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In response to climate change, governments around the world have committed to reducing greenhouse gas emissions, which contribute to global warming, through the energy transition from fossil fuels to renewable energy sources and electrification of transportation. This article outlines the design procedure for the electrification of a railway vehicle used for maintenance services on the rail network. The proposed methodology consists of the design of both an all-electric propulsion system and storage system with the aim of zero emissions when the vehicle is operating in tunnels and to minimise noise during maintenance services in cities. After highlighting the characteristics of the railway vehicle under consideration, a simulation model of the propulsion and generation system was developed in order to calculate the energy consumption of the entire railway system. Finally, experimental tests carried out on the prototype proved the effectiveness of the design procedure adopted and the proposed mathematical model, showing a good matching with the simulated results.

GABAergic projections from the nucleus accumbens core to the dorsolateral ventral pallidum are necessary for drug-conditioned cues to initiate relapse-like drug seeking. Astrocytes in the ventral pallidum are situated perisynaptically and regulate GABA transmission through expression of GABA uptake transporters, but whether they are involved in regulating drug seeking is unknown. To determine the contribution of ventral pallidal astrocytes to heroin seeking, we labeled astrocytes in male and female rats with a membrane-bound fluorescent tag and used confocal microscopy to quantify astroglial expression of the GABA transporter GAT-3 and astrocyte synaptic proximity after withdrawal from heroin self-administration and during 15 min of cued heroin seeking. We found that GAT-3 was upregulated in rats that had extinguished heroin seeking, but not in animals that were withdrawn from heroin without extinction training or in rats that extinguished sucrose seeking. When GAT-3 upregulation was reversed using a vivo-morpholino oligo, heroin seeking was restored in the extinguished context and extinction of cued heroin seeking was disrupted compared to control animals. Although astrocyte synaptic proximity was not altered overall after heroin withdrawal, examination of astrocyte proximity to accumbens D1- or D2-expressing afferents revealed a selective increase in astrocyte proximity with D1-expressing terminals during extinction of heroin self-administration. Experimentally-induced reduction of astrocyte synaptic proximity through knockdown of the astrocyte-selective actin-binding protein ezrin also markedly disrupted extinction of heroin seeking. Notably, GAT-3 or ezrin knockdown had no impact on context- or cue-induced seeking in sucrose-trained animals. These data show that astrocytes in the ventral pallidum undergo plasticity after extinction of heroin use that reduces seeking and highlight the importance of astrocyte-neuron interactions in shaping behaviors associated with opioid use disorder.

Antipsychotic-induced dopamine supersensitivity, or behavioral supersensitivity, is a problematic consequence of long-term antipsychotic treatment characterized by the emergence of motor abnormalities, refractory symptoms, and rebound psychosis. The underlying mechanisms are unclear and no approaches exist to prevent or reverse these unwanted effects of antipsychotic treatment. Here we demonstrate that behavioral supersensitivity stems from long-lasting pre, post and perisynaptic plasticity, including insertion of Ca2+-permeable AMPA receptors and loss of D2 receptor-dependent inhibitory postsynaptic currents (IPSCs) in D2 receptor-expressing medium spiny neurons (D2-MSNs) in the nucleus accumbens core (NAcore). The resulting hyperexcitability, prominent in a subpopulation of D2-MSNs (21%), caused locomotor sensitization to cocaine and was associated with behavioral endophenotypes of antipsychotic treatment resistance and substance use disorder, including disrupted extinction learning and augmented cue-induced cocaine-seeking behavior. Chemogenetic restoration of IPSCs in D2-MSNs in the NAcore was sufficient to prevent antipsychotic-induced supersensitivity, pointing to an entirely novel therapeutic direction for overcoming this condition.

