Lipid Dys-Homeostasis Contributes to APOE4-Associated AD Pathology.

The association of the APOE4 (vs. APOE3) isoform with an increased risk of Alzheimer's disease (AD) is unequivocal, but the underlying mechanisms remain incompletely elucidated. A prevailing hypothesis incriminates the impaired ability of APOE4 to clear neurotoxic amyloid-ß peptides (Aß) from the brain as the main mechanism linking the apolipoprotein isoform to disease etiology. The APOE protein mediates lipid transport both within the brain and from the brain to the periphery, suggesting that lipids may be potential co-factors in APOE4-associated physiopathology. The present study reveals several changes in the pathways of lipid homeostasis in the brains of mice expressing the human APOE4 vs. APOE3 isoform. Carriers of APOE4 had altered cholesterol turnover, an imbalance in the ratio of specific classes of phospholipids, lower levels of phosphatidylethanolamines bearing polyunsaturated fatty acids and an overall elevation in levels of monounsaturated fatty acids. These modifications in lipid homeostasis were related to increased production of Aß peptides as well as augmented levels of tau and phosphorylated tau in primary neuronal cultures. This suite of APOE4-associated anomalies in lipid homeostasis and neurotoxic protein levels may be related to the accrued risk for AD in APOE4 carriers and provides novel insights into potential strategies for therapeutic intervention.

Specific Mutations in the Cholesterol-Binding Site of APP Alter Its Processing and Favor the Production of Shorter, Less Toxic Aß Peptides.

Excess brain cholesterol is strongly implicated in the pathogenesis of Alzheimer's disease (AD). Here we evaluated how the presence of a cholesterol-binding site (CBS) in the transmembrane and juxtamembrane regions of the amyloid precursor protein (APP) regulates its processing. We generated nine point mutations in the APP gene, changing the charge and/or hydrophobicity of the amino-acids which were previously shown as part of the CBS. Most mutations triggered a reduction of amyloid-ß peptides Aß40 and Aß42 secretion from transiently transfected HEK293T cells. Only the mutations at position 28 of Aß in the APP sequence resulted in a concomitant significant increase in the production of shorter Aß peptides. Mass spectrometry (MS) confirmed the predominance of Aßx-33 and Aßx-34 with the APPK28A mutant. The enzymatic activity of α-, ß-, and γ-secretases remained unchanged in cells expressing all mutants. Similarly, subcellular localization of the mutants in early endosomes did not differ from the APPWT protein. A transient increase of plasma membrane cholesterol enhanced the production of Aß40 and Aß42 by APPWT, an effect absent in APPK28A mutant. Finally, WT but not CBS mutant Aß derived peptides bound to cholesterol-rich exosomes. Collectively, the present data revealed a major role of juxtamembrane amino acids of the APP CBS in modulating the production of toxic Aß species. More generally, they underpin the role of cholesterol in the pathophysiology of AD.

TAAR1 dependent and independent actions of the potential antipsychotic and dual TAAR1/5-HT1A receptor agonist SEP-383856.

SEP-383856 (SEP-856) is a novel antipsychotic under clinical development. It displays a unique pattern of receptor interaction, with only weak (partial agonist) activity at dopamine D2 receptors, yet more potent agonist activity at the trace amine associated receptor (TAAR1) and 5-hydroxytryptamine 1 A receptor (5-HT1A). Nonetheless, these observations await independent confirmation and more detailed characterization of the in vitro and in vivo actions of SEP-856 at TAAR1 and 5-HT1A receptors would be instructive. Herein, we employed luminescence complementation technology in heterologous live cell systems, confocal microscopy, voltage clamp electrophysiology, behavioral readouts and TAAR1 knockout (KO) mice to study SEP-856 in further detail. We provide evidence for the ability of SEP-856 to activate TAAR1 at the surface plasma membrane, and show that this interaction results in Gαs recruitment (pEC50: 6.08 ± 0.22 EMAX: 96.41% ± 15.26) and by extension, to G-protein inwardly rectifying potassium (GIRK) channel activation. Using TAAR1-KO mice, we find TAAR1 to be indispensable for SEP-856 control of body temperature, baseline locomotion reduction and for "antipsychotic-like" efficacy as characterized by a reversal of dizocilipine (MK-801) mediated disruption of pre-pulse inhibition. Conversely, the inhibition by SEP-856 of MK-801 induced locomotion was unaffected in TAAR1 KO mice. SEP-856 behaved as a low-potency, partial agonist at the 5-HT1A receptor, while it partially inhibited recruitment of D2 receptor-coupled Gα and GIRK by DA and acted as a weak partial agonist with low potency at the same receptor when applied alone. Our findings corroborate and extend previous observations on the molecular substrates engaged by this unique, dual TAAR1/5-HT1A receptor agonist and potential antipsychotic that could prove to have major advantages in the treatment of schizophrenia and other psychotic disorders.

