and 5-HT in two groups of rats. Compared to sham-operated rats, the duration of A412997 and L741742 action on the firing rate of neurons was markedly shortened in the lesioned rats. Collectively, these findings suggest that D4 receptors in the LHb are involved in the regulation of anxiety-like behaviors, and degeneration of the nigrostriatal pathway down-regulates function and/or expression of these receptors.

Opponent control of reinforcement by striatal dopamine and serotonin.

The neuromodulators dopamine (DA) and serotonin (5-hydroxytryptamine; 5HT) powerfully regulate associative learning1-8. Similarities in the activity and connectivity of these neuromodulatory systems have inspired competing models of how DA and 5HT interact to drive the formation of new associations9-14. However, these hypotheses have not been tested directly because it has not been possible to interrogate and manipulate multiple neuromodulatory systems in a single subject. Here, we establish a mouse model enabling simultaneous genetic access to the brain's DA and 5HT neurons. Anterograde tracing revealed the nucleus accumbens (NAc) to be a putative hotspot for the integration of convergent DA and 5HT signals. Simultaneous recording of DA and 5HT axon activity, together with genetically encoded DA and 5HT sensor recordings, revealed that rewards increase DA signaling and decrease 5HT signaling in the NAc. Optogenetically dampening DA or 5HT reward responses individually produced modest behavioral deficits in an appetitive conditioning task, while blunting both signals together profoundly disrupted learning and reinforcement. Optogenetically reproducing DA and 5HT reward responses together was sufficient to drive acquisition of new associations and supported reinforcement more potently than either manipulation alone. Together, these results demonstrate that striatal DA and 5HT signals shape learning by exerting opponent control of reinforcement.

A dual-signal sensing platform based on single atomic iron-nitrogen-carbon nanozyme for the detection of neurodegenerative disease-related bioactive molecules acetylcholinesterase and dopamine

In this work, a novel iron-nitrogen-carbon single-atom nanozyme (Fe-N800 SAzyme) with peroxidase-like activity was synthesized by doping Fe in zeolitic imidazolate frameworks (ZiF-8) and utilizing graphitic C3N4 (g-C3N4) as a nitrogen source in the pyrolysis process. Acetylcholine (ACh) was continuously oxidized by acetylcholinesterase (AChE) and choline oxidase (CHO) to generate H2O2 through an enzymatic cascade reaction. The interaction between Fe-N800 SAzyme and H2O2 led to the generation of reactive oxygen species (ROS) that could then oxidize 3,3’,5,5’-tetramethylbenzidine (TMB) to oxidized TMB (oxTMB), which exhibited an absorption peak at 650 nm. Lysozyme (LZ)-functionalized 5-methyl-2-thiouracil (MTU) gold/silver nanoclusters (Au/Ag/LZ-MTU), which exhibited a fluorescence peak at 610 nm, could be quenched by oxTMB through the inner filter effect (IFE). Dopamine (DA) was able to consume ROS and hinder the oxidation of TMB. Therefore, by monitoring the change of fluorescence at 610 nm and absorption at 650 nm, a dual signal fluorometric and colorimetric sensing platform for AChE and DA was established. The AChE activity was monitored through the variation of fluorescence (I610) or colorimetric (A650) intensity, which had a low limit of detection (LOD) of 0.057 U/L and 0.11 U/L, respectively. The fluorescence and colorimetric methods were also able to sensitively monitor the DA activity with a LOD of 0.83 μM and 2.7 μM, respectively. Finally, the developed method could satisfactorily quantify AChE and DA in human serum, whole blood, and DA hydrochloride injection samples.

Opposite-sex pairing alters social interaction-induced GCaMP and dopamine activity in the insular cortex of male prairie voles.

