Dopamine Response Research Articles

Circulating catecholamines, endothelin-1, and nitric oxide releases do not explain the preserved FMD following acute resistance exercise in strength-trained men.

Acute resistance exercise decreases endothelial function in sedentary individuals but not in strength-trained (ST) individuals. However, the underlying mechanism(s) of vascular protection in ST individuals remains unclear. Herein, we compared catecholamines, endothelin-1 (ET-1), and nitric oxide (NOx) releases after acute resistance exercise between sedentary and ST individuals. The untrained (UT) group comprised 12 male individuals with no regular training, while the ST group comprised 12 male individuals. Participants performed a session of resistance exercise, which consisted of 3 sets of 10 repetitions at 75% of one repetition maximum. Heart rate (HR) and blood pressure were measured during resistance exercise. Brachial artery flow-mediated dilation (FMD), blood pressure, HR, and blood collection were undertaken before and 10, 30, and 60 min after the resistance exercise. No significant difference was found in baseline brachial artery FMD between the groups (P > 0.05). Brachial artery FMD was significantly reduced in the UT group (P < 0.05) but it was prevented in the ST group after the resistance exercise. Significant differences were found at 10, 30, and 60 min after the resistance exercise in brachial artery ΔFMD from baseline between groups (P < 0.05). Blood pressure, HR, plasma epinephrine, norepinephrine, dopamine, serum endothelin-1, and plasma NOx responses did not differ between groups throughout the experimental period. In conclusion, preserved endothelial function in response to acute resistance exercise in ST male individuals is independent of catecholamines, ET-1, and NOx responses.

Effect of intermittent subchronic MK-801 administration on dopamine synthesis capacity and responsiveness in the prefrontal cortex.

The therapeutic potential of N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists, particularly ketamine, in mood disorders, is linked to their modulation of dopamine dynamics in the medial prefrontal cortex (mPFC). However, conflicting effects of distinct NMDAR antagonists, like ketamine and phencyclidine, on mPFC dopamine levels stem from variances in their receptor affinity profiles. This study investigates the impact of intermittent subchronic administration of an NMDAR antagonist on dopamine synthesis capacity and responsiveness within the mPFC, focusing on Dizocilpine (MK-801), a highly selective NMDAR antagonist. In vivo microdialysis and high-performance liquid chromatography assessed extracellular dopamine levels in the mPFC following subchronic MK-801 treatment. Locomotor activity was measured using a computed video tracking system. Intermittent subchronic MK-801 administration, followed by a 24-h withdrawal, preserved both dopamine synthesis capacity and responsiveness to MK-801 challenge in the mPFC. However, altered locomotor activity was observed, deviating from previous findings indicating impaired dopamine synthesis and responsiveness in the mPFC with twice-daily subchronic NMDAR antagonist treatment. These findings offer crucial biochemical insights into the diverse impacts of NMDAR antagonists on dopamine dynamics and the distinct therapeutic mechanisms associated with ketamine in depression treatment. However, further investigation is imperative to pinpoint potential inconsistencies stemming from variances in drug type, dosage, or administration frequency.

Phasic dopamine signals are reduced in the spontaneously hypertensive rat and increased by methylphenidate.

The spontaneously hypertensive rat (SHR) is a selectively bred animal strain that is frequently used to model attention-deficit hyperactivity disorder (ADHD) because of certain genetically determined behavioural characteristics. To test the hypothesis that the characteristically altered response to positive reinforcement in SHRs may be due to altered phasic dopamine response to reward, we measured phasic dopamine signals in the SHRs and Sprague Dawley (SD) rats using in vivo fast-scan cyclic voltammetry. The effects of the dopamine reuptake inhibitor, methylphenidate, on these signals were also studied. Phasic dopamine signals during the pairing of a sensory cue with electrical stimulation of midbrain dopamine neurons were significantly smaller in the SHRs than in the SD rats. Over repeated pairings, the dopamine response to the sensory cue increased, whereas the response to the electrical stimulation of dopamine neurons decreased, similarly in both strains. However, the final amplitude of the response to the sensory cue after pairing was significantly smaller in SHRs than in the SD rats. Methylphenidate increased responses to sensory cues to a significantly greater extent in the SHRs than in the SD rats, due largely to differences in the low dose effect. At a higher dose, methylphenidate increased responses to sensory cues and electrical stimulation similarly in SHRs and SD rats. The smaller dopamine responses may explain the reduced salience of reward-predicting cues previously reported in the SHR, whereas the action of methylphenidate on the cue response suggests a potential mechanism for the therapeutic effects of low-dose methylphenidate in ADHD.

