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The aim of the study was to assess if there is a time difference (operative time, ischemia time, planning time and hospitalization) between computer-assisted surgery (CAS) and conventional planning in cranio-maxillofacial surgery. An electronic search was performed in June 2018. Studies comparing time difference between CAS and traditional planning were included. 28 publications were included, with 536 patients in the CAS group and 784 in the control group. 18 studies reported on mandibular/maxillary reconstruction and a meta-analysis was conducted on 15 of these studies. This meta-analysis was undertaken to demonstrate the difference between the groups regarding operative time, ischemia time and hospitalization for mandibular/maxillary reconstruction and showed a decreased operative time for the CAS group with a mean difference of -84.61 min, 95% confidence interval [-106.77, -62,45], p 0.001. Ischemia time was also decreased, with a mean difference of -36.14 min, 95% confidence interval [-50.57, -21.71], p 0.001. This systematic review and meta-analysis suggests that CAS is shortening the operative time and ischemia time for mandibular/maxillary reconstruction. It also leads to a reduction in hospitalization. Additionally, CAS seems to shorten the preoperative planning time for orthognathic surgery.

Sepsis is a severe condition which affects 300-800/100,000 persons each year. There are indications that the prehospital identification of patients with sepsis is difficult. The aim of the study was, among patients with a final hospital diagnosis of sepsis, to compare emergency medical service (EMS) field assessments of patients in whom there was a prehospital suspicion of sepsis with those without this suspicion.The study had a retrospective, observational design. The data used in the study were retrieved from the prehospital and hospital medical records of patients with a final hospital diagnosis of sepsis, transported to hospital by the EMS within a region in the south west of Sweden during a period of one year.Among patients with a final diagnosis of sepsis (n=353), the EMS identified the condition in 36% of the cases. These patients were characterised by more abnormal vital signs (a higher respiratory rate and heart rate and more frequent temperature abnormalities) and were more ambitiously assessed (more lung auscultations and more assessments of the degree of consciousness).The EMS was already able to identify 36% of patients with a final diagnosis of sepsis in the prehospital phase. There were minor differences in the prehospital assessment between patients who were identified by the EMS nurse and those who were not.

Background: Synaptic proteins are increasingly studied as biomarkers for synaptic dysfunction and loss, which are early and central events in Alzheimer’s disease (AD) and strongly correlate with the degree of cognitive decline. In this study, we specifically investigated the synaptic binding partners neurexins (NRXN) and neuroligins (Nlgn), to assess their biomarker’s potential. Methods: We developed a parallel reaction monitoring mass spectrometric method for the simultaneous quantification of NRXNs and Nlgns in cerebrospinal fluid (CSF) of neurodegenerative diseases, focusing on AD. Specifically, NRXN-1α, NRXN-1β, NRXN-2α, NRXN-3α and Nlgn1, Nlgn2, Nlgn3 and Nlgn4 proteins were targeted. Findings: The proteins were investigated in a clinical cohort including CSF from controls (n=22), mild cognitive impairment (MCI) due to AD (n=44), MCI due to other conditions (n=46), AD (n=77) and a group of non-AD dementia (n=28). No difference in levels of NRXNs and Nlgns was found between AD (both at dementia and MCI stages) or controls or the non-AD dementia group for any of the targeted proteins. NRXN and Nlgn proteins correlated strongly with each other, but only a weak correlation with the AD core biomarkers and the synaptic biomarkers neurogranin and growth-associated protein 43, was found, possibly reflecting different pathogenic processing at the synapse. Interpretation: We conclude that NRXN and Nlgn proteins do not represent suitable biomarkers for synaptic pathology in AD. The panel developed here could aid in future investigations of the potential involvement of Nlgns and NRXNs in synaptic dysfunction in other disorders of the central nervous system. Funding: HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG- 720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen for Gamla Tjanarinnor, Hjarnfonden, Sweden (#FO2019-0228), the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. KB is supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB- 201809- 2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjarnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), and European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236). The funders had no role in data collection, analysis, or decision to publish. EC received support from Gamla tjanarinnor, Stohnes stiftelse, Demensfonden and Emil och Maria Palms stiftelse. AV is supported by Fondation Ophtalmologique Adolphe de Rothschild, Fondation Chatrier and AAIHP association. Declaration of Interest: HZ has served at scientific advisory boards for Eisai, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies and CogRx, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. KB has served as a consultant or at advisory board for Axon, Biogen, CogRx, Lilly, MegQu, Novartis and Roche Diagnostics. OH has acquired research support (for the institution) from Roche, Pfizer, GE Healthcare, Biogen, Eli Lilly and AVID Radiopharmaceuticals. In the past 2 years, he has received consultancy/speaker fees (paid to the institution) from Biogen and Roche. All other authors have nothing to declare. Ethical Approval: The use of these patient samples was approved by the Ethics Committee at the University of Gothenburg (EPN 140811).