The prairie vole ( Microtus ochrogaster ) is a monogamous rodent species which displays selective social behaviors to conspecifics after establishing a pair bonded relationship, specifically partner-directed affiliation and stranger-directed aggression. This social selectivity relies on the ability of an individual to respond appropriately to a social context and requires salience detection and valence assignment. The anterior insular cortex (aIC) has been implicated in stimulus processing and categorization across a variety of contexts and is well-situated to integrate environmental stimuli and internal affective states to modulate complex goal-directed behaviors and social decision-making. Surprisingly, the contribution of the aIC to the expression of pair bond-induced social selectivity in prairie voles has been drastically understudied. Here we examined whether neural activity and gene expression in the aIC change in response to opposite-sex pairing and/or as a function of pairing length in male prairie voles. Opposite-sex pairing was characterized by changes to calcium and dopamine (DA) transients in the aIC that corresponded with the display of social selectivity across pair bond maturation. Furthermore, D1 and D2 receptor mRNA expression was significantly higher in males after 48 hrs of cohabitation with a female partner compared to same-sex housed males, and D2 mRNA remained significantly higher in males with a female partner compared to same-sex housed males after a week of cohabitation. Together, these results implicate a role for DA and its receptors in the aIC across the transition from early-to late-phase pair bonding.

Rational integration of fluorogenic and quenching activity of dopamine for reversed ratiometric and semi-quantitative visual detection of tyramine

A facile and efficient reversed ratiometric fluorescence (RF) method has been developed for the sensitive and accurate detection of tyramine (Tyr), an essential marker for food spoilage in fermented or aged foods. This method utilizes an “activation-quenching integration” strategy involving the fluorogenic reactivity and quenching capacity of dopamine (DA), the tyrosinase (TYR) catalyzed products of Tyr. Under alkaline conditions, DA reacts with resorcinol to form azamonardine, exhibiting strong blue emission. Additionally, DA is oxidized to o-dopaquinone by TYR, which quenches the red fluorescence of CdTe quantum dots (QDs). Under optimized conditions, a Tyr-specific RF sensor was established, featuring a linear detection range from 0.1 to 6 mg/mL and a detection limit of 8.50 × 10−3 mg/L. The fabricated reversed RF sensing system was successfully applied for quantitative analysis of Tyr in real samples and semi-quantitative visual detection of Tyr in fermented food samples upon integration with a pseudo-color-assisted approach.

Modulation of Hypothalamic Dopamine Neuron Activity by Interaction Between Caloric State and Amphetamine in Zebrafish Larvae.

Dopamine (DA) signaling is evoked by both food and drugs that humans come to abuse. Moreover, physiological state (e.g., hunger versus satiety) can modulate the response. However, there is great heterogeneity among DA neurons. Limited studies have been performed that could resolve the interaction between physiological state and drug responsivity across groups of DA neurons. Here, we measured the activity of neurons in transgenic Tg (th2:GCaMP7s) zebrafish larva that expresses a calcium indicator (GCaMP7s) in A11 (posterior tuberculum) and a part of A14 (caudal hypothalamus and intermediate hypothalamus) DA populations located in the hypothalamus of the larval zebrafish. Fish were recorded in one of two physiological states: ad-libitum fed (AL) and food deprived (FD) and before and after acute exposure to different doses of the stimulant drug amphetamine (0, 0.7, and 1.5 μM). We quantified fluorescence change, activity duration, peak rise/fall time, and latency in the calcium spikes of the DA neurons. Our results show that baseline DA neuron activity amplitude, spike duration, and correlation between inter- and intra-DA neurons were higher in the FD than in the AL state. Dose-dependent AMPH treatment further increased the intensity of these parameters in the neuron spikes but only in the FD state. The DA activity correlation relatively increased in AL state post-AMPH treatment. Given that hunger increases drug reactivity and the probability of relapse to drug seeking, the results support populations of DA neurons as potential critical mediators of the interaction between physiological state and drug reinforcement.

Prevalence and features of headache in Parkinson's disease: the role of dopamine.