Glutamate inputs send prediction error of reward, but not negative value of aversive stimuli, to dopamine neurons

Midbrain dopamine neurons are thought to signal reward prediction errors (RPEs), but the mechanisms underlying RPE computation, particularly the contributions of different neurotransmitters, remain poorly understood. Here, we used a genetically encoded glutamate sensor to examine the pattern of glutamate inputs to dopamine neurons in mice. We found that glutamate inputs exhibit virtually all of the characteristics of RPE rather than conveying a specific component of RPE computation, such as reward or expectation. Notably, whereas glutamate inputs were transiently inhibited by reward omission, they were excited by aversive stimuli. Opioid analgesics altered dopamine negative responses to aversive stimuli into more positive responses, whereas excitatory responses of glutamate inputs remained unchanged. Our findings uncover previously unknown synaptic mechanisms underlying RPE computations; dopamine responses are shaped by both synergistic and competitive interactions between glutamatergic and GABAergic inputs to dopamine neurons depending on valences, with competitive interactions playing a role in responses to aversive stimuli.

Distributional reinforcement learning in prefrontal cortex

The prefrontal cortex is crucial for learning and decision-making. Classic reinforcement learning (RL) theories center on learning the expectation of potential rewarding outcomes and explain a wealth of neural data in the prefrontal cortex. Distributional RL, on the other hand, learns the full distribution of rewarding outcomes and better explains dopamine responses. In the present study, we show that distributional RL also better explains macaque anterior cingulate cortex neuronal responses, suggesting that it is a common mechanism for reward-guided learning.

A perylene diimide electrochemical probe with persulfate as a signal enhancer for dopamine sensing.

Dopamine (DA) is an important biomarker related to parkinsonism, schizophrenia and renal disease. Traditional electrochemical sensors for DA were based on the direct electrochemical oxidation of DA. In this paper, we report a new sensing strategy using N,N'-di(trimethylaminoethyl)perylene diimide (TMPDI) as an electrochemical probe and K2S2O8 as a signal enhancer for DA detection between 0 and -0.7 V with the DPV technique. MoS2 nanoflowers prepared by the hydrothermal method were used as a nanocarrier to load TMPDI. The reduction current of TMPDI was found to show a stepwise and significant increase at -0.24 V with the increase of concentration of K2S2O8 due to the continuous cycle of TMPDI molecules' electrochemical reduction and chemical oxidation. The presence of DA caused a large decrease of the reduction current of TMPDI due to the synergistic interaction of the competitive consumption of DA for K2S2O8 and the blocking effect of polyDA adhering to the electrode surface. The decreased current exhibited a linear response for DA from 10 pM to 100 μM with a detection limit of 4.1 pM and the proposed sensor showed high selectivity and excellent feasibility in human urine/serum sample detection.

Inactivation of ERK1/2 Signaling in Dopaminergic Neurons by Map Kinase Phosphatase MKP3 Regulates Dopamine Signaling and Motivation for Cocaine.