Agomelatine for the treatment of generalized anxiety disorder: focus on its distinctive mechanism of action.

Generalized anxiety disorder (GAD), the most frequently diagnosed form of anxiety, is usually treated by cognitive-behavioural approaches or medication; in particular, benzodiazepines (acutely) and serotonin or serotonin/noradrenaline reuptake inhibitors (long term). Efficacy, compliance, and acceptability are, however, far from ideal, reinforcing interest in alternative options. Agomelatine, clinically employed in the treatment of major depression, expresses anxiolytic properties in rodents and was effective in the treatment of GAD (including severely ill patients) in several double-blind, short-term (12 weeks) and relapse-prevention (6 months) studies. At active doses, the incidence of adverse effects was no higher than for placebo. Agomelatine possesses a unique binding profile, behaving as a melatonin (MT1/MT2) receptor agonist and 5-HT2C receptor antagonist, yet recognizing neither monoamine transporters nor GABAA receptors. Extensive evidence supports a role for 5-HT2C receptors in the induction of anxious states, and their blockade likely plays a primary role in mediating the anxiolytic actions of agomelatine, including populations in the amygdala and bed nucleus of stria terminalis, as well as the hippocampus. Recruitment of MT receptors in the suprachiasmatic nucleus, thalamic reticular nucleus, and hippocampus appears to fulfil a complimentary role. Downstream of 5-HT2C and MT receptors, modulation of stress-sensitive glutamatergic circuits and altered release of the anxiogenic neuropeptides, corticotrophin-releasing factor, and vasopressin, may be implicated in the actions of agomelatine. To summarize, agomelatine exerts its anxiolytic actions by mechanisms clearly distinct from those of other agents currently employed for the management of GAD. Plain Language Summary: How agomelatine helps in the treatment of anxiety disorders. Introduction: • Anxiety disorders have a significant negative impact on quality of life.• The most common type of anxiety disorder, called generalized anxiety disorder (GAD), is associated with nervousness and excessive worry.• These symptoms can lead to additional symptoms like tiredness, sleeplessness, irritability, and poor attention.• GAD is generally treated through either cognitive-behavioural therapy or medication. However, widely used drugs like benzodiazepines and serotonin reuptake inhibitors have adverse effects.• Agomelatine, a well-established antidepressant drug, has shown anxiety-lowering ('anxiolytic') properties in rats and has been shown to effectively treat GAD with minimal side effects.• However, exactly how it acts on the brain to manage GAD is not yet clear.• Thus, this review aims to shed light on agomelatine's mechanism of action in treating GAD. Methods: • The authors reviewed studies on how agomelatine treats anxiety in animals.• They also looked at clinical studies on the effects of agomelatine in people with GAD. Results: • The study showed that agomelatine 'blocks' a receptor in nerve cells, which plays a role in causing anxiety, called the 5-HT2C receptor.• Blocking this receptor, especially in specific brain regions such as nerve cells of the amygdala, bed nucleus of stria terminalis, and hippocampus, produced the anxiety reduction seen during agomelatine treatment.• Agomelatine also activates the melatonin (MT) receptor, which is known to keep anxiety in check, promote sleep, and maintain the sleep cycle.• Agomelatine should thus tackle sleep disturbances commonly seen in patients with GAD.• Beyond 5-HT2C and MT receptors, signalling molecules in nerve cells that are known to be involved in anxiety disorders (called 'neurotransmitters' and 'neuropeptides') are also affected by agomelatine. Conclusion: • Agomelatine's anxiolytic effects are caused by mechanisms that are distinct from those of other medications currently used to treat GAD.• This explains its therapeutic success and minimal adverse side effects.

Interaction of the preferential D3 agonist (+)PHNO with dopamine D3-D2 receptor heterodimers and diverse classes of monoamine receptor: relevance for PET imaging.

