"Narcan encounters:" overdose and naloxone rescue experiences among people who use opioids.

BACKGROUND: Communities across the United States are confronting the precipitous rise in opioid overdose fatalities that has occurred over the past decade. Naloxone, an opioid antagonist, is a safe rescue medication that laypeople can administer to reverse an overdose. Community naloxone training programs have been well-documented. Less is known about overdose survivors' subjective experiences with naloxone reversal and its impacts on drug use behavior.Methods: Semi-structured interviews were conducted with 35 community-dwelling adults who had been reversed at least once with naloxone. Inductive thematic content analysis incorporating Atlas.ti software was used to identify themes.Results: Four broad thematic categories were identified. (1) Overdose experience and memory: Most participants remembered taking the drugs one minute and waking up the next-sometimes in different surroundings; (2) Naloxone rescue-waking up: Participants described acute withdrawal symptoms, disorientation, and volatile emotions; (3) Reasons for overdose: Polypharmacy; changes in opioid tolerance, or presence of fentanyl were the most common explanations. (4) Impacts of naloxone rescue: A variety of contextual factors influenced participants' responses to naloxone rescue, especially acute withdrawal symptoms. While some participants altered or tempered their opioid use, others resumed opioid use-especially to mitigate withdrawal. Participants overwhelmingly emphasized that naloxone saved their lives.Conclusion: Results suggest that a naloxone rescue may not be a wake-up call for many people who use opioids, but access to naloxone is an effective overdose harm reduction option, supporting its widespread implementation. The study findings underscore the importance of ongoing community overdose prevention and harm reduction initiatives, including take-home naloxone (THN) and medication assisted treatment in the Emergency Department.

Treatment Experiences Among People Who Use Opioids: A Social Ecological Approach.

The prevalence of opioid use disorder (OUD) and surge in overdose deaths remain key public health concerns. Despite evidence supporting the efficaciousness of medications for opioid use disorder, most people with OUD do not receive treatment. In this qualitative study, semi-structured interviews were conducted with 35 adults in a northeastern city to learn about their experiences with substance use treatment. Qualitative data were analyzed using an inductive thematic content analysis approach, and a social ecological model was applied to examine contextual factors affecting participants' experiences accessing and engaging in treatment. While we organized our findings following the individual, interpersonal, community, and society levels of the socio-ecological model, we also observed overlap and interconnectedness between and across these levels. Our findings suggest that retention in treatment often depends upon personal motivation, treatment availability, the match of the treatment modality to an individual's needs, and social support. A person-centered approach is needed to promote individualized care and tailor treatment components to the patient's needs.

Susac syndrome - the current review of knowledge and own experience presentation.

Susac syndrome is a rare autoimmune vasculopathy involving the small precapillary arterioles of the brain, retina, and inner ear. It is characterized by a triad of symptoms: encephalopathy, visual disturbances due to obstruction of retinal artery branches, and sensorineural hearing loss. The study aimed to review the current medical knowledge on Susac syndrome and present our clinical experience regarding this disease entity. The paper also presents a case of a 25-year-old patient who was diagnosed with Susac's syndrome based on the clinical picture and the results of additional tests. This syndrome should be considered in the differential diagnosis of multiple sclerosis and other multifocal lesions of the central nervous system because early diagnosis of the disease and immunosuppressive treatment significantly alleviates its course and improves the prognosis.

Susac syndrome - A review of current knowledge and own experience.

Susac syndrome is a rare connective tissue disorder. The pathology affects the small vessels of the brain, retina, and inner ear, and therefore the main symptoms of the disease include encephalopathy, visual disturbances, and sensorineural hearing loss. The aim of this article is to review the current medical knowledge on Susac syndrome and to present our clinical experience regarding this disease entity. In the paper, we are also presenting a case of a 25-year-old patient who was diagnosed with Susac syndrome on the basis of clinical presentation and additional test results. Susac syndrome should be differentiated from multiple sclerosis and other causes of multifocal brain damage as early diagnosis and treatment play a key role in later prognosis.

Development of Ligands for the Super Conserved Orphan G Protein-Coupled Receptor GPR27 with Improved Efficacy and Potency.

The orphan G protein-coupled receptor GPR27 appears to play a role in insulin production, secretion, lipid metabolism, neuronal plasticity, and l-lactate homeostasis. However, investigations on the function of GPR27 are impaired by the lack of potent and efficacious agonists. We describe herein the development of di- and trisubstituted benzamide derivatives 4a-e, 7a-z, and 7aa-ai, which display GPR27-specific activity in a ß-arrestin 2 recruitment-based assay. Highlighted compounds are PT-91 (7p: pEC50 6.15; Emax 100%) and 7ab (pEC50 6.56; Emax 99%). A putative binding mode was revealed by the docking studies of 7p and 7ab with a GPR27 homology model. The novel active compounds exhibited no GPR27-mediated activation of G proteins, indicating that the receptor may possess an atypical profile. Compound 7p displays high metabolic stability and brain exposure in mice. Thus, 7p represents a novel tool to investigate the elusive pharmacology of GPR27 and assess its potential as a drug target.