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra, but dopamine also plays a role in the pathophysiology of migraine. The aim of this study is to assess lifetime and previous year prevalence rates of headache in PD patients compared with controls. We enrolled 101 patients (57M and 44W) and 101 controls (62M and 39W), comparable for age and gender, who underwent a semi-structured questionnaire to assess the occurrence and the features of headache, and Beck Depression Inventory (BDI). We did not find any significant differences in the overall prevalence of lifetime and last 12-month headache between the two groups, as well as lifetime and last year tension-type headache (TTH) and migraine. Patients, especially those suffering from migraine and treated with dopamine agonists (DA), more frequently showed headache remission after the onset of motor symptoms compared to the age-related remission observed in controls(p = 0.001). Patients affected by headache were less frequently treated with DA in comparison with those without (p = 0.051). Depression of mood was more severe among PD patients with migraine than with TTH (p = 0.021). PD patients with headache exhibiting the akinetic-rigid subtype more frequently reported motor fluctuations than those presenting with tremor-dominant disease (p = 0.040). The prevalence of headache in PD follows that described in the general population, but dopaminergic pathway degeneration, loss of dopamine activation on the trigeminal-vascular system, and DA treatment might favor migraine improvement and remission in PD patients.

Early disruption of entorhinal dopamine in a knock-in model of Alzheimer's disease.

The entorhinal cortex (EC) is a critical brain area for memory formation, while also the region exhibiting the earliest histological and functional alterations in Alzheimer's disease (AD). The EC thus has been long hypothesized as one of the originating brain areas of AD pathophysiology, although circuit mechanisms causing its selective vulnerability remain poorly understood. We found that dopamine neurons projecting their axons to the lateral EC (LEC), critical for memory formation in healthy brains, become dysfunctional and cause memory impairments in early AD brains. In amyloid precursor protein knock-in mice with associative memory impairment, LEC dopamine activity and associative memory encoding of LEC layer 2/3 neurons were disrupted in parallel from the early pathological stage. Optogenetic reactivation of LEC dopamine fibers, as well as L- DOPA treatment, rescued associative learning behavior. These results suggest that dysfunction of LEC-projecting dopamine neurons underlies memory impairment in AD from early stages, pointing to a need for clinical investigation of LEC dopamine in AD patients.

Glassy Carbon Fiber‐Like Multielectrode Arrays for Neurochemical Sensing and Electrophysiology Recording

AbstractReal‐time measurement of neurochemical and electrophysiological activities in the living brain is vital for advancing neuroscience and understanding brain disorders. Carbon fiber microelectrodes (CFEs) have been widely utilized for in vivo electrochemical detection due to their subcellular size, biocompatibility, and desirable electrochemical properties, and CFE arrays have demonstrated excellent multi‐site chronic sensing of dopamine (DA) and neural activity recording capabilities. However, manual fabrication of CFE arrays lacks reproducibility and batch production capacity. Alternatively, photolithography enables batch fabrication of glassy carbon (GC) multielectrode arrays (GC‐MEAs) with high resolution and reproducibility, but the insertion of planar flexible MEAs poses challenges. In this study, GC fiber‐like (GCF) MEAs are presented and fabricated using photolithography. The GCF MEAs feature fiber‐like GC electrodes with small cross‐sections, facilitating self‐insertion into brain tissue without additional aids. Batch fabrication of GCF MEAs allows for customizable designs with minimal manual intervention. Comparative analysis with CFEs demonstrates improved electrochemical properties of GCF. In vivo experiments in mouse brains confirm the GCF MEAs' ability to measure neurotransmitter concentrations and record neural activities. This novel fabrication approach is promising for multimodal electrical and chemical measurements with minimal footprint, offering significant advancements in neural interface technology for neuroscience research and clinical applications.

Linking the reversal of gestational insulin resistance to postpartum depression.