(+)-4-Propyl-9-hydroxynaphthoxazine ((+)PHNO) is a high affinity, preferential dopamine D3 versus D2 agonist employed in view of its high specificity and excellent signal-to-noise ratio as a radiotracer for positron emission tomography (PET) imaging. Surprisingly, its profile at other classes of monoamine receptor remains undocumented. In addition to hD3 and hD2L receptors, (+)PHNO revealed high affinity at hD4.4 but not hD1 or hD5 receptors. It also revealed significant affinity for several other G protein-coupled monoaminergic receptors, in particular h5-HT1A and h5-HT7. (+)PHNO behaved as a full agonist at hD4.4 and h5-HT1A receptors with potencies comparable to its actions at hD3 and hD2L receptors, and with less potency at 5-HT7 receptors. In binding assays with membranes derived from cells co-expressing hD3 and hD2L receptors and labeled with [3H]Nemonapride or [3H]Spiperone, the proportion of high affinity binding sites recognized by (+)PHNO was higher than an equivalent mixture of membranes from cells expressing hD3or hD2L receptors, suggesting that (+)PHNO promotes formation of hD3-hD2L heterodimers. Further, in cells co-expressing hD3 and hD2L receptors, (+)PHNO showed higher efficacy for inhibiting forskolin stimulated adenylyl cyclase and inducing adenylyl cyclase super-sensitization than in cells transfected with only hD2L receptors. In conclusion, (+)PHNO is a potent agonist at hD4.4, h5-HT1A and h5-HT7 as well as hD3 and hD2L receptors, and it potently activates dopamine hD3-hD2L heterodimers. These interactions should be considered when interpreting PET studies with [11C](+)PHNO and may be relevant to its functional and potential clinical properties in Parkinson's disease and other disorders.

P62 accumulates through neuroanatomical circuits in response to tauopathy propagation.

In Alzheimer's disease and related tauopathies, trans-synaptic transfer and accumulation of pathological tau from donor to recipient neurons is thought to contribute to disease progression, but the underlying mechanisms are poorly understood. Using complementary in vivo and in vitro models, we examined the relationship between these two processes and neuronal clearance. Accumulation of p62 (a marker of defective protein clearance) correlated with pathological tau accumulation in two mouse models of tauopathy spread; Entorhinal Cortex-tau (EC-Tau) mice where tau pathology progresses in time from EC to other brain regions, and PS19 mice injected with tau seeds. In both models and in several brain regions, p62 colocalized with human tau in a pathological conformation (MC1 antibody). In EC-Tau mice, p62 accumulated before overt tau pathology had developed and was associated with the presence of aggregation-competent tau seeds identified using a FRET-based assay. Furthermore, p62 accumulated in the cytoplasm of neurons in the dentate gyrus of EC-Tau mice prior to the appearance of MC1 positive tauopathy. However, MC1 positive tau was shown to be present at the synapse and to colocalize with p62 as shown by immuno electron microscopy. In vitro, p62 colocalized with tau inclusions in two primary cortical neuron models of tau pathology. In a three-chamber microfluidic device containing neurons overexpressing fluorescent tau, seeding of tau in the donor chamber led to tau pathology spread and p62 accumulation in both the donor and the recipient chamber. Overall, these data are in accordance with the hypothesis that the accumulation and trans-synaptic spread of pathological tau disrupts clearance mechanisms, preceding the appearance of obvious tau aggregation. A vicious cycle of tau accumulation and clearance deficit would be expected to feed-forward and exacerbate disease progression across neuronal circuits in human tauopathies.

Trace Amine-Associated Receptor 1 Contributes to Diverse Functional Actions of O-Phenyl-Iodotyramine in Mice but Not to the Effects of Monoamine-Based Antidepressants.

Trace Amine-Associated Receptor 1 (TAAR1) is a potential target for the treatment of depression and other CNS disorders. However, the precise functional roles of TAAR1 to the actions of clinically used antidepressants remains unclear. Herein, we addressed these issues employing the TAAR1 agonist, o-phenyl-iodotyramine (o-PIT), together with TAAR1-knockout (KO) mice. Irrespective of genotype, systemic administration of o-PIT led to a similar increase in mouse brain concentrations. Consistent with the observation of a high density of TAAR1 in the medial preoptic area, o-PIT-induced hypothermia was significantly reduced in TAAR1-KO mice. Furthermore, the inhibition of a prepulse inhibition response by o-PIT, as well as its induction of striatal tyrosine hydroxylase phosphorylation and elevation of extracellular DA in prefrontal cortex, were all reduced in TAAR1-KO compared to wildtype mice. O-PIT was active in both forced-swim and marble-burying tests, and its effects were significantly blunted in TAAR1-KO mice. Conversely, the actions on behaviour and prefrontal cortex dialysis of a broad suite of clinically used antidepressants were unaffected in TAAR1-KO mice. In conclusion, o-PIT is a useful tool for exploring the hypothermic and other functional antidepressant roles of TAAR1. By contrast, clinically used antidepressants do not require TAAR1 for expression of their antidepressant properties.