Facial fractures often result in changes of the orbital volume. These changes can be measured in three-dimensional (3D) computed tomography (CT) scans for preoperative planning and postoperative evaluation. The aim of this study was to analyze the orbital volume and shape before and after surgical treatment of unilateral orbital fractures using semi-automatic image segmentation and registration techniques. The orbital volume in 21 patients was assessed by a semi-automatic model-based segmentation method. The fractured orbit was compared relative to the contralateral orbit. The same procedure was performed for the postoperative evaluation. Two observers performed the segmentation procedure, and the inter- and intraobserver variability was evaluated. The interobserver variability (mean volume difference ± 1.96 SD) was -0.6 ± 1.0 ml in the first trial and 0.7 ± 0.8 ml in the second trial. The intra-observer variability was -0.2 ± 0.7 ml for the first observer and 1.1 ± 0.9 ml for the second observer. The average volume overlap (Dice similarity coefficient) between the fractured and contralateral side increased after surgery, while the mean and maximum surface distance decreased, indicating that the surgery contributed to a re-establishment of size and shape. In conclusion, our study shows that the semi-automatic segmentation method has precision for detecting volume differences down to 1.0 ml. The combination of semi-automatic segmentation and 3D shape analysis provides a powerful tool for planning and evaluating treatment of orbital fractures.

The muscarinic M2 receptor (M2R) has been shown to display voltage-sensitive agonist binding, based on G protein-activated inward rectifier potassium channel (GIRK) opening and radioligand binding at different membrane voltages. A conserved aspartate in transmembrane segment (TM) II of M2R, D69, has been proposed as the voltage sensor. While a recent paper instead presented evidence of tyrosines in TMs III, VI, and VII acting as voltage sensors, these authors were not able to record GIRK channel activation by a D69N mutant M2R. In the present study, we succeeded in recording ACh-induced GIRK channel activation by this mutant at −80 and 0 mV. The acetylcholine EC50 was about 2.5-fold higher at 0 mV, a potency shift very similar to that observed at wild-type M2R, indicating that voltage sensitivity persists at the D69N mutant. Thus, our present observations corroborate the notion that D69 is not responsible for voltage sensitivity of the M2R.

Three-dimensional (3D) computer-assisted planning requires detailed visualisation of the craniomaxillofacial region and interocclusal relationship. The aim of this study was to establish and evaluate a method to create a 3D model of the craniomaxillofacial region and to adopt intraoral digital scanning to place the lower jaw into a centric relation (CR) without the need of additional plaster casts and model surgery. A standard plastic skull modified by metallic dental wires and brackets was subjected to computed tomography (CT), cone beam computed tomography (CBCT), and intraoral digital scanning. We evaluated two different virtual bite registrations, a digital scan of the buccal dental surfaces and scanning of the wax bites to position the lower jaw into a CR, and assessed the accuracy of the integration of intraoral scanning to the CT/CBCT scans. The mean registration error of corresponding mesh points for the CT and intraoral scanned images was 0.15 ± 0.12 mm, while this error was 0.18 ± 0.13 mm for the CBCT and intraoral scanned images. The mean accuracy of the two virtual bite registrations ranged from 0.41 to 0.49 mm (buccal scan technique) and from 0.65 to 1.3 mm (virtualised wax bite technique). A method for virtual bite registration was developed. It has the potential to eliminate plaster casts and model surgery and may facilitate 3D computer-assisted planning of orthognathic surgery cases.