Postpartum depression (PPD) constitutes a significant mental health disorder affecting almost one fifth of pregnancies globally. Despite extensive research, the precise etiological mechanisms underlying PPD remain elusive. However, several risk factors like genetic predisposition, hormonal fluctuations, and stress-related environmental and psychosocial triggers have been found to be implicated in its development. MAIN: Recently, an increased risk of PPD has been reported to be associated with gestational diabetes mellitus (GDM), which is characterized by the disruption of glucose metabolism, primarily attributed to the emergence of insulin resistance (IR). While IR during pregnancy seems to be an evolutionary adaptative mechanism to handle the profound metabolic alterations during pregnancy, its subsequent resolution following delivery necessitates a reconfiguration of the metabolic landscape in both peripheral tissues and the central nervous system (CNS). Considering the pivotal roles of energy metabolism, particularly glucose metabolism, in CNS functions, we propose a novel model that such pronounced changes in IR and the associated glucose metabolism seen postpartum might account for PPD development. This concept is based on the profound influences from insulin and glucose metabolism on brain functions, potentially via modulating neurotransmitter actions of dopamine and serotonin. Their sudden postpartum disruption is likely to be linked to mood changes, as observed in PPD. The detailed pathogenesis of PPD might be multifactorial and still remains to be fully elucidated. Nevertheless, our hypothesis might account in part for an additional etiological factor to PPD development. If our concept is validated, it can provide guidance for future PPD prevention, diagnosis, and intervention.

Reward and punishment contingency shifting reveals distinct roles for VTA dopamine and GABA neurons in behavioral flexibility.

In dynamic environments where stimuli predicting rewarding or aversive outcomes unexpectedly change, it is critical to flexibly update behavior while preserving recollection of previous associations. Dopamine and GABA neurons in the ventral tegmental area (VTA) are implicated in reward and punishment learning, yet little is known about how each population adapts when the predicted outcome valence changes. We measured VTA dopamine and GABA population activity while male and female rats learned to associate three discrete auditory cues to three distinct outcomes: reward, punishment, or no outcome within the same session. After learning, the reward and punishment cue-outcome contingencies were reversed, and subsequently re-reversed. As expected, the dopamine population rapidly adapted to learning and contingency reversals by increasing the response to appetitive stimuli and decreasing the response to aversive stimuli. In contrast, the GABA population increased activity to all sensory events regardless of valence, including the neutral cue. Reversing learned contingencies selectively influenced GABA responses to the reward-predictive cue, prolonging increased activity within and across sessions. The observed valence-specific dissociations in the directionality and temporal progression of VTA dopamine and GABA calcium activity indicates that these populations are independently recruited and serve distinct roles during appetitive and aversive associative learning and contingency reversal.

Peripheral dopamine suppression and elevated cystatin C in early diabetic nephropathy in spontaneously diabetic rats.

Intrarenal dopamine plays a protective role against the development of diabetic nephropathy during the early stages of the disease. In streptozotocin-induced diabetic mice with renal-specific catechol-O-methyl transferase knockout, intrarenal dopamine was found to suppress glomerular hyperfiltration, reduce oxidative stress and inflammation, and inhibit fibrosis. However, although dopamine activation in streptozotocin-induced diabetic models has been shown to provide renal protection, the role of dopamine in models of naturally induced diabetes mellitus is still unclear. In the present study, we orally administered 10 mg/kg benserazide, a peripheral decarboxylase inhibitor, to spontaneously diabetic Torii rats daily to investigate the activation of the renal dopaminergic system during the progression of diabetic nephropathy. Our findings show that peripheral dopamine decreased urinary 8-iso-prostaglandin F2α and suppressed increases in plasma cystatin C levels. This study demonstrates that a reduction in peripheral dopamine can exacerbate renal dysfunction, even in the early stages of diabetic nephropathy characterized by glomerular hyperfiltration, thereby clarifying the pivotal role of endogenous peripheral dopamine in modulating oxidative stress and kidney performance.NEW & NOTEWORTHY By administering a peripheral decarboxylase inhibitor, we revealed that peripheral dopamine inhibits both the increase in urinary 8-iso-prostaglandin F2α, an oxidative stress marker, and the increase in plasma cystatin C, an early renal dysfunction marker, even in the early stages of diabetic nephropathy characterized by glomerular hyperfiltration. By visualizing renal dopamine precursor distribution, we highlighted the role of endogenous renal dopamine in oxidative stress and renal function following the onset of glomerular hyperfiltration.

Microdialysis perfusion of COA-Cl enhances dopamine metabolism in the dorsal striatum of freely moving mice.