Dopaminergic neuromodulation of prefrontal cortex activity requires the NMDA receptor coagonist d-serine.

Prefrontal control of cognitive functions critically depends upon glutamatergic transmission and N-methyl D-aspartate (NMDA) receptors, the activity of which is regulated by dopamine. Yet whether the NMDA receptor coagonist d-serine is implicated in the dopamine-glutamate dialogue in the prefrontal cortex (PFC) and other brain areas remains unexplored. Here, using electrophysiological recordings, we show that d-serine is required for the fine-tuning of glutamatergic neurotransmission, neuronal excitability, and synaptic plasticity in the PFC through the actions of dopamine at D1 and D3 receptors. Using in vivo microdialysis, we show that D1 and D3 receptors exert a respective facilitatory and inhibitory influence on extracellular levels and activity of d-serine in the PFC, with actions expressed primarily via the cAMP/protein kinase A (PKA) signaling cascade. Further, using functional magnetic resonance imaging (fMRI) and behavioral assessment, we show that d-serine is required for the potentiation of cognition by D3R blockade as revealed in a test of novel object recognition memory. Collectively, these results unveil a key role for d-serine in the dopaminergic neuromodulation of glutamatergic transmission and PFC activity, findings with clear relevance to the pathogenesis and treatment of diverse brain disorders involving alterations in dopamine-glutamate cross-talk.

TAAR1-Dependent and -Independent Actions of Tyramine in Interaction With Glutamate Underlie Central Effects of Monoamine Oxidase Inhibition.

BACKGROUND: Monoamine oxidase inhibitors (MAOIs) exert therapeutic actions by elevating extracellular levels of monoamines in the brain. Irreversible MAOIs cause serious hypertensive crises owing to peripheral accumulation of tyramine, but the role of tyramine in the central effects of MAOIs remains elusive, an issue addressed herein. To achieve robust inhibition of MAOA/B, the clinically used antidepressant tranylcypromine (TCP) was employed. METHODS: Behavioral, histological, mass spectrometry imaging, and biosensor-mediated measures of glutamate were conducted with MAOIs in wild-type and TAAR1-knockout (KO) mice. RESULTS: Both antidepressant and locomotion responses to TCP were enhanced in TAAR1-KO mice. A recently developed fluoromethylpyridinium-based mass spectrometry imaging method revealed robust accumulation of striatal tyramine on TCP administration. Furthermore, tyramine accumulation was higher in TAAR1-KO versus wild-type mice, suggesting a negative feedback mechanism for TAAR1 in sensing tyramine levels. Combined histoenzymological and immunohistological studies revealed hitherto unknown TAAR1 localization in brain areas projecting to the substantia nigra/ventral tegmental area. Using an enzyme-based biosensor technology, we found that both TCP and tyramine reduced glutamate release in the substantia nigra in wild-type but not in TAAR1-KO mice. Moreover, glutamate measures in freely moving animals treated with TCP demonstrated that TAAR1 prevents glutamate accumulation in the substantia nigra during hyperlocomotive states. CONCLUSIONS: These observations suggest that tyramine, in interaction with glutamate, is involved in centrally mediated behavioral, transcriptional, and neurochemical effects of MAOIs.

Impaired working memory, cognitive flexibility and reward processing in mice genetically lacking Gpr88: Evidence for a key role for Gpr88 in multiple cortico-striatal-thalamic circuits.