Background: Cocaine affects not only the central nervous system but also systemic immunity. The role of cocaine in gut mucosal integrity is not fully understood. Methods: Here we evaluated the effect of cocaine use on gut endothelial permeability and system inflammation in rats that self-administered cocaine or saline and humans using immunohistochemistry, qPCR, ELISA, and Transepithelial/transendothelial electrical resistance (TEER). Results: Cocaine administration maintained intact and undisturbed intestinal mucosal structures, increased tight junction claudin 1 and 2 mRNA expression, and decreased plasma TNF-α levels, compared to the control group, at the end of the study in rats. Further, cocaine treatment decreased gut endothelial permeability in a dose-dependent manner in human epithelial Caco-2 cells in vitro. Consistently, chronic cocaine users exhibited decreased plasma levels of TNF-α compared with non-drug users in vivo. However, plasma IL-6 levels were similar between cocaine use and control groups both in humans and rats in vivo. Conclusions: Our results from both human and rat studies in vivo and in vitro suggest that cocaine use may exert a protective effect on the integrity of gut mucosa and suppresses plasma TNF-α levels. This study may provide information on some beneficial effects of cocaine use on gut endothelial cells integrity and systemic inflammation.

With the upcoming launch of large constellations of satellites in the low-Earth orbit (LEO) region it will become important to organize the physical space occupied by the different operating satellites in order to minimize critical conjunctions and avoid collisions. Here, we introduce the definition of space occupancy as the domain occupied by an individual satellite as it moves along its nominal orbit under the effects of environmental perturbations throughout a given interval of time. After showing that space occupancy for the zonal problem is intimately linked to the concept of frozen orbits and proper eccentricity, we provide frozen-orbit initial conditions in osculating element space and obtain the frozen-orbit polar equation to describe the space occupancy region in closed analytical form. We then analyze the problem of minimizing space occupancy in a realistic model including tesseral harmonics, third-body perturbations, solar radiation pressure, and drag. The corresponding initial conditions, leading to what we call minimum space occupancy (MiSO) orbits, are obtained numerically for a set of representative configurations in LEO. The implications for the use of MiSO orbits to optimize the design of mega-constellations are discussed., Submitted to The Journal of Guidance, Control, and Dynamics

Background:The therapeutic effects of antipsychotic drugs (APDs) are mainly attributed to their postsynaptic inhibitory functions on the dopamine D2 receptor, which, however, cannot explain the delayed onset of full therapeutic efficacy. It was previously shown that APDs accumulate in presynaptic vesicles during chronic treatment and are released like neurotransmitters in an activity-dependent manner triggering an auto-inhibitory feedback mechanism. Although closely mirroring therapeutic action onset, the functional consequence of the APD accumulation process remained unclear.Aims:Here we tested whether the accumulation of the APD haloperidol (HAL) is required for full therapeutic action in psychotic-like rats.Methods:We designed a HAL analog compound (HAL-F), which lacks the accumulation property of HAL, but retains its postsynaptic inhibitory action on dopamine D2 receptors.Results/outcomes:By perfusing LysoTracker fluorophore-stained cultured hippocampal neurons, we confirmed the accumulation of HAL and the non-accumulation of HAL-F. In an amphetamine hypersensitization psychosis-like model in rats, we found that subchronic intracerebroventricularly delivered HAL (0.1 mg/kg/day), but not HAL-F (0.3–1.5 mg/kg/day), attenuates psychotic-like behavior in rats.Conclusions/interpretation:These findings suggest the presynaptic accumulation of HAL may serve as an essential prerequisite for its full antipsychotic action and may explain the time course of APD action. Targeting accumulation properties of APDs may, thus, become a new strategy to improve APD action.