Dysfunctions of the vestibular organ in patients with migrainous vertigo in the results of objective tests of the equilibrium system.

<b>Introduction:</b> Migrainous vertigo (MV) is one of the most common causes of episodic vertigo. Diagnostic criteria for MV are described in the appendix to the third edition of the International Classification of Headache Disorders (Beta Version). The dysfunction exerts its impact on certain peripheral and central structures within the vestibular system. </br></br> <b>Aim:</b> The aim of the study was to assess the function of the central and peripheral vestibular system in patients with MV based on the results of objective clinical tests including videonystagmography (VNG) and cervical vestibular evoked myogenic potentials (cVEMP) depending on the duration of the disease. </br></br> <b>Material and methods:</b> A query of the medical records of patients receiving vertigo treatment at the Department of Otolaryngo-logy of the Centre of Postgraduate Medical Education over the last four years returned a total of 84 cases of patients diagnosed with MV; the patients were assigned to either of the following two groups: study group I (SG1) - 42 patients with MV in whom the symp-tom onset had occurred within one year prior to hospital admission, and study group II (SG2) - 42 patients who had been suffering from vertigo for about 10 years. </br></br> <b>Results:</b> Patients in both groups (SG1 and SG2) were diagnosed with all three types of vestibular dysfunction (central, peri-pheral and mixed), with peripheral vestibular dysfunction being the predominant finding. A thorough analysis of the dura-tion of vestibular attacks revealed that the patients suffering from MV for a longer period of time (SG2) suffered from vertigo attacks which were longer than those in the patients with the shorter lasting-disorder (SG1). The duration of vertigo episodes was also estimated to be prolonged in peripheral and mixed types of vestibular disorders. The percentage of individuals with peripheral and mixed vestibular disorders increased significantly with increasing MV episode durations.

Superconserved receptors expressed in the brain: Expression, function, motifs and evolution of an orphan receptor family.

GPR27, GPR85 and GPR173 constitute a small family of G protein-coupled receptors (GPCR) that share the distinctive characteristics of being highly conserved throughout vertebrate evolution and predominantly expressed in the brain. Accordingly, they have been coined as "Superconserved Receptors Expressed in the Brain" (SREB), although their expression profile is more complex than what was originally thought. SREBs have no known validated endogenous ligands and are thus labeled as "orphan" receptors. The investigation of this particular category of uncharacterized receptors holds great promise both in terms of physiology and drug development. In the largest GPCR family, the Rhodopsin-like or Class A, around 100 receptors are considered orphans. Because GPCRs are the most successful source of drug targets, the discovery of a novel function or ligand most likely will lead to significant breakthroughs for the discovery of innovative therapies. The high level of conservation is one of the characteristic features of the SREBs. We propose herein a detailed analysis of the putative evolutionary origin of this family. We highlight the properties that distinguish SREBs from other rhodopsin-like GPCRs. We present the current evidence for these receptors downstream signaling pathways and functions. We discuss the pharmacological challenge for the identification of natural or synthetic ligands of orphan receptors like SREBs. The different SREB-related scientific questions are presented with a highlight on what should be addressed in the near future, including the confirmation of published evidence and their validation as drug targets. In particular, we discuss in which pathological conditions these receptors may be of great relevance to solve unmet medical needs.

Structure-activity relationships of agonists for the orphan G protein-coupled receptor GPR27.

GPR27 belongs, with GPR85 and GPR173, to a small subfamily of three receptors called "Super-Conserved Receptors Expressed in the Brain" (SREB). It has been postulated to participate in key physiological processes such as neuronal plasticity, energy metabolism, and pancreatic ß-cell insulin secretion and regulation. Recently, we reported the first selective GPR27 agonist, 2,4-dichloro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (I, pEC50 6.34, Emax 100%). Here, we describe the synthesis and structure-activity relationships of a series of new derivatives and analogs of I. All products were evaluated for their ability to activate GPR27 in an arrestin recruitment assay. As a result, agonists were identified with a broad range of efficacies including partial and full agonists, showing higher efficacies than the lead compound I. The most potent agonist was 4-chloro-2,5-difluoro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7y, pEC50 6.85, Emax 37%), and the agonists with higher efficacies were 4-chloro-2-methyl-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7p, pEC50 6.04, Emax 123%), and 2-bromo-4-chloro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7r, pEC50 5.99, Emax 123%). Docking studies predicted the putative binding site and interactions of agonist 7p with GPR27. Selected potent agonists were found to be soluble and devoid of cellular toxicity within the range of their pharmacological activity. Therefore, they represent important new tools to further characterize the (patho)physiological roles of GPR27.