Newer, "atypical" antipsychotics carry a lower risk of motor side-effects than older, "typical" compounds. It has been proposed that a ~100-fold faster dissociation from the dopamine D2 receptor (D2R) distinguishes atypical from typical antipsychotics. Furthermore, differing antipsychotic D2R affinities have been suggested to reflect differences in dissociation rate constants (koff), while association rate constants (kon) were assumed to be similar. However, it was recently demonstrated that lipophilic accumulation of ligand in the cell interior and/or membrane can cause underestimation of koff, and as high-affinity D2R antagonists are frequently lipophilic, this may have been a confounding factor in previous studies. In the present work, a functional electrophysiology assay was used to measure the recovery of dopamine-mediated D2R responsivity from antipsychotic antagonism, using elevated concentrations of dopamine to prevent the potential bias of re-binding of lipophilic ligands. The variability of antipsychotic kon was also reexamined, capitalizing on the temporal resolution of the assay. kon was estimated from the experimental recordings using a simple mathematical model assumed to describe the binding process. The time course of recovery from haloperidol (typical antipsychotic) was only 6.4- to 2.5-fold slower than that of the atypical antipsychotics, amisulpride, clozapine, and quetiapine, while antipsychotic kons were found to vary more widely than previously suggested. Finally, affinities calculated using our kon and koff estimates correlated well with functional potency and with affinities reported from radioligand binding studies. In light of these findings, it appears unlikely that typical and atypical antipsychotics are primarily distinguished by their D2R binding kinetics.

Development of workflow for recording virtual bite in the planning of orthognathic operations

Glycogen synthesis is initiated by self-glucosylation of the glycosyltransferases glycogenin-1 and -2 that, in the presence of UDP-glucose, form both the first glucose-O-tyrosine linkage, and then stepwise add a series of α1,4-linked glucoses to a growing chain of variable length. Glycogen-1 and -2 coexist in liver glycogen preparations where the proteins are known to form homodimers, and they also have been shown to interact with each other. In order to study how glycogenin-1 and -2 interactions may influence each other's glucosylations we setup a cell-free expression system for in vitro production and glucosylation of glycogenin-1 and -2 in various combinations, and used a mass spectrometry based workflow for the characterization and quantitation of tryptic glycopeptides originating from glycogenin-1 and -2. The analysis revealed that the self-glucosylation endpoint was the incorporation of 4-8 glucose units on Tyr 195 of glycogenin-1, but only 0-4 glucose units on Tyr-228 of glycogenin-2. The glucosylation of glycogenin-2 was enhanced to 2-4 glucose units by the co-presence of enzymatically active glycogenin-1. Glycogenin-2 was, however, unable to glucosylate inactive glycogenin-1, at least not an enzymatically inactivated Thr83Met glycogenin-1 mutant, recently identified in a patient with severe glycogen depletion.

Glycogenin-1 initiates the glycogen synthesis in skeletal muscle by the autocatalytic formation of a short oligosaccharide at tyrosine 195. Glycogenin-1 catalyzes both the glucose-O-tyrosine linkage and the α1,4 glucosidic bonds linking the glucose molecules in the oligosaccharide. We recently described a patient with glycogen depletion in skeletal muscle as a result of a non-functional glycogenin-1. The patient carried a Thr83Met substitution in glycogenin-1. In this study we have investigated the importance of threonine 83 for the catalytic activity of glycogenin-1. Non-glucosylated glycogenin-1 constructs, with various amino acid substitutions in position 83 and 195, were expressed in a cell-free expression system and autoglucosylated in vitro. The autoglucosylation was analyzed by gel-shift on western blot, incorporation of radiolabeled UDP-14C-glucose and nano-liquid chromatography with tandem mass spectrometry (LC/MS/MS). We demonstrate that glycogenin-1 with the Thr83Met substitution is unable to form the glucose-O-tyrosine linkage at tyrosine 195 unless co-expressed with the catalytically active Tyr195Phe glycogenin-1. Our results explain the glycogen depletion in the patient expressing only Thr83Met glycogenin-1 and why heterozygous carriers without clinical symptoms show a small proportion of unglucosylated glycogenin-1.