We performed a microdialysis study to examine the effects of local perfusion of COA‑Cl on the extracellular levels of dopamine (DA) and its metabolites in the dorsal striatum of mice in vivo. The mice were perfused with Ringer's solution (control) and COA‑Cl (0.05, 0.1, or 0.5 mM) into the dorsal striatum. Dialysate samples were collected every 30 min and then analyzed using high‑performance liquid chromatography coupled with an electrochemical detector. We found that local perfusion of COA‑Cl (0.1 or 0.5 mM) into the dorsal striatum of living mice produced a significant and dose‑dependent increase in extracellular levels of DA, 3‑methoxytyramine (3‑MT), and homovanillic acid (HVA), where only 0.5 mM COA‑Cl increased dihydroxyphenylacetic acid (DOPAC) levels. However, 0.05 mM of COA‑Cl did not significantly affect either DA levels or its metabolites. Then, we administered the monoamine oxidase (MAO) inhibitor clorgyline alone or in combination with COA‑Cl (0.1 mM) to test whether COA‑Cl‑induced increases in DOPAC and HVA are mediated by increased MAO activity. Clorgyline alone increased 3‑MT levels and decreased DOPAC and HVA levels but not DA levels. When combined with COA‑Cl, clorgyline increased 3‑MT levels and reversed the decrease in DOPAC and HVA levels caused by clorgyline. The increase in DA metabolism induced by COA‑Cl suggests that some DA was further metabolized into DOPAC, 3‑MT, and HVA. This indicates that COA‑Cl plays a role in DA metabolism via increased DA release and/or activation of MAO, offering new insights into the effects of COA‑Cl on DA metabolism in the brain.

Ventral tegmental area dopamine neural activity switches simultaneously with rule representations in the prefrontal cortex and hippocampus.

This study examines neural activity in mammalian brain networks that support the ability to respond flexibly to changing contexts. We use a rule-switching spatial task to examine whether the key reward-responsive and predictive dopamine (DA) activity changes in coordination with changes in rule representations in key cognitive regions, the prefrontal cortex (PFC) and hippocampus. We first established distinct rule representations in PFC and hippocampus, and predictive coding of reward outcomes by DA neuronal activity. We show that the rule-specific DA reward prediction after a rule switch develops in temporal coordination with changes in rule representations especially in PFC, eventually leading to behavioral changes. These results thus provide an integrated understanding of reward prediction, cognitive representations of rules and behavioral adaptation.

Orphan receptor-GPR52 inverse agonist efficacy in ameliorating chronic stress-related deficits in reward motivation and phasic accumbal dopamine activity in mice

Reward processing dysfunctions e.g., anhedonia, apathy, are common in stress-related neuropsychiatric disorders including depression and schizophrenia, and there are currently no established therapies. One potential therapeutic approach is restoration of reward anticipation during appetitive behavior, deficits in which co-occur with attenuated nucleus accumbens (NAc) activity, possibly due to NAc inhibition of mesolimbic dopamine (DA) signaling. Targeting NAc regulation of ventral tegmental area (VTA) DA neuron responsiveness to reward cues could involve either the direct or indirect—via ventral pallidium (VP)—pathways. One candidate is the orphan G protein-coupled receptor GPR52, expressed by DA receptor 2 NAc neurons that project to VP. In mouse brain-slice preparations, GPR52 inverse agonist (GPR52-IA) attenuated evoked inhibitory postsynaptic currents at NAc-VP neurons, which could disinhibit VTA DA neurons. A mouse model in which chronic social stress leads to reduced reward learning and effortful motivation was applied to investigate GPR52-IA behavioral effects. Control and chronically stressed mice underwent a discriminative learning test of tone-appetitive behavior-sucrose reinforcement: stress reduced appetitive responding and discriminative learning, and these anticipatory behaviors were dose-dependently reinstated by GPR52-IA. The same mice then underwent an effortful motivation test of operant behavior-tone-sucrose reinforcement: stress reduced effortful motivation and GPR52-IA dose-dependently restored it. In a new cohort, GRABDA-sensor fibre photometry was used to measure NAc DA activity during the motivation test: in stressed mice, reduced motivation co-occurred with attenuated NAc DA activity specifically to the tone that signaled reinforcement of effortful behavior, and GPR52-IA ameliorated both deficits. These findings: (1) Demonstrate preclinical efficacy of GPR52 inverse agonism for stress-related deficits in reward anticipation during appetitive behavior. (2) Suggest that GPR52-dependent disinhibition of the NAc-VP-VTA-NAc circuit, leading to increased phasic NAc DA signaling of earned incentive stimuli, could account for these clinically relevant effects.