Tracking of the biochemical changes upon pleomorphic adenoma progression using vibrational microspectroscopy.

Head and neck tumors can be very challenging to treat because of the risk of problems or complications after surgery. Therefore, prompt and accurate diagnosis is extremely important to drive appropriate treatment decisions, which may reduce the chance of recurrence. This paper presents the original research exploring the feasibility of Fourier transform infrared (FT-IR) and Raman spectroscopy (RS) methods to investigate biochemical alterations upon the development of the pleomorphic adenoma. Principal component analysis (PCA) was used for a detailed assessment of the observed changes and to determine the spectroscopic basis for salivary gland neoplastic pathogenesis. It is implied that within the healthy margin, as opposed to the tumoral tissue, there are parts that differ significantly in lipid content. This observation shed new light on the crucial role of lipids in tissue physiology and tumorigenesis. Thus, a novel approach that eliminates the influence of lipids on the elucidation of biochemical changes is proposed. The performed analysis suggests that the highly heterogeneous healthy margin contains more unsaturated triacylglycerols, while the tumoral section is rich in proteins. The difference in protein content was also observed for these two tissue types, i.e. the healthy tissue possesses more proteins in the anti-parallel ß-sheet conformation, whereas the tumoral tissue is dominated by proteins rich in unordered random coils. Furthermore, the pathogenic tissue shows a higher content of carbohydrates and reveals noticeable differences in nucleic acid content. Finally, FT-IR and Raman spectroscopy methods were proposed as very promising methods in the discrimination of tumoral and healthy tissues of the salivary gland.

Saliva as a non-invasive material for early diagnosis.

The proper diagnosis is a critical factor to reduce further disturbances at the early stage of the disease and plays an important role in increasing the success rate of the therapy. The traditional diagnostic tools such as biopsy or blood collection are always associated with patient's discomfort, the possibility of infections and time-consuming procedures. This article describes the non-invasive and easily accessible saliva as a source of numerous molecular biomarkers. The salivary fluid can provide information about the pathological changes not only in the oral area but also in other parts of the body, therefore salivary tests may be promising tools for risk prediction and treatment monitoring of many disorders.

Simultaneous activation of muscarinic and GABAB receptors as a bidirectional target for novel antipsychotics.

Recent preclinical studies point to muscarinic and GABAB receptors as novel therapeutic targets for the treatment of schizophrenia. This study was aimed to assess the role of muscarinic and GABAB receptor interactions in animal models of schizophrenia, using positive allosteric modulators (PAMs) of GABAB receptor (GS39783), muscarinic M4 (VU0152100) and M5 (VU0238429) receptor, and partial allosteric agonist of M1 receptor (VU0357017). DOI-induced head twitches, social interaction and novel object recognition tests were used as the models of schizophrenia. Analyses of DOI-induced increases in sEPSCs (spontaneous excitatory postsynaptic currents) were performed as complementary experiments to the DOI-induced head twitch studies. Haloperidol-induced catalepsy and the rotarod test were used to examine the adverse effects of the drugs. All three activators of muscarinic receptors were active in DOI-induced head twitches. When administered together with GS39783 in subeffective doses, only the co-administration of VU0152100 and GS39783 was effective. The combination also reduced the frequency but not the amplitude of DOI-induced sEPSCs. Neither VU0357017 nor VU0238429 were active in social interaction test when given alone, and also the combination of VU0152100 and GS39783 failed to reverse MK-801-induced deficits observed in this test. All muscarinic activators when administered alone or in combination with GS39783 reversed the MK-801-induced disruption of memory in the novel object recognition test, and their actions were blocked by specific antagonists. None of the tested compounds or their combinations influenced the motor coordination of the animals. The compounds had no effect on haloperidol-induced catalepsy and did not induce catalepsy when administered alone. Pharmacokinetic analysis confirmed lack of possible drug-drug interactions after combined administration of GS39783 with VU0357017 or VU0152100; however, when the drug was co-administered with VU0238429 its ability to pass the blood-brain barrier slightly decreased, suggesting potential drug-drug interactions. Our data show that modulation of cholinergic and GABAergic systems can potentially be beneficial in the treatment of the positive and cognitive symptoms of schizophrenia without inducing the adverse effects typical for presently used antipsychotics.