The GPR88 orphan G protein-coupled receptor is expressed throughout the striatum, being preferentially localised in medium spiny neurons. It is also present in lower densities in frontal cortex and thalamus. Rare mutations in humans suggest a role in cognition and motor function, while common variants are associated with psychosis. Here we evaluate the influence of genetic deletion of GPR88 upon performance in translational tasks interrogating motivation, reward evaluation and cognitive function. In an automated radial arm maze 'N-back' working memory task, Gpr88 KO mice showed impaired correct responding, suggesting a role for GPR88 receptors in working memory circuitry. Associative learning performance was similar to wild-type controls in a touchscreen task but performance was impaired at the reversal learning stage, suggesting cognitive inflexibility. Gpr88 KO mice showed higher breakpoints, reduced latencies and lengthened session time in a progressive ratio task consistent with enhanced motivation. Simultaneously, locomotor hyperactivity was apparent in this task, supporting previous findings of actions of GPR88 in a cortico-striatal-thalamic motor loop. Evidence for a role of GPR88 in reward processing was demonstrated in a touchscreen-based equivalent of the Iowa gambling task. Although both Gpr88 KO and wild-type mice showed a preference for an optimum contingency choice, Gpr88 KO mice selected more risky choices at the expense of more advantageous lower risk options. Together these novel data suggest that striatal GPR88 receptors influence activity in a range of procedures integrated by prefrontal, orbitofrontal and anterior cingulate cortico-striatal-thalamic loops leading to altered cognitive, motivational and reward evaluation processes.

A Subset of Purposeless Oral Movements Triggered by Dopaminergic Agonists Is Modulated by 5-HT2C Receptors in Rats: Implication of the Subthalamic Nucleus.

Dopaminergic medication for Parkinson's disease is associated with troubling dystonia and dyskinesia and, in rodents, dopaminergic agonists likewise induce a variety of orofacial motor responses, certain of which are mimicked by serotonin2C (5-HT2C) receptor agonists. However, the neural substrates underlying these communalities and their interrelationship remain unclear. In Sprague-Dawley rats, the dopaminergic agonist, apomorphine (0.03-0.3 mg/kg) and the preferential D2/3 receptor agonist quinpirole (0.2-0.5 mg/kg), induced purposeless oral movements (chewing, jaw tremor, tongue darting). The 5-HT2C receptor antagonist 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxyl]-5-pyridyl]carbamoyl]-6-trifluoromethylindone (SB 243213) (1 mg/kg) reduced the oral responses elicited by specific doses of both agonists (0.1 mg/kg apomorphine; 0.5 mg/kg quinpirole). After having confirmed that the oral bouts induced by quinpirole 0.5 mg/kg were blocked by another 5-HT2C antagonist (6-chloro-5-methyl-1-[6-(2-methylpiridin-3-yloxy)pyridine-3-yl carbamoyl] indoline (SB 242084), 1 mg/kg), we mapped the changes in neuronal activity in numerous sub-territories of the basal ganglia using c-Fos expression. We found a marked increase of c-Fos expression in the subthalamic nucleus (STN) in combining quinpirole (0.5 mg/kg) with either SB 243213 or SB 242084. In a parallel set of electrophysiological experiments, the same combination of SB 243213/quinpirole produced an irregular pattern of discharge and an increase in the firing rate of STN neurons. Finally, it was shown that upon the electrical stimulation of the anterior cingulate cortex, quinpirole (0.5 mg/kg) increased the response of substantia nigra pars reticulata neurons corresponding to activation of the "hyperdirect" (cortico-subthalamonigral) pathway. This effect of quinpirole was abolished by the two 5-HT2C antagonists. Collectively, these results suggest that induction of orofacial motor responses by D2/3 receptor stimulation involves 5-HT2C receptor-mediated activation of the STN by recruitment of the hyperdirect (cortico-subthalamonigral) pathway.

Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing.

The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner - a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes.

Dual-acting agents for improving cognition and real-world function in Alzheimer's disease: Focus on 5-HT6 and D3 receptors as hubs.

To date, there are no interventions that impede the inexorable progression of Alzheimer's disease (AD), and currently-available drugs cholinesterase (AChE) inhibitors and the N-Methyl-d-Aspartate receptor antagonist, memantine, offer only modest symptomatic benefit. Moreover, a range of mechanistically-diverse agents (glutamatergic, histaminergic, monoaminergic, cholinergic) have disappointed in clinical trials, alone and/or in association with AChE inhibitors. This includes serotonin (5-HT) receptor-6 antagonists, despite compelling preclinical observations in rodents and primates suggesting a positive influence on cognition. The emphasis has so far been on high selectivity. However, for a multi-factorial disorder like idiopathic AD, 5-HT6 antagonists possessing additional pharmacological actions might be more effective, by analogy to "multi-target" antipsychotics. Based on this notion, drug discovery programmes have coupled 5-HT6 blockade to 5-HT4 agonism and inhibition of AchE. Further, combined 5-HT6/dopamine D3 receptor (D3) antagonists are of especial interest since D3 blockade mirrors 5-HT6 antagonism in exerting broad-based pro-cognitive properties in animals. Moreover, 5-HT6 and dopamine D3 antagonists promote neurocognition and social cognition via both distinctive and convergent actions expressed mainly in frontal cortex, including suppression of mTOR over-activation and reinforcement of cholinergic and glutamatergic transmission. In addition, 5-HT6 blockade affords potential anti-anxiety, anti-depressive and anti-epileptic properties, and antagonising 5-HT6 receptors may be associated with neuroprotective ("disease-modifying") properties. Finally D3 antagonism may counter psychotic episodes and D3 receptors themselves offer a promising hub for multi-target agents. The present article reviews the status of "R and D" into multi-target 5-HT6 and D3 ligands for improved treatment of AD and other neurodegenerative disorders of aging. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.