Aim: This study examined whether the application of calcite-silicon mediated particle film (CaPF) at veraison can mitigate a drought-induced increase in leaf temperature on grapevine, thus contributing to improved leaf functionality, yield and grape composition traits.Methods and results: A total of 48 five-year-old Merlot (Vitis vinifera L.) vines grafted onto SO4 were grown (in 20 L PVC pots) under Mediterranean conditions (Southern Italy). The vines were pruned to a single spur with 3 winter buds irrigated daily to 100 % field capacity, and fertilised weekly.At veraison and using a 2×2 factorial experimental design, the two main factors, thermoregulation and water, were imposed at two levels: spraying with a thermoregulation compound (CaPF) and no spraying (NS); irrigation (WW) and drought stress (D)). A group of 24 vines was subjected to a 15-day drought period by receiving, every day, 25 % (D) of the daily water consumption of WW vines. The other 24 vines continued to be fully irrigated on a daily basis (WW). Twelve vines per group were sprayed (WW+CaPF, D+CaPF) with calcite-silicon mediate (3 % V/V) at the beginning of drought imposition, the remaining 24 vines were not sprayed (WW-NS, D-NS). Soil water moisture and stem water potential values were monitored from 11.30 to 13:30 nearly every week, and other vegetative and reproductive parameters were also measured.During the experiment, air temperature peaked at ≈35°C at midday, VPD at about 3.7 kPa and PAR reached ≈2000 µmol m-2 s–1. Results show that in CaPF sprayed vines, leaf-air temperature differences were lower than in unsprayed vines in both irrigated and drought stressed groups. WW+CaPF vines retained significantly more leaf area and showed the highest value of accumulated vine transpiration.Conclusion: Calcite-silicon mediated particle film could enhance the resilience of grapevine to adverse environmental conditions and may contribute to preserve terroir elements in highly reputed wine grape growing areas.Significance of the study: The study showed that foliar application of calcite silicon-mediated processed particles films can be used in arid regions to mitigate leaf temperatures in grapevines.

Uchiyama et al. provide a theoretical framework to explain the gap between reported gene–environment interactions and real-life epidemiological statistics. Through cultural evolution, informed behavioral approaches mitigate the impact of environmental risk on disease onset. Similarly, here we propose that fostering certain behavioral traits, transmitted culturally or through access to scientific knowledge, could confer resilience to mental illnesses such as schizophrenia.

Increase of frequency, duration, and intensity of drought and heatwave and related water and heat crops stress are among the principal effects of climate change. This paper reports: (i) the effect of calcite particle film (CaPF) as a mitigation strategy against heat stress in well-watered (WW) or in drought-stress (D) conditions; and (ii) response of leaf angle variation to stomatal conductance changes induced by drought stress of Aleatico grapevine cultivar. Results have showed that CaPF, under WW conditions, reduced leaf temperature, and increased gas exchange, but, under very severe water stress, CaPF treatment was ineffective. Leaf angle ranged from 70° (WW vines) to 100° (drought stressed vines) and showed a good fit (R2=0.81) with stomatal conductance within the range of 0.25 – 0.05 mol m-2s–1proving it might be a reliable proxy of vine water status.

The insulation system’s dielectric of the electric motor is very often subjected to severe electrical stress generated by the high dv/dt seen at the machine’s terminals. The electrical stress and high reflected wave transient overvoltage are even more evident in case of high-speed machines fed by high-frequency (HF) converters featuring very fast wide-bandgap devices. They are promoting the occurrence of partial discharges and consequently accelerate ageing. As this is serious issue and the main cause of the drive failure, it is important to analyse and characterise the surges at the motor terminals. Several HF models of motors have been proposed in the literature for this purpose. This article presents a survey on HF motor models, which is crucial in understanding and studying the most critical parameter identification and overvoltage mitigation techniques. Moreover, it offers a comparison of the models’ main features as well as a comparison with the experimental voltage waveform at motor terminals. A general overview of the partial discharge (PD) phenomenon is also provided, as it is favoured by HF operation and together with HF motor modelling provides key insights to the insulation ageing issue. In particular, an analysis of the effects of PWM waveform affecting insulation is given, as well as useful methods for developing strategies for the inspection and maintenance of winding insulation.