[The efficacy of tympanopunction in children with OMS]. / Skutecznosc tympanopunkcji w leczeniu dzieci chorych na wysiekowe zapalenie ucha srodkowego.

INTRODUCTION: Otitis media with effusion is the most frequent cause of conductive hearing impairement (HL) at pediatric age. This entity can be asymptomatic for an important period of time (silent OME). There is a surgical and a nonsurgical approach for OME. In case of failure of conservative treatment of OME the ventilation tube insertion (VT) with adenoidectomy alone or combined with tonsillectomy should be choosed. If the hearing loss is less than 20 dB children are candidates for conservative treatment and myringotomy. MATERIAL AND METHODS: From 1999 to 2003, 50 children with bilateral and 9 with unilateral OME underwent the surgical treatment in our ENT Department. Mean age of patient population was 6,8 years. Clinical evaluation of the OME treatment outcome was done in 2004. Surgical procedure involved myringotomy, aspiration of the middle ear effusion, middle ear irrigation with soline solution 0.9 % Sodium Chloride (NaCl) followed by suction of diluted glue. Depo-Medrol (methylprednisolone acetate) was administrated into the middle ear. Our procedure included the management of the upper airways obstruction. RESULTS: Good long-term outcomes after surgical treatment of OME were obtained in 30 patients (79%). In this group of children the upper airways management included adenoidectomy and partial tonsillectomy. 8 children presented poor response to the treatment. In this group the surgical procedure consisted of adenoidectomy and inferior turbinate reduction. Two children presented acute otitis media and improved after conservative treatment. Other children with poor outcome were: a boy who underwent multiple surgical procedures due to laryngotracheal stenosis, a girl who suffered from chondrodysplasia. Remaining two patients presented few months ago aggravation of conductive hearing loss. According to positive familial history they underwent allergical examinations. One boy was planned for readenoidectomy and laser myringotomy, a girl already operated at the age of tree years, was planned for ventilation tubes insertion and readenoidectomy in another ENT Department.

Neurochemical changes underlying schizophrenia-related behavior in a modified forced swim test in mice.

The modified forced swim test (MFST) has excellent predictive validity for investigating the antipsychotic activity of drugs, with particular emphasis on their activity toward negative symptoms of schizophrenia. However, its face and construct validity are less understood. Therefore, in the present study, some biochemical changes within GABAergic and serotonergic neurotransmission that could be related to observed MK-801-induced disturbances and the activity of compounds active at those neurotransmitters were investigated. In biochemical experiments, mice were treated acutely or chronically with MK-801 (13 days, 0.4 mg/kg). Their brains were dissected and frontal cortices and hippocampi were taken for further analysis. The levels of neurotransmitters were investigated with HPLC, and the expression of surrogate markers of schizophrenia (5-HT1A receptors, GAD65, and GAD67, at both protein and mRNA levels) was measured via western blotting and qRT-PCR. The modified forced swim test and locomotor activity were used to assess the activity of GABAB and 5-HT1A-related compounds. Repeated MK-801 treatment (13 days, 0.4 mg/kg dose) led to decreases in the DOPAC/DA, 3MT/DA and HVA/DA metabolic ratios. Increased 5-HT1A protein expression and decreased GAD65 and GAD67 protein expression was observed in both the cortex and hippocampus. mRNA levels for all proteins were decreased. The increased immobility in the forced swim test was reversed both by a GABAB agonist (SKF97541, 0.025 or 0.05 mg/kg), a positive allosteric modulator of GABAB receptor (racBHFF, 5 or 10 mg/kg) and by a 5-HT1A agonist ((R)-(+)-8-OH-DPAT 0.01 or 0.025 mg/kg). Our research supports the hypothesis that changes in the levels of GABA and/or 5-HT1A receptors may contribute to the schizophrenia-like phenotype, and GABAergic and serotonergic agents may be good candidates for treating negative symptoms of schizophrenia.

Negative Allosteric Modulators of mGlu7 Receptor as Putative Antipsychotic Drugs.

The data concerning antipsychotic-like activity of negative allosteric modulators (NAMs)/antagonists of mGlu7 receptors are limited. The only available ligands for this receptor are MMPIP and ADX71743. In the present studies, we used stable cell line expressing mGlu7 receptor and it was shown that both compounds dose-dependently potentiated forskolin elevated cAMP concentration in the T-REx 293 cells, showing their inverse agonist properties. Subsequently, pharmacokinetic studies were performed. Both compounds were given intraperitoneally (i.p.) at the dose of 10 mg/kg and reached Cmax 0.25-0.5 h after administration, and then they declined rapidly, ADX71743 being almost undetectable 2 h after administration, while the concentration of MMPIP was still observed, suggesting that the concentration of MMPIP was more stable. Finally