Prevention of Psychosis: Advances in Detection, Prognosis, and Intervention.

Importance: Detection, prognosis, and indicated interventions in individuals at clinical high risk for psychosis (CHR-P) are key components of preventive psychiatry. Objective: To provide a comprehensive, evidence-based systematic appraisal of the advancements and limitations of detection, prognosis, and interventions for CHR-P individuals and to formulate updated recommendations. Evidence Review: Web of Science, Cochrane Central Register of Reviews, and Ovid/PsychINFO were searched for articles published from January 1, 2013, to June 30, 2019, to identify meta-analyses conducted in CHR-P individuals. MEDLINE was used to search the reference lists of retrieved articles. Data obtained from each article included first author, year of publication, topic investigated, type of publication, study design and number, sample size of CHR-P population and comparison group, type of comparison group, age and sex of CHR-P individuals, type of prognostic assessment, interventions, quality assessment (using AMSTAR [Assessing the Methodological Quality of Systematic Reviews]), and key findings with their effect sizes. Findings: In total, 42 meta-analyses published in the past 6 years and encompassing 81 outcomes were included. For the detection component, CHR-P individuals were young (mean [SD] age, 20.6 [3.2] years), were more frequently male (58%), and predominantly presented with attenuated psychotic symptoms lasting for more than 1 year before their presentation at specialized services. CHR-P individuals accumulated several sociodemographic risk factors compared with control participants. Substance use (33% tobacco use and 27% cannabis use), comorbid mental disorders (41% with depressive disorders and 15% with anxiety disorders), suicidal ideation (66%), and self-harm (49%) were also frequently seen in CHR-P individuals. CHR-P individuals showed impairments in work (Cohen d = 0.57) or educational functioning (Cohen d = 0.21), social functioning (Cohen d = 1.25), and quality of life (Cohen d = 1.75). Several neurobiological and neurocognitive alterations were confirmed in this study. For the prognosis component, the prognostic accuracy of CHR-P instruments was good, provided they were used in clinical samples. Overall, risk of psychosis was 22% at 3 years, and the risk was the highest in the brief and limited intermittent psychotic symptoms subgroup (38%). Baseline severity of attenuated psychotic (Cohen d = 0.35) and negative symptoms (Cohen d = 0.39) as well as low functioning (Cohen d = 0.29) were associated with an increased risk of psychosis. Controlling risk enrichment and implementing sequential risk assessments can optimize prognostic accuracy. For the intervention component, no robust evidence yet exists to favor any indicated intervention over another (including needs-based interventions and control conditions) for preventing psychosis or ameliorating any other outcome in CHR-P individuals. However, because the uncertainty of this evidence is high, needs-based and psychological interventions should still be offered. Conclusions and Relevance: This review confirmed recent substantial advancements in the detection and prognosis of CHR-P individuals while suggesting that effective indicated interventions need to be identified. This evidence suggests a need for specialized services to detect CHR-P individuals in primary and secondary care settings, to formulate a prognosis with validated psychometric instruments, and to offer needs-based and psychological interventions.

Comparative Pro-cognitive and Neurochemical Profiles of Glycine Modulatory Site Agonists and Glycine Reuptake Inhibitors in the Rat: Potential Relevance to Cognitive Dysfunction and Its Management.