Background Little is known about chronic cannabis smoking-associated oral microbiome and its effects on central nervous system (CNS) functions. Methods In the current study, we have analyzed the saliva microbiome in individuals who chronically smoked cannabis with cannabis use disorder (n = 16) and in non-smoking controls (n = 27). The saliva microbiome was analyzed using microbial 16S rRNA sequencing. To investigate the function of cannabis use-associated oral microbiome, mice were orally inoculated with live Actinomyces meyeri, Actinomyces odontolyticus, or Neisseria elongata twice per week for six months, which mimicked human conditions. Findings We found that cannabis smoking in humans was associated with oral microbial dysbiosis. The most increased oral bacteria were Streptococcus and Actinomyces genus and the most decreased bacteria were Neisseria genus in chronic cannabis smokers compared to those in non-smokers. Among the distinct species bacteria in cannabis smokers, the enrichment of Actinomyces meyeri was inversely associated with the age of first cannabis smoking. Strikingly, oral exposure of Actinomyces meyeri, an oral pathobiont, but not the other two control bacteria, decreased global activity, increased macrophage infiltration, and increased β-amyloid 42 protein production in the mouse brains. Interpretation This is the first study to reveal that long-term oral cannabis exposure is associated oral enrichment of Actinomyces meyeri and its contributions to CNS abnormalities.

The purpose of this work is to build a model of diesel engine useful for studying new hybrid solutions for power generation. This kind of study is of significant interest particularly for the marine sector, due to recent limitations on fuel consumption and constraints imposed on the minimum powertrain efficiency. In this paper a variable-speed diesel generator model is presented. The model simulates both the dynamic behavior of the engine and the fuel consumption during the operating cycle. This model was developed using experimental results of bench tests conducted on the VL1716C2-MLL engine by Isotta Fraschini Motori (IFM) SpA. Diesel engine dynamics is based on the formulation found in the technical literature on mean value models and then adjusted through experimental data. Special attention was paid to developing the procedure to find the minimum specific fuel consumption for a given load. Initially, the presented resutls concern the correct response of the model under different load conditions. Then, the improvement in specific fuel consumption (obtained by adjusting the engine speed according to the load), in comparison with fixed speed operation, is shown.

Carbon (C) budget at cropping systems has not only agronomic but also environmental relevance because of their contribution to both emissions and removals of greenhouse gases (GHGs). Ideally, sustainable orchards are expected to remove atmospheric CO2 at a rate greater than that of the emissions because of (i) optimized biology of the system and (ii) reduced on-site/offsite inputs sourced by the technosphere. However, such a computation might produce inconsistent results and in turn biased communication on sustainability of the cropping systems because C accounting framework(s) are used under unclear context. This study examined the sustainability of orchards in terms of impact on GHGs focusing its significance at the field, ecosystem and global dimension analyzing some operational aspects and limitations of existing frameworks (e.g., net ecosystem carbon balance (NECB), life cycle assessment (LCA)). Global relevance of sustainable orchard was also discussed considering the C sequestration at cropland as instructed by Intergovernmental Panel on Climate Change (IPCC). The uniqueness of olive tree lifespan duration and C sequestration is discussed within the Product Environmental Footprint of agrifood product. The paper also highlighted overlapping components among the NECB, LCA and IPCC frameworks and the need for an integrated C accounting scheme for a more comprehensive and detailed mapping of sustainability in agriculture.

The reconstruction of atmospheric properties encountered during Mars entry trajectories is a crucial element of postflight mission analysis. This paper proposes a deep learning architecture using a long short-term memory (LSTM) network for the reconstruction of Martian density and wind profiles from inertial measurements and guidance commands. The LSTM is trained on a large set of Mars entry trajectories controlled through the fully numerical predictor-corrector entry guidance (FNPEG) algorithm, with density and wind from the Mars Global Reference Atmospheric Model (GRAM) 2010. The training of the network is examined, ensuring that the LSTM generalizes well to samples not present in the training set, and the performance of the network is assessed on a separate training set. The errors of the reconstructed density and wind profiles are, respectively, within 0.54 and 1.9%. Larger wind errors take place at high altitudes due to the decreased sensitivity of the trajectory in regions of low dynamic pressure. The LSTM architecture reliably reproduces the atmospheric density and wind encountered during descent.