The mesolimbic dopamine system is a crucial component of reward and reinforcement processing, including the psychotropic effects of drugs of abuse such as cocaine. Drugs of abuse can activate intracellular signaling cascades that engender long-term molecular changes to brain reward circuitry, which can promote further drug use. However, gaps remain about how the activity of these signaling pathways, such as ERK1/2 signaling, can affect cocaine-induced neurochemical plasticity and cocaine-associated behaviors specifically within dopaminergic cells. To enable specific modulation of ERK1/2 signaling in dopaminergic neurons of the ventral tegmental area, we utilize a viral construct that Cre dependently expresses Map kinase phosphatase 3 (MKP3) to reduce the activity of ERK1/2, in combination with transgenic rats that express Cre in tyrosine hydroxylase (TH)-positive cells. Following viral transfection, we found an increase in the surface expression of the dopamine transporter (DAT), a protein associated with the regulation of dopamine signaling, dopamine transmission, and cocaine-associated behavior. We found that inactivation of ERK1/2 reduced post-translational phosphorylation of the DAT, attenuated the ability of cocaine to inhibit the DAT, and decreased motivation for cocaine without affecting associative learning as tested by conditioned place preference. Together, these results indicate that ERK1/2 signaling plays a critical role in shaping the dopamine response to cocaine and may provide additional insights into the function of dopaminergic neurons. Further, these findings lay important groundwork toward the assessment of how signaling pathways and their downstream effectors influence dopamine transmission and could ultimately provide therapeutic targets for treating cocaine use disorders.

Complex 33-beam simulated galactic cosmic radiation exposure impacts cognitive function and prefrontal cortex neurotransmitter networks in male mice

Astronauts will encounter extended exposure to galactic cosmic radiation (GCR) during deep space exploration, which could impair brain function. Here, we report that in male mice, acute or chronic GCR exposure did not modify reward sensitivity but did adversely affect attentional processes and increased reaction times. Potassium (K+)-stimulation in the prefrontal cortex (PFC) elevated dopamine (DA) but abolished temporal DA responsiveness after acute and chronic GCR exposure. Unlike acute GCR, chronic GCR increased levels of all other neurotransmitters, with differences evident between groups after higher K+-stimulation. Correlational and machine learning analysis showed that acute and chronic GCR exposure differentially reorganized the connection strength and causation of DA and other PFC neurotransmitter networks compared to controls which may explain space radiation-induced neurocognitive deficits.

Differential patterns of basal and naloxone-evoked dopamine efflux in the rat dorsal and ventral striatum following prolonged-intermittent exposure to morphine.

Hypodopaminergia in the ventral striatum is a putative neurobiological correlate of withdrawal in opioid-dependent individuals. This perspective stands in contrast to brain imaging studies with chronic opioid users showing that naloxone-enhanced dopamine (DA) release in the dorsal striatum is positively correlated with withdrawal aversion. Here, we examined regional differences in striatal DA function associated with opioid withdrawal in rats exposed to intermittent morphine injections for 31 days. Basal concentrations of DA were reduced (i.e., indicating a hypodopaminergic state) in the ventral striatum on Day 10 of morphine exposure, whereas a more prolonged period of morphine treatment was required to reveal hypodopaminergia in the dorsal striatum on Day 31. The ventral striatum consistently exhibited naloxone-induced transient reductions in DA below the hypodopaminergic basal levels, whereas morphine enhanced DA efflux. In the dorsal striatum, DA responsivity to naloxone shifted from a significant decrease on Day 10 to a notable increase above hypodopaminergic basal levels on Day 31, corroborating the findings in the human dorsal striatum. Unexpectedly, the magnitude of morphine-evoked increases in DA efflux on Day 31 was significantly blunted relative to values on Day 10. These findings indicate that prolonged-intermittent access to morphine results in a sustained hypodopaminergic state as reflected in basal levels in the striatum, which is accompanied by regional differences in DA responsivity to naloxone and morphine. Overall, our findings suggest that prolonging the duration of morphine exposure to 31 days is sufficient to reveal neuroadaptations that may underlie the transition from initial drug exposure to opioid dependence.