Frontocortical NMDA receptors are pivotal in regulating cognition and mood, are hypofunctional in schizophrenia, and may contribute to autistic spectrum disorders. Despite extensive interest in agents potentiating activity at the co-agonist glycine modulatory site, few comparative functional studies exist. This study systematically compared the actions of the glycine reuptake inhibitors, sarcosine (40-200 mg/kg) and ORG24598 (0.63-5 mg/kg), the agonists, glycine (40-800 mg/kg), and D-serine (10-160 mg/kg) and the partial agonists, S18841 (2.5 mg/kg s.c.) and D-cycloserine (2.5-40 mg/kg) that all dose-dependently prevented scopolamine disruption of social recognition in adult rats. Over similar dose ranges, they also prevented a delay-induced impairment of novel object recognition (NOR). Glycine reuptake inhibitors specifically elevated glycine but not D-serine levels in rat prefrontal cortical (PFC) microdialysates, while glycine and D-serine markedly increased levels of glycine and D-serine, respectively. D-Cycloserine slightly elevated D-serine levels. Conversely, S18841 exerted no influence on glycine, D-serine, other amino acids, monamines, or acetylcholine. Reversal of NOR deficits by systemic S18841 was prevented by the NMDA receptor antagonist, CPP (20 mg/kg), and the glycine modulatory site antagonist, L701,324 (10 mg/kg). S18841 blocked deficits in NOR following microinjection into the PFC (2.5-10 µg/side) but not the striatum. Finally, in rats socially isolated from weaning (a neurodevelopmental model of schizophrenia), S18841 (2.5 and 10 mg/kg s.c.) reversed impairment of NOR and contextual fear-motivated learning without altering isolation-induced hyperactivity. In conclusion, despite contrasting neurochemical profiles, partial glycine site agonists and glycine reuptake inhibitors exhibit comparable pro-cognitive effects in rats of potential relevance to treatment of schizophrenia and other brain disorders where cognitive performance is impaired.

DRD3 (dopamine receptor D3) but not DRD2 activates autophagy through MTORC1 inhibition preserving protein synthesis.

Growing evidence shows that autophagy is deficient in neurodegenerative and psychiatric diseases, and that its induction may have beneficial effects in these conditions. However, as autophagy shares signaling pathways with cell death and interferes with protein synthesis, prolonged use of autophagy inducers available nowadays is considered unwise. The search for novel autophagy inducers indicates that DRD2 (dopamine receptor 2)-DRD3 ligands may also activate autophagy, though critical aspects of the action mechanisms and effects of dopamine ligands on autophagy are still unknown. In order to shed light on this issue, DRD2- and DRD3-overexpressing cells and drd2 KO, drd3 KO and wild-type mice were treated with the DRD2-DRD3 agonist pramipexole. The results revealed that pramipexole induces autophagy through MTOR inhibition and a DRD3-dependent but DRD2-independent mechanism. DRD3 activated AMPK followed by inhibitory phosphorylation of RPTOR, MTORC1 and RPS6KB1 inhibition and ULK1 activation. Interestingly, despite RPS6KB1 inhibition, the activity of RPS6 was maintained through activation of the MAPK1/3-RPS6KA pathway, and the activity of MTORC1 kinase target EIF4EBP1 along with protein synthesis and cell viability, were also preserved. This pattern of autophagy through MTORC1 inhibition without suppression of protein synthesis, contrasts with that of direct allosteric and catalytic MTOR inhibitors and opens up new opportunities for G protein-coupled receptor ligands as autophagy inducers in the treatment of neurodegenerative and psychiatric diseases. ABBREVIATIONS: AKT/Protein kinase B: thymoma viral proto-oncogene 1; AMPK: AMP-activated protein kinase; BECN1: beclin 1; EGFP: enhanced green fluorescent protein; EIF4EBP1/4E-BP1: eukaryotic translation initiation factor 4E binding protein 1; GPCR; G protein-coupled receptor; GFP: green fluorescent protein; HEK: human embryonic kidney; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAP2K/MEK: mitogen-activated protein kinase kinase; MAPK1/ERK2: mitogen-activated protein kinase 1; MAPK3/ERK1: mitogen-activated protein kinase 3; MDA: malonildialdehyde; MTOR: mechanistic target of rapamycin kinase; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PPX: pramipexole; RPTOR/raptor: regulatory associated protein of MTOR, complex 1; RPS6: ribosomal protein S6; RPS6KA/p90S6K: ribosomal protein S6 kinase A; RPS6KB1/p70S6K: ribosomal protein S6 kinase B1; SQSTM1/p62: sequestosome 1; ULK1: unc-51 like autophagy activating kinase 1; WT: wild type.

Genetic deletion of GPR88 enhances the locomotor response to L-DOPA in experimental parkinsonism while counteracting the induction of dyskinesia.