GABAergic projections from the nucleus accumbens core to the dorsolateral ventral pallidum are necessary for drug-conditioned cues to initiate relapse-like drug seeking. Astrocytes in the ventral pallidum are situated perisynaptically and regulate GABA transmission through expression of GABA uptake transporters, but whether they are involved in regulating drug seeking is unknown. To determine the contribution of ventral pallidal astrocytes to heroin seeking, we labeled astrocytes in male and female rats with a membrane-bound fluorescent tag and used confocal microscopy to quantify astroglial expression of the GABA transporter GAT-3 and astrocyte synaptic proximity after withdrawal from heroin self-administration and during 15 min of cued heroin seeking. We found that GAT-3 was upregulated in rats that had extinguished heroin seeking, but not in animals that were withdrawn from heroin without extinction training or in rats that extinguished sucrose seeking. When GAT-3 upregulation was reversed using a vivo-morpholino oligo, heroin seeking was restored in the extinguished context and extinction of cued heroin seeking was disrupted compared to control animals. Although astrocyte synaptic proximity was not altered overall after heroin withdrawal, examination of astrocyte proximity to accumbens D1- or D2-expressing afferents revealed a selective increase in astrocyte proximity with D1-expressing terminals during extinction of heroin self-administration. Experimentally-induced reduction of astrocyte synaptic proximity through knockdown of the astrocyte-selective actin-binding protein ezrin also markedly disrupted extinction of heroin seeking. Notably, GAT-3 or ezrin knockdown had no impact on context- or cue-induced seeking in sucrose-trained animals. These data show that astrocytes in the ventral pallidum undergo plasticity after extinction of heroin use that reduces seeking and highlight the importance of astrocyte-neuron interactions in shaping behaviors associated with opioid use disorder.

Background Little is known about chronic cannabis smoking-associated oral microbiome and its effects on central nervous system (CNS) functions. Results In the current study, we have analyzed the saliva microbiome in individuals who chronically smoked cannabis with cannabis use disorder and in non-smoking controls. We found that cannabis smoking in humans was associated with oral microbial dysbiosis. The most increased oral bacteria were Streptococcus and Actinomyces genus and the most decreased bacteria were Neisseria genus in chronic cannabis smokers compared to those in non-smokers. To investigate the function of cannabis use-associated microbiome, mice were orally exposured to Actinomyces. meyeri, Actinomyces. odontolyticus, or Neisseria. elongate through oral gavage twice per week for six months which mimics human conditions. Strikingly, oral exposure of Actinomyces meyeri, an oral pathobiont, but not the other two control bactreria, decreased global activity and increased β-amyloid 42 protein production in the mouse brains. Conclusions This is the first study to reveal that cannabis-associated enrichment of Actinomyces meyeri may contribute to a hallmark of neuropathology.

Antipsychotic-induced behavioral supersensitivity is a problematic consequence of long-term treatment with antipsychotic drugs and is characterized by emergence of refractory symptoms and dyskinesias. The underlying mechanisms are unknown, and no rational approaches exist to prevent or reverse antipsychotic-induced supersensitivity. Here we describe major adaptations impacting populations of striatal medium spiny neurons (MSNs) during the development of behavioral supersensitivity and reveal a prominent role played by D2 receptor expressing MSNs. We show that enhanced D2-MSN activity underlies several symptoms spanning from psychostimulant sensitization, to antipsychotic treatment resistance and drug addiction. Our data warn against severe adverse events following antipsychotic treatment discontinuation and offer insight that may inform therapeutic approaches to overcome antipsychotic-induced supersensitivity.