Simultaneous determination of dopamine and uric acid based on electrocatalytic oxidation of Cu2O-Au and polyaniline nanocomposites

Effective detection of dopamine (DA) and uric acid (UA) has significant diagnostic values, while the analytical methods with high convenience, distinguishability and sensitivity still need to be developed. A highly sensitive and selective electrochemical sensor based on a polyaniline (PANI) nanocomposite embedding Au and Cu2O hybrid (PANI/Cu2O-Aux) with adjustable proportions of Cu2O and Au was developed for simultaneous detection of dopamine (DA) and uric acid (UA) in the presence of high concentrations of ascorbic acid (AA) and other interferents. The Cu2O-Aux architecture improved the electrocatalytic activity by inducing a modifiable synergistic effect between Au and Cu2O. Differential pulse voltammetry (DPV) responses of DA and UA on modified electrodes of PANI/Cu2O-Aux showed remarkable enhancement compared to the single-component Au or Cu2O-decorated PANI. The optimal ratio of Cu2O: Au was 1:1, which gave the highest redox signals for DA and UA. The DPV response ranges of simultaneous detection were 0.01–200 μM for DA and 0.1–1000 μM for UA, with detection limits (S/N = 3) of 0.0076 μM and 0.035 μM, respectively. The sensor also exhibited excellent anti-interference and stability, and was successfully applied to measure DA and UA in human urine samples with high accuracy. This research demonstrates the tunability of catalytic properties in PANI/Cu2O-Aux nanocomposites by the integration of binary nanocatalysts, providing insights into both structural and practical aspects.

Amphetamine-induced dopamine release in rat: Whole-brain spatiotemporal analysis with [11C]raclopride and positron emission tomography.

Whole-brain mapping of drug effects are needed to understand the neural underpinnings of drug-related behaviors. Amphetamine administration is associated with robust increases in striatal dopamine (DA) release. Dopaminergic terminals are, however, present across several associative brain regions, which may contribute to behavioral effects of amphetamine. Yet the assessment of DA release has been restricted to a few brain regions of interest. The present work employed positron emission tomography (PET) with [11C]raclopride to investigate regional and temporal characteristics of amphetamine-induced DA release across twenty sessions in adult female Sprague Dawley rats. Amphetamine was injected intravenously (2 mg/kg) to cause displacement of [11C]raclopride binding from DA D2-like receptors, assessed using temporally sensitive pharmacokinetic PET model (lp-ntPET). We show amphetamine-induced [11C]raclopride displacement in the basal ganglia, and no changes following saline injections. Peak occupancy was highest in nucleus accumbens, followed by caudate-putamen and globus pallidus. Importantly, significant amphetamine-induced displacement was also observed in several extrastriatal regions, and specifically in thalamus, insula, orbitofrontal cortex, and secondary somatosensory area. For these, peak occupancy occurred later and was lower as compared to the striatum. Collectively, these findings demonstrate distinct amphetamine-induced DA responses across the brain, and that [11C]raclopride-PET can be employed to detect such spatiotemporal differences.

Dopaminergic error signals retune to social feedback during courtship.

Hunger, thirst, loneliness and ambition determine the reward value of food, water, social interaction and performance outcome1. Dopamine neurons respond to rewards meeting these diverse needs2-8, but it remains unclear how behaviour and dopamine signals change as priorities change with new opportunities in the environment. One possibility is that dopamine signals for distinct drives are routed to distinct dopamine pathways9,10. Another possibility is that dopamine signals in a given pathway are dynamically tuned to rewards set by the current priority. Here we used electrophysiology and fibre photometry to test how dopamine signals associated with quenching thirst, singing a good song and courting a mate change as male zebra finches (Taeniopygia guttata) were provided with opportunities to retrieve water, evaluate song performance or court a female. When alone, water reward signals were observed in two mesostriatal pathways but singing-related performance error signals were routed to Area X, a striatal nucleus specialized for singing. When courting a female, water seeking was reduced and dopamine responses to both water and song performance outcomes diminished. Instead, dopamine signals in Area X were driven by female calls timed with the courtship song. Thus the dopamine system handled coexisting drives by routing vocal performance and social feedback signals to a striatal area for communication and by flexibly re-tuning to rewards set by the prioritized drive.