Parkinson's disease (PD) is characterized by progressive loss of midbrain dopaminergic neurons and treated with the dopamine precursor, 3,4-dihydroxy-l-phenylalanine (L-DOPA). Prolonged L-DOPA treatment is however associated with waning efficacy and the induction of L-DOPA induced dyskinesia (LID). GPR88 is an orphan G-protein Coupled Receptor (GPCR) expressed in dopaminoceptive striatal medium spiny neurons (MSNs) and their afferent corticostriatal glutamatergic neurons. Here, we studied the role of GPR88 in experimental parkinsonism and LID. Chronic L-DOPA administration to male GPR88 KO mice, subjected to unilateral 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle, resulted in more rotations than in their WT counterparts. Conversely, GPR88 KO mice had a lower abnormal involuntary movements (AIMs) score. These behavioral responses were accompanied by altered transcription of L-DOPA upregulated genes in lesioned GPR88 KO compared to WT striata. In accordance with a role for serotonin neurons in LID development, WT but not GPR88 KO striata exhibited 5-hydroxytryptamine displacement upon repeated L-DOPA treatment. Intact male GPR88 KO mice showed diminished tacrine-induced PD-like tremor and spontaneous hyperlocomotion. Dopamine and its metabolites were not increased in male GPR88 KO mice, but biosensor recordings revealed increased spontaneous/basal and evoked glutamate release in striata of male GPR88 KO mice. In conclusion, genetic deletion of GPR88 promotes l-DOPA-induced rotation and spontaneous locomotion yet suppresses the induction of LIDs and also reduces tremor. These data provide behavioral, neurochemical and molecular support that GPR88 antagonism may favour motor relief in PD patients without aggravating the induction of motor side effects.

Knock-Down of GPR88 in the Dorsal Striatum Alters the Response of Medium Spiny Neurons to the Loss of Dopamine Input and L-3-4-Dyhydroxyphenylalanine.

The effects of L-3-4-dyhydroxyphenylalanine (L-DOPA) treatment for replacing the dopamine (DA) loss in Parkinson's disease (PD) progressively wear off and are hindered by the development of dyskinesia, prompting the search for new treatments. The orphan G protein-coupled receptor 88 (Gpr88) represents a potential new target, as it is highly and almost exclusively expressed in the projecting gamma-Aminobutyric Acid-ergic (GABAergic) medium spiny neurons of the striatum, is implicated in motor activity, and is downregulated by 6-hydroxydopamine (6-OHDA) lesions, an effect that is reversed by L-DOPA. Thus, to evaluate Gpr88 as a potential target for the management of PD and L-DOPA-induced dyskinesia (LID), we inactivated Gpr88 by lentiviral-mediated knock-down with a specifically designed microRNA (miR) (KD-Gpr88) in a 6-OHDA rat model of hemiparkinsonism. Then, we investigated the effects of the KD-Gpr88 in the DA-deprived dorsal striatum on circling behavior and LID as well as on specific markers of striatal neuron activity. The KD-Gpr88 reduced the acute amphetamine-induced and increased L-DOPA-induced turning behavior. Moreover, it normalized the upregulated expression of striatal Gad67 and proenkephalin provoked by the 6-OHDA lesion. Finally, despite promoting ΔFosB accumulation, the KD-Gpr88 was associated neither with the upregulation of prodynorphin, which is causally linked to the severity of LID, nor with the aggravation of LID following chronic L-DOPA treatment in 6-OHDA-lesioned rats. These results thus justify further evaluation of Gpr88 as a potentially novel target for the management of PD as an alternative to L-DOPA therapy.

European college of neuropsychopharmacology network on the prevention of mental disorders and mental health promotion (ECNP PMD-MHP).

Prevention is the most promising way to reduce the high personal, familial, societal, clinical and economic costs of mental disorders in Europe and worldwide. A complementary approach is to go beyond the prevention of mental ill health, to promote good mental health. This manuscript highlights the first European consortium fostering cutting-edge multidisciplinary research in these two areas. The ECNP-funded Network on the Prevention of Mental Disorders and Mental Health Promotion (ECNP PMD-MHP) brings together European sites of excellence with different expertise for translational research collaboration, including partnerships with the industry. The ECNP PMD-MHP Network adopts a transdiagnostic, lifespan, clinical staging model which cuts across different mental disorders and different methodologies. The main aims of the ECNP PMD-MHP Network are to facilitate multidisciplinary collaboration, enhance knowledge and data sharing, standardise core assessment and outcome measures, promote clinical research, apply for grant funding, and generate research reports. By supporting collaborative research, the ECNP PMD-MHP Network will be vital for fostering European psychiatry in the field of prevention of mental disorders and promotion of good mental health.