Reward system neurodynamics during menstrual pain modulated by COMT Val158Met polymorphisms.

Primary dysmenorrhea (PDM), characterized by cyclic pain, may involve pain modulation within the reward system (RS). The Catechol-O-methyltransferase (COMT) Val158Met polymorphism, which significantly influences dopamine activity, is linked to the regulation of both acute and chronic pain. This study examines the differential neurodynamic modulation in the RS associated with COMT Val158Met polymorphisms during menstrual pain among PDM subjects. Ninety-one PDM subjects underwent resting-state fMRI during menstruation and were genotyped for COMT Val158Met polymorphisms. The amplitude of low-frequency fluctuation (ALFF) and functional connectivity (FC) analyses were used to assess the RS response. Psychological evaluations included the McGill Pain Questionnaire, Pain Catastrophizing Scale, Beck Anxiety Inventory, and Beck Depression Inventory. Val/Val homozygotes (n = 50) and Met carriers (n = 41) showed no significant differences in McGill Pain Questionnaire, Beck Anxiety Inventory, and Beck Depression Inventory. However, Met carriers exhibited lower scores on the Pain Catastrophizing Scale. Distinct FC patterns was observed between Val/Val homozygotes and Met carriers, specifically between the nucleus accumbens (NAc) and prefrontal cortex, NAc and inferior parietal lobe, ventral tegmental area (VTA) and prefrontal cortex, VTA and precentral gyrus, and VTA and superior parietal lobe. Only Met carriers showed significant correlations between ALFF and FC values of the NAc and VTA with pain-related metrics (McGill Pain Questionnaire and Pain Catastrophizing Scale scores). NAc ALFF and NAc-prefrontal cortex FC values positively correlated with pain-related metrics, while VTA ALFF and VTA-prefrontal cortex and VTA-superior parietal lobe FC values negatively correlated with pain-related metrics. This study reveals that the COMT Val158Met polymorphism results in genotype-specific functional changes in the brain's RS during menstrual pain. In Met carriers, engagement of these regions is potentially linked to motivational reward-seeking and top-down modulation. This polymorphism likely influences the RS's responses, significantly contributing to individual differences in pain regulation.

Amperometric Determination of Dopamine and Ascorbic Acid with a Carbon Paste‐Yttrium Oxide Electrode

AbstractThis report presents a new application for yttrium oxide (YOX) in the modification of carbon paste electrodes with excellent electroactivity for the independent detection of dopamine (DA) and ascorbic acid (AA). The surface of the YOX‐modified electrode was characterized with SEM and EDS. The electroactive properties of DP and AA were studied with cyclic voltammetry (CV), square wave voltammetry (SWV) and amperometry (Am). The activity of DA and AA increased by more than 100 % when YOX/CPE was used, which allowed us to obtain detection limits of 0.04 and 0.06 μmol/L for DA and AA, respectively. The usefulness of YOX/CPE was tested with real human urine, fresh orange juice and vitamin C tablets, and the results were acceptable.

Kappa opioid receptor availability predicts severity of anhedonia in schizophrenia.