Distinct sub-second dopamine signaling in dorsolateral striatum measured by a genetically-encoded fluorescent sensor

The development of genetically encoded dopamine sensors such as dLight has provided a new approach to measuring slow and fast dopamine dynamics both in brain slices and in vivo, possibly enabling dopamine measurements in areas like the dorsolateral striatum (DLS) where previously such recordings with fast-scan cyclic voltammetry (FSCV) were difficult. To test this, we first evaluated dLight photometry in mouse brain slices with simultaneous FSCV and found that both techniques yielded comparable results, but notable differences in responses to dopamine transporter inhibitors, including cocaine. We then used in vivo fiber photometry with dLight in mice to examine responses to cocaine in DLS. We also compared dopamine responses during Pavlovian conditioning across the striatum. We show that dopamine increases were readily detectable in DLS and describe transient dopamine kinetics, as well as slowly developing signals during conditioning. Overall, our findings indicate that dLight photometry is well suited to measuring dopamine dynamics in DLS.

Salt-induced nanoporous gold electrodes: One-step scalable fabrication of high-performance flexible electrochemical sensors from gold nanoparticles

Here, a simple filtration method for the fabrication of salt-induced nanoporous gold electrodes (SINPGEs) from gold nanoparticles (AuNPs) is reported. This method employs sodium chloride (NaCl) to trigger the aggregation, room-temperature sintering and region-selective deposition of AuNPs on patterned polyvinylidene fluoride (PVDF) membranes during filtration, which enables the one-step scalable fabrication of flexible SINPGEs three-electrode arrays with high conductivity, good mechanical property, large surface area and extremely low cost. Moreover, compared with traditional gold disc electrodes, the nanoporous structure of SINPGEs was demonstrated to apparently improve the electrochemical responses of various electroactive species, e.g., dopamine (DA), uric acid (UA), ascorbic acid (AA) and hydrogen peroxide (H2O2), reflected by the apparent enlargement of redox currents. In addition, the passivation effect of chloride ions (Cl−) on the oxidation of H2O2 at SINPGEs can be greatly repressed by a simple electrochemical activation approach, producing a sensitive H2O2 sensor with a calibration range of 1.0–1000 μM in the presence of 0.1 M Cl−. The present work thus establishes a new approach to the scalable construction of gold electrode-based electrochemical sensors with high performance and low cost.

Ultrasensitive and selective electrochemical sensor for nanomolar dopamine determination based on MnS/Co3S4 hybrids embedded on electrochemically reduced graphene oxide

An ultrasensitive and selective electrochemical sensor has been constructed for the quantitative assay of dopamine (DA) based on hollow tubular manganese-cobalt sulfide (MnS/Co3S4) hybrids embedded on electrochemically reduced graphene oxide (ErGO). The MnS/Co3S4 heterostructures were created by two-step ion exchange method, of which Co9S8 with hollow tubular structures was fabricated by solvothermal method using the self-made cobalt chloride carbonate hydroxide (CO(CO3)0.35Cl0.20(OH)1.10) as precursor and sodium disulfide monohydrate as sulfur source and manganese chloride as manganese source. The MnS/Co3S4-ErGO/GCE could exhibit strong catalytic ability for the redox reaction of DA. Under the optimal conditions, the developed sensor exhibits a wide linear response for DA ranging from 6.0 nM to 20.0 μM by second-order derivative linear sweep voltammetry (SDLSV), with a detection limit of 2.0 nM. In addition, the developed method exhibited high sensitivity and selectivity, good reproducibility and low-cost. It is a very promising analytical method for the determination of DA in pharmaceutical and biological samples.

Effect of temporal interference electrical stimulation on phasic dopamine release in the striatum

BackgroundTemporal interference stimulation (TIS) is a neuromodulation technique that could stimulate deep brain regions by inducing interfering electrical signals based on high-frequency electrical stimulations of multiple electrode pairs from outside the brain. Despite numerous TIS studies, however, there has been limited investigation into the neurochemical effects of TIS. ObjectiveWe performed two experiments to investigate the effect of TIS on the medial forebrain bundle (MFB)-evoked phasic dopamine (DA) response. MethodsIn the first experiment, we applied TIS next to a carbon fiber microelectrode (CFM) to examine the modulation of the MFB-evoked phasic DA response in the striatum (STr). Beat frequencies and intensities of TIS were 0, 2, 6, 10, 20, 60, 130 Hz and 0, 100, 200, 300, 400, 500 μA. In the second experiment, we examined the effect of TIS with a 2 Hz beat frequency (based on the first experiment) on MFB-evoked phasic DA release when applied above the cortex (with a simulation-based stimulation site targeting the striatum). We employed 0 Hz and 2 Hz beat frequencies and a control condition without stimulation. ResultsIn the first experiment, TIS with a beat frequency of 2 Hz and an intensity of 400 μA or greater decreased MFB-evoked phasic DA release by roughly 40%, which continued until the experiment's end. In contrast, TIS at beat frequencies other than 2 Hz and intensities less than 400 μA did not affect MFB-evoked phasic DA release. In the second experiment, TIS with a 2 Hz beat frequency decreased only the MFB-evoked phasic DA response, but the reduction in DA release was not sustained. ConclusionsSTr-applied and cortex-applied TIS with delta frequency dampens evoked phasic DA release in the STr. These findings demonstrate that TIS could influence the neurochemical modulation of the brain.