Voltage-gated ion channels are key players in fast neuronal signalling. Detailed knowledge about channel gating is essential for our understanding of channel function in general and of drug action of channels in particular. Despite a number of recent atomic channel structures, the opening of voltage-gated channels is the subject of heated debates. Here we will discuss two of the controversies: one concerning the mechanism of opening and closing the pore, and the other concerning the location and movement of the voltage sensor. The channels were originally suggested to open at a conserved proline rich sequence (PVP) at the intracellular end of the transmembrane segment 6 (S6). The crystallization of a channel in the open state instead suggested an opening involving a conserved glycine hinge located in the middle portion of S6. Based on pharmacological studies, autodocking and molecular dynamics simulations we have found support for the PVP-bend model. The voltage sensor, transmembrane segment 4 (S4), was originally suggested to be buried in the channel protein, undergoing a helical-screw-like motion to open the channel. A recent crystallographic study suggested that S4 is located in the periphery, facing lipid, and undergoing a paddle-like motion to open the channel. We have found experimental evidence for a novel helical-screw model; with the voltage sensor moving in a screw-like fashion but being located in the periphery of the channel. This model opens up for understanding how lipophilic drugs and toxins directly affect the voltage sensor.

Dizziness is a common and often untreated symptom in the general population. The aim of this study was to investigate the effects of a combined cognitive-behavioral/vestibular rehabilitation (VR) program, using a randomized control design. A total of 29 participants were randomized to treatment consisting of psychoeducation, vestibular exercises, relaxation and cognitive interventions, or to serve as waiting list controls. Measures of dizziness-related handicap, dizziness-provoking movements, and daily diary registrations of dizziness symptoms at pre- and post-treatment showed statistically significant improvements in many domains, which translated to moderate effect sizes. These findings provide preliminary support for the combination of Cognitive-behavioral therapy (CBT) and VR methods in the treatment of dizziness.

Objective Transcranial magnetic stimulation (TMS) can be used to map the corticomotor representations of hand muscles in the precentral motor-cortex (PMC). The spatial peak of the corticomotor representations is often not located in the primary motor cortex (M1HAND), but shows an anterior shift towards the dorsal premotor cortex (PMd). Here we used magnetic resonance imaging (MRI) to test the hypothesis that the PMC shows different structural and functional properties in individuals with a clear “premotor” representation compared to individuals with a preponderant “primary-motor” representation of hand muscles. Methods MRI-measurements and neuronavigated-TMS were performed on twenty-four volunteers (mean age: 24.3 ± 0.9 SE, 12 women). Participants underwent structural MRI to evaluate cortical thickness and curvature of the PMC. We also performed fMRI to evaluate precentral functional activation in the hand-knob during a simple motor task. Sulcus-shape based TMS-mapping was used to obtain mediolateral and posterior-anterior corticomotor excitability profiles of the left abductor-digiti-minimi and first-dorsal-interosseus muscles. Results In 14 out of 24 individuals (58%), TMS mapping disclosed a clear spatial peak in the stimulation lines overlying the PMd, whereas the remaining 10 subjects (42%) showed maximal motor responses more posteriorly along M1HAND. During fMRI, the “premotor” group displayed a stronger task-related activation in the PMd relative to the “primary-motor” group ( p = 0.002). No difference between two groups was evident for curvature and cortical thickness. Conclusion The results confirm that many individuals have a more premotor corticomotor representation of small hand muscles when measured with TMS. This premotor phenotype in terms of corticomotor representation is associated with a stronger premotor activation during simple movements. This association supports the notion of two distinct functional phenotypes of corticomotor hand representations in human PMC: a primary motor and a premotor phenotype.

The local anaesthetic bupivacaine has recently been proposed to inhibit Na+ channels indirectly by making the resting potential less negative. To test this hypothesis we analysed the effects of bupivacaine on voltage and current clamped nodes of Ranvier. Contrary to the hypothesis, the leak current and the resting potential were unaffected. The Na+ and K+ channels were, however, affected at relatively low concentrations (33 microM). Steady-state activation curves were decreased without notable shift effects, whereas the Na+ inactivation curve was decreased and shifted in negative direction. The effect on the Na+ current was tentatively explained by a single-site, state-dependent binding model (Kd = 44 microM), while that on the K+ current was explained by two population-specific mechanisms, one open-state dependent (Kd = 550 microM) and one state independent (Kd = 59 microM). The binding stoichiometry was higher than 1:1 for the main sites of action. In conclusion, bupivacaine exerts its main anaesthetic action on myelinated nerve axons by a direct modification of Na+ channels.