The kappa opioid receptor (KOR) and its endogenous agonist dynorphin have been implicated in multiple psychiatric conditions including psychotic disorders. We tested the hypotheses that kappa expression is elevated and associated with psychotic symptoms in schizophrenia. We measured kappa expression in unmedicated patients with schizophrenia (7 female, 6 male) and matched controls (7 female, 6 male) with positron emission tomography (PET). We also acquired a measurement of cumulative dopamine activity over the life span in the same subjects using neuromelanin sensitive MRI. We hypothesized that neuromelanin accumulation would be higher in patients than controls and that in patients there would be a positive association between KOR availability and neuromelanin accumulation. Fourteen patients and thirteen controls were enrolled. Whole brain dynamic PET imaging data using the KOR selective tracer [18F]LY245998 were acquired. Distribution volume (VT) was measured with region of interest analysis in 14 brain regions. Neuromelanin accumulation in midbrain dopaminergic nuclei was assessed in the same subjects. Positive and negative symptoms were measured by a clinical psychologist. We did not observe group level differences in KOR expression, neuromelanin accumulation or relationships of these to positive symptoms. Unexpectedly, we did observe strong positive associations between KOR expression and symptoms of anhedonia in the patients (Pearson r > 0.7, uncorrected p < 0.01 in 8 cortical brain regions). We also observed moderate associations between KOR expression and neuromelanin levels in patients. In conclusion, we did not observe a relationship between kappa and symptoms of psychosis but the observed relationship to the negative symptom of anhedonia is in line with recent work testing kappa antagonism as a therapy for anhedonia in depression.

Dopamine and Norepinephrine Differentially Mediate the Exploration-Exploitation Tradeoff.

Dopamine (DA) and norepinephrine (NE) have been repeatedly implicated in neuropsychiatric vulnerability, in part via their roles in mediating the decision-making processes. Although two neuromodulators share a synthesis pathway and are coactivated under states of arousal, they engage in distinct circuits and modulatory roles. However, the specific role of each neuromodulator in decision-making, in particular the exploration-exploitation tradeoff, remains unclear. Revealing how each neuromodulator contributes to exploration-exploitation tradeoff is important in guiding mechanistic hypotheses emerging from computational psychiatric approaches. To understand the differences and overlaps of the roles of these two catecholamine systems in regulating exploration, a direct comparison using the same dynamic decision-making task is needed. Here, we ran male and female mice in a restless two-armed bandit task, which encourages both exploration and exploitation. We systemically administered a nonselective DA antagonist (flupenthixol), a nonselective DA agonist (apomorphine), a NE beta-receptor antagonist (propranolol), and a NE beta-receptor agonist (isoproterenol) and examined changes in exploration within subjects across sessions. We found a bidirectional modulatory effect of dopamine on exploration. Increasing dopamine activity decreased exploration and decreasing dopamine activity increased exploration. The modulatory effect of beta-noradrenergic receptor activity on exploration was mediated by sex. Reinforcement learning model parameters suggested that dopamine modulation affected exploration via decision noise and norepinephrine modulation affected exploration via sensitivity to outcome. Together, these findings suggested that the mechanisms that govern the exploration-exploitation transition are sensitive to changes in both catecholamine functions and revealed differential roles for NE and DA in mediating exploration.

Opioid-environment interaction: Contrasting effects of morphine administered in a novel versus familiar environment on acute and repeated morphine induced behavioral effects and on acute morphine ERK activation in reward associated brain areas

We report that environmental context can have a major impact on morphine locomotor behavior and ERK effects. We manipulated environmental context in terms of an environmental novelty/ familiarity dimension and measured morphine behavioral effects in both acute and chronic morphine treatment protocols. Wistar rats (n=7 per group) were injected with morphine 10 mg/kg or vehicle (s.c.), and immediately placed into an arena for 5 min, and locomotor activity was measured after one or 5 days. The morphine treatments were initiated either when the environment was novel or began after the rats had been familiarized with the arena by being given 5 daily nondrug tests in the arena. The results showed that acute and chronic morphine effects were strongly modified by whether the environment was novel or familiar. Acute morphine administered in a novel environment increased ERK activity more substantially in several brain areas, particularly in reward-associated areas such as the VTA in comparison to when morphine was given in a familiar environment. Repeated morphine treatments initiated in a novel environment induced a strong locomotor sensitization, whereas repeated morphine treatments initiated in a familiar environment did not induce a locomotor stimulant effect but rather a drug discriminative stimulus dis-habituation effect. The marked differential effects of environmental novelty/familiarity and ongoing dopamine activity on acute and chronic morphine treatments may be of potential clinical relevance for opioid drug addiction.