Abstract P395: Clozapine Treatment For Schizophrenia May Cause Salt-sensitive Hypertension By Reducing The Expression Of The Renal Dopamine D4 Receptor

Clozapine (CLZ) is the most effective antipsychotic for treatment-resistant schizophrenia which affects approximately 24 million people worldwide. Schizophrenics are 3-4 times more likely to die from cardiovascular disease due to increased incidence of hypertension. CLZ is a high affinity antagonist for the dopamine type 4 receptor (D 4 R). Studies have shown that germline deletion of D 4 R in mice caused hypertension, and CLZ administered subcutaneously in mice induced hypertension. Since the proximal tubule (PT) regulates about 75% of excreted Na + we cultured renal proximal tubule cells excreted in the urine (uRPTCs) from individuals treated with and without clozapine and previously found that CLZ decreased D 4 R recruitment to cell surface and increased reactive oxygen species in healthy controls (HC). Recently, western blot analysis showed D 4 R expression was reduced in CLZ treated patients (CLZ 0.85±0.08 n=12 vs HC 1.09±0.09 n=11, p&lt;0.05 t-test). The total D 4 R protein was also decreased under CLZ treatment in RPTCs from HC. This suggests that the reduction in D 4 R occurred in PTs when treated with CLZ in-vivo but this was a durable effect still measurable through the process of culturing the cells, and is replicated in-vitro using healthy control cells. In In-vivo CLZ treated patient cells, D 4 R expression is not further reduced when treated in-vitro. Moreover, the natriuretic dopamine D1 receptor (D 1 R) was significantly increased under ClZ treatment of uRPTCs from HC, but not RPTCs from CLZ treated patients (VEH 0.37±0.07 vs CLZ 0.5±0.08 n=11, p&lt;0.05 paired t-test; CLZ/VEH, HC 1.51±0.18 n=11 vs CLZ 0.99±0.01 n=12, p&lt;0.05 t-test). Interestingly, high salt (HS) treatment on these uRPTCs showed a similar trend with CLZ treatment (VEH 0.33±0.06 vs CLZ 0.47±0.08, n=10, p&lt;0.05 paired t-test; HS/VEH, HC 1.55±0.29 n=11 vs CLZ 0.99±0.01 n=12, p&lt;0.05 t-test), indicating these CLZ treated patients may have a blunted dopamine response to excess sodium and therefore develop salt sensitive hypertension. In Summary, CLZ induced hypertension in these schizophrenia patients may be caused by a disrupted dopaminergic system. Further investigations also need to be done including response of sodium transporters and modulation of the renin-angiotensin system.

Inhibition of STAT-mediated cytokine responses to chemically-induced colitis prevents inflammation-associated neurobehavioral impairments