Schizophrenia is a multi-dimensional disorder with a complex and mostly unknown etiology, leading to a severe decline in life quality. Antipsychotic drugs (APDs) remain beneficial interventions in the treatment of the disorder, but vary significantly in binding profile, clinical effects and adverse reactions. The present review summarizes the main principles of APD mechanisms of action with a particular focus on recent findings in APD accumulation and its role in the therapeutic efficacy and treatment failure. High and low doses of APDs were shown to be effective in different dimensions of antipsychotic-like behaviour in rodent models. Efficacy of the APDs correlates with high dopamine D2 receptor occupancy, which occurs quickly after drug administration. However, onset and peak of action are delayed up to several days or weeks. APD accumulation via acidic trapping in synaptic vesicles is considered to underlie the time course of APD action. Use-dependent exocytosis, co-release with dopamine and serotonin and inhibition of ion channels impact on the neuronal transmission and determine effects of APDs. Disruption in accumulating properties leads to diminished APD effects. In addition, long-term APD administration at therapeutic doses leads to treatment failure both in animal models and in humans. APD failure was associated with treatment induced neuroadaptations, including a decline in extracellular dopamine levels, dopamine transporter upregulation, and altered neuronal firing. However, enhanced synaptic vesicle release has also been reported. APD loss of efficacy may be reversed through inhibition of the dopamine transporter or switching the administration regimen from continuous to intermittent. Thus, manipulating the accumulation properties of APDs, changes in the administration regimen and doses, or co-administration with dopamine transporter inhibitors may be considered to yield benefits in the development of new effective strategies in the treatment of schizophrenia.

D2 receptor blockade has been cited as a principal mechanism of action of all antipsychotic medications, but is poorly predictive of symptom improvement or neurophysiological responses recorded using human brain imaging. A potential hurdle in interpreting such human imaging studies arises from the inability to distinguish activity within neuronal subcircuits. We used single cell resolution imaging to record activity in distinct populations of medium spiny neurons in vivo within the mouse ventral striatum, a structure associated with schizophrenia symptoms and antipsychotic therapeutic efficacy. While we expected the antipsychotic haloperidol to excite D2 receptor expressing neurons, we report a strong cellular depression mediated by the hypofunctional NMDA channel, which may be mediated in part by the action of haloperidol on the sigma1 receptor. Altogether, the impact of haloperidol on Ca2+ events in D2 receptor expressing neurons predicted psychomotor inhibition. Our results elucidate mechanisms by which antipsychotics act rapidly in the brain to impact psychomotor outputs.

Luna 3 (or Lunik 3 in Russian sources) was the first spacecraft to perform a flyby of the Moon. Launched in October 1959 on a translunar trajectory with large semimajor axis and eccentricity, it collided with the Earth in late March 1960. The short, 6-month dynamical lifetime has often been explained through an increase in eccentricity due to the Lidov–Kozai effect. However, the classical Lidov–Kozai solution is only valid in the limit of small semi-major axis ratio, a condition that is satisfied only for solar (but not for lunar) perturbations. We undertook a study of the dynamics of Luna 3 with the aim of assessing the principal mechanisms affecting its evolution. We analyze the Luna 3 trajectory by generating accurate osculating solutions, and by comparing them to integrations of singly and doubly averaged equations of motion in vectorial form. Lunar close encounters, which cannot be reproduced in an averaging approach, decisively affect the trajectory and break the doubly averaged dynamics. Solar perturbations induce oscillations of intermediate period that affect the geometry of the close encounters and cause the singly averaged and osculating inclinations to change quadrants (the orbital plane “flips”). We find that the peculiar evolution of Luna 3 can only be explained by taking into account lunar close encounters and intermediate-period terms; such terms are averaged out in the Lidov–Kozai solution, which is not adequate to describe translunar or cislunar trajectories. Understanding the limits of the Lidov–Kozai solution is of particular significance for the motion of objects in the Earth–Moon environment and of exoplanetary systems.

Introduction Many plants can modify their leaf profile rapidly in response to environmental stress. Image-based data are increasingly used to retrieve reliable information on plant water status in a non-contact manner that has the potential to be scaled to high-throughput and repeated through time. This paper examined the variation of leaf angle as measured by both 3D images and goniometer in progressively drought stressed grapevine. Grapevines, grown in pots, were subjected to a 21-day period of drought stress receiving 100% (CTRL), 60% (IRR60%) and 30% (IRR30%) of maximum soil available water capacity. Leaf angle was (i) measured manually (goniometer) and (ii) computed by a 3D reconstruction method (multi-view stereo and structure from motion). Stomatal conductance, leaf water potential, fluorescence (Fv/Fm), leaf area and 2D RGB data were simultaneously collected during drought imposition. Throughout the experiment values of leaf water potential ranged from -0.4 (CTRL) to -1.1 MPa (IRR30%) and it linearly influenced the leaf angle when measured manually (R2=0.86) and with 3D image (R2=0.73). Drought was negatively related to stomatal conductance and leaf area growth particularly in IRR30% while photosynthetic parameters (i.e. Fv/Fm) were not impaired by water restriction. A model for leaf area estimation based on the number of pixel of 2D RGB images developed at a different phenotyping robotized platform in a closely related experiment was successfully employed (R2=0.78). At the end of the experiment, top view 2D RGB images showed a approx. 50% reduction of greener fraction (GGF) in CTRL and IRR60% vines compared to initial values, while GGF in IRR30% increased by approx. 20%. The influence of juvenile dichromatism of leaf occurring for specific varieties on the determination of colour-based indexes has been discussed.

Antipsychotic drugs are effective interventions in schizophrenia. However, the efficacy of these agents often decreases over time, which leads to treatment failure and symptom recurrence. We report that antipsychotic efficacy in rat models declines in concert with extracellular striatal dopamine levels rather than insufficient dopamine D2 receptor occupancy. Antipsychotic efficacy was associated with a suppression of dopamine transporter activity, which was reversed during failure. Antipsychotic failure coincided with reduced dopamine neuron firing, which was not observed during antipsychotic efficacy. Synaptic field responses in dopamine target areas declined during antipsychotic efficacy and showed potentiation during failure. Antipsychotics blocked synaptic vesicle release during efficacy but enhanced this release during failure. We found that the pharmacological inhibition of the dopamine transporter rescued antipsychotic drug treatment outcomes, supporting the hypothesis that the dopamine transporter is a main target of antipsychotic drugs and predicting that dopamine transporter blockers may be an adjunct treatment to reverse antipsychotic treatment failure.

All antipsychotics bind to the dopamine D2 receptor. An “optimal” level of D2 receptor blockade with antipsychotics is thought to ameliorate the positive symptoms of schizophrenia. However, persistent D2 receptor blockade is associated with a deteriorating clinical response in a subset of patients. Interestingly, antipsychotics with a weaker D2 receptor binding profile appear somewhat superior in this respect. This evidence challenges the hypothesis that D2 receptor blockade is the sole mechanism of antipsychotic efficacy and points to consistent inter-individual responses to antipsychotic treatment. Here, we hypothesize that clinically effective doses of antipsychotics would lead to the formation of a D2 receptor “reserve” that is likely composed of presynaptic dopamine D2 autoreceptors. The majority of the remaining postsynaptic dopamine receptors are instead occupied by antipsychotics. Endogenous dopamine would then mainly interact with this D2 autoreceptor reserve, thereby reducing the presynaptic synthesis and release of dopamine and resulting in an indirect antipsychotic effect. This new proposal reconciles conceptual and empirical gaps encountered when clinical outcomes are compared to the pharmacology of antipsychotics.

Antipsychotic treatment resistance in schizophrenia remains a major issue in psychiatry. Nearly 30% of patients with schizophrenia do not respond to antipsychotic treatment, yet the underlying neurobiological causes are unknown. All effective antipsychotic medications are thought to achieve their efficacy by targeting the dopaminergic system. Here we review early literature describing the fundamental mechanisms of antipsychotic drug efficacy, highlighting mechanistic concepts that have persisted over time. We then reconsider the original framework for understanding antipsychotic efficacy in light of recent advances in our scientific understanding of the dopaminergic effects of antipsychotics. Based on these new insights, we describe a role for the dopamine transporter in the genesis of both antipsychotic therapeutic response and primary resistance. We believe that this discussion will help delineate the dopaminergic nature of antipsychotic treatment-resistant schizophrenia.