The mechanism of action of the neuroprotective agent riluzole, clinically used against amyotrophic lateral sclerosis (ALS), is poorly understood. Studies have indicated multiple effects on several ion channel types. For instance, Kv1.5 and Kv3.1 have been reported to be blocked in the closed and inactivated states. In the present study the effects on Kv1.1, Kv1.3 and Kv2.1 channels expressed in Xenopus oocytes were studied, using the two-electrode voltage-clamp system. Riluzole reversibly inhibited the channels in a concentration dependent manner with IC50 values for fully open channels of 250, 150 and 700 mikroM, respectively. The slow inactivation of Kv1.1 was accelerated and the steady state inactivation and the peak activation curves were shifted to the left. However, the corresponding curves for Kv2.1 did not show shifts. The preliminary results of an kinetic analysis suggest that riluzole blocks both Kv1 channels in the open state, while the Kv2.1 channel was blocked both in the open and a closed state. The results do not show a block of inactivated channels, thus suggesting that the riluzole effects on Kv1.1, Kv1.3 and Kv2.1 may deviate in several respects from those on Kv1.5 and Kv3.1.

The lower liability of atypical antipsychotics to produce side-effects correlates with their faster rates of dissociation from the dopamine D2 receptor. Recent studies indicate that the novel D2 ligands, ACR16 and OSU6162, act as antagonists with similarly high dissociation rates. However, those studies measured dissociation of radiolabeled ligand from membrane preparations or used modified G proteins to study calcium release. We examined relative antagonist dissociation rates in living cells, using a time-resolved assay based on activation of G protein-coupled potassium channels (GIRK) by native G proteins. GIRK responses to dopamine receptor activation were studied using two-electrode voltage clamp in Xenopus oocytes expressing D2 receptors and GIRK. First, dopamine was applied, resulting in a “baseline” response. Next, antagonist was washed in, in the continued presence of dopamine. After attaining steady-state response inhibition, antagonist was washed out, still in the presence of dopamine. Response recovery was recorded over six minutes, and the time-course and relative amplitude of recovery were taken as measures of antagonist dissociation. Significant differences in response recovery T1/2 and recovery amplitudes were observed between the different D2 receptor antagonists: In experiments with haloperidol, risperidone, and aripiprazole, virtually no response recovery was observed. With clozapine and quetiapine, similar recovery amplitudes and recovery time courses were observed (T1/2 ∼ 40 s). ACR16 and OSU6162 behaved as antagonists, lacking detectable efficacy in the GIRK assay. These compounds washed out with similar time courses (T1/2 ∼ 8 s); significantly faster than the other antagonists. ACR16 and OSU6162 appear to dissociate faster than clozapine and quetiapine, a finding which has not been reported earlier. Such very rapid dissociation might be relevant to the low incidence of side effects reported from clinical trials with these compounds.

Local anaesthetics (LAs) are generally assumed to block action potentials by binding to Nav channels, preferentially when in inactivated and/or open state. Recently, it has been suggested that they, in addition or preferentially, bind to Nav channels when in intermediate closed states. This is based on the finding that LAs reduce the peak current more at low voltage steps than at high in voltage clamp experiments.In previous studies we have concluded that LAs preferentially block Kv channels by binding to exclusively open channels. In the present study we have reanalysed the effect, with special reference to the new findings of closed state binding. We analysed the effects of bupivacaine on Kv3.1 channels expressed in Xenopus oocytes. In contrast to the results from the Na studies, bupivacaine reduced the early current more at higher voltages than at lower. Nevertheless, analysing kinetic models we found that the results are explained by binding preferentially to open channels.We thus conclude that bupivacaine block K channels mainly in the open state. We also conclude that a time and voltage-dependent block, similar to that reported for Na channels, does not necessarily imply binding of channels in different closed states. Furthermore, the results stress the general fact that a block of the early current in voltage clamp experiments does not necessarily imply that LAs bind to the channel when in closed state, contrary to a widely held view.