Depression can be associated with chronic systemic inflammation, and production of peripheral proinflammatory cytokines and upregulation of the kynurenine pathway have been implicated in pathogenesis of depression. However, the mechanistic bases for these comorbidities are not yet well understood. As tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO), which convert tryptophan to kynurenine, are rate-limiting enzymes of the kynurenine pathway, we screened TDO or IDO inhibitors for effects on the production of proinflammatory cytokines in a mouse macrophage cell line. The TDO inhibitor 680C91 attenuated LPS-induced pro-inflammatory cytokines including IL-1β and IL-6. Surprisingly, this effect was TDO-independent, as it occurred even in peritoneal macrophages from TDO knockout mice. Instead, the anti-inflammatory effects of 680C91 were mediated through the suppression of signal transducer and activator of transcription(STAT) signaling. Furthermore, 680C91 suppressed production of proinflammatory cytokines and STAT signaling in an animal model of inflammatory bowel disease. Specifically, 680C91 effectively attenuated acute phase colon cytokine responses in male mice subjected to dextran sulfate sodium (DSS)-induced colitis. Interestingly, this treatment also prevented the development of anxiodepressive-like neurobehaviors in DSS-treated mice during the recovery phase. The ability of 680C91 to prevent anxiodepressive-like behavior in response to chemically-induced colitis appeared to be due to rescue of attenuated dopamine responses in the nucleus accumbens. Thus, inhibition of STAT-mediated, but TDO-independent proinflammatory cytokines in macrophages can prevent inflammation-associated anxiety and depression. Identification of molecular mechanisms involved may facilitate the development of new treatments for gastrointestinal-neuropsychiatric comorbidity.

A mouse model of the 3-hit effects of stress: Genotype controls the effects of life adversities in females

Helplessness is a dysfunctional coping response to stressors associated with different psychiatric conditions. The present study tested the hypothesis that early and adult adversities cumulate to produce helplessness depending on the genotype (3-hit hypothesis of psychopathology). To this aim, we evaluated whether Chronic Unpredictable Stress (CUS) differently affected coping and mesoaccumbens dopamine (DA) responses to stress challenge by adult mice of the C57BL/6J (B6) and DBA/2J (D2) inbred strains depending on early life experience (Repeated Cross Fostering, RCF). Three weeks of CUS increased the helplessness expressed in the Forced Swimming Test (FST) and the Tail Suspension Test by RCF-exposed female mice of the D2 strain. Moreover, female D2 mice with both RCF and CUS experiences showed inhibition of the stress-induced extracellular DA outflow in the Nucleus Accumbens, as measured by in vivo microdialysis, during and after FST. RCF-exposed B6 mice, instead, showed reduced helplessness and increased mesoaccumbens DA release. The present results support genotype-dependent additive effects of early experiences and adult adversities on behavioral and neural responses to stress by female mice. To our knowledge, this is the first report of a 3-hit effect in an animal model. Finally, the comparative analyses of behavioral and neural phenotypes expressed by B6 and D2 mice suggest some translationally relevant hypotheses of genetic risk factors for psychiatric disorders.

Predictability of inter-regional cerebral perfusion similarity on dopamine responsiveness and the moderation role of cognition in PD patients

BackgroundLarge heterogeneity can be found in dopamine responsiveness of patients with Parkinson's disease (PD). Instantly and objectively understanding dopamine responsiveness of patients may help clinical practice. PurposeThis PD study explored the predictability of off-state inter-regional cerebral blood flow (CBF) perfusion similarity on patient's dopamine responsiveness and tested whether the predictive power could be moderated by patient's cognitive status. Materials and methodThe PD cohort with 192 patients (containing off state and on state (PD-off and PD-on)) and the normal control (NC) cohort with 92 subjects were included. The intra-individual CBF relative variation networks were constructed and compared between PD-off and PD-on, PD-off and NC to identify the alterations caused by dopamine depletion. Based on that, regression analysis of off-state inter-regional CBF perfusion similarity on patient's dopamine responsiveness was performed. Finally, moderation analysis was conducted to test the moderation role of cognition on the regression model. ResultsIn the PD-off cohort, a total of 82 edges in the network were identified that affected by dopamine depletion. Off-state inter-regional CBF perfusion similarity was found that had a significant influence on patient's dopamine responsiveness. Cognitive status was validated that positively moderated the relationship between off-state inter-regional CBF perfusion similarity and dopamine responsiveness. ConclusionDopamine responsiveness of PD patient could be predicted by off-state inter-regional CBF perfusion similarity. Patient's cognitive status might have a positive moderation effect on his/her dopamine responsiveness.