All antipsychtics currently in clinical use are antagonists or weak partial agonists at the dopamine D2 receptor (D2R). Antipsychotic medication is associated with adverse effects such as extrapyramidal symptoms (EPS). The lower EPS liability of newer, so-called atypical antipsychotics, typified by clozapine, has been proposed to reflect their faster rates of dissociation from the D2R, as compared to older, typical antipsychotics such as haloperidol. This hypothesis has received increasing attention in recent years, and several pharmaceutical companies have endeavored to developed their own "fast off"-antipsychotics.However, previous studies have measured dissociation of radiolabeled antipsychotics or used modified G proteins to study receptor activation-induced calcium release, which confers certain limitations in terms of temporal resolution. We have examined antagonist dissociation in living cells, employing an assay based on the activation of G protein coupled potassium channels. This assay uses native G proteins and has higher temporal resolution than previous studies.Our preliminary data suggest that there may be larger differences between different atypical antipsychotics than has previously been appreciated. Furthermore, the differences between atypical and typical drugs appear to relate mainly to the differential hydrophilicities of these drugs.

Purpose of the study: Antipsychotic medication is often associated with adverse effects such as extrapyramidal symptoms (EPS) and increased serum prolactin. There is evidence that the lower liability to produce EPS and increased prolactin attributed to newer, so-called atypical antipsychotics, is correlated with their faster rates of dissociation from the dopamine D2 receptor [1]. Recent studies have indicated that the novel D2 receptor ligands, ACR16 and (−)-OSU6162, initially described as “dopamine stabilizers,” act as antagonists with similarly high dissociation rates [2,3]. However, these previous studies of antagonist unbinding rates measured either dissociation of radiolabeled ligand from membrane preparations [1] or used modified G proteins to study receptor activation-induced calcium release in living cells [2,3]. We wanted to examine the relative kinetics of antagonist dissociation in living cells, using an assay based an activation of G protein-coupled potassium (GIRK) channels. This assay uses native G proteins and has higher temporal resolution than previously used assays. Methods used: Xenopus oocytes were injected with cRNA encoding the human dopamine D2S receptor, Regulator of G protein Signalling (RGS)-4, and GIRK1/4 channel subunits. GIRK current responses to dopamine receptor activation were recorded at −80mV using twoelectrode voltage clamp. First, dopamine (100 nM) was applied, resulting in a “baseline” GIRK response. Next, a maximally effective concentration of antagonist was washed in, in the continued presence of dopamine. After achieving steady-state response inhibition the antagonist was washed out, still in the presence of dopamine. Response recovery was recorded over six minutes, and the recovery time-course and the amplitude of the (pseudo)steady state current relative to the baseline response were taken as measures of antagonist dissociation. Summary of results: Significant differences (P< 0.05; Student’s t-test) in response recovery T1/2 (time to half-maximal recovery) and recovery amplitudes were observed between the different D2 receptor antagonists: In experiments with haloperidol, risperidone, paliperidone, aripiprazole, and bifeprunox, no response recovery was detected. With clozapine, quetiapine, and N-desmethylclozapine, similar recovery time courses were observed (T1/2 = 48±5.5 s, 60±2.2 s, and 46±3.7 s, respectively). With clozapine and quetiapine, about 50% response recovery was seen, whereas N-desmethylclozapine washout allowed 80% recovery. The “stabilizer” compounds ACR16 and (−)-OSU6162, along with the structurally related experimental antipsychotic, (−)-3-PPP, behaved as antagonists, lacking detectable efficacy in the assay. These compounds washed out with similar time courses (T1/2 = 8.2±1.8 s, 6.1±0.44 s, and 7.8±0.87 s, respectively); significantly faster than the other antagonists in the study, and allowed near-complete response recovery. Conclusions: The present data support the idea that the atypical antipsychotics, clozapine and quetiapine, dissociate faster from D2 receptors than the typical antipsychotic haloperidol, but also faster than several other atypical drugs in the study, including risperidone, paliperidone, and aripiprazole. Furthermore, the “dopamine stabilizers” ACR16 and (−)-OSU6162 appear to dissociate faster than clozapine and quetiapine, a finding which has not been reported earlier. Such very rapid dissociation might be relevant to the low incidence of side effects reported from clinical trials with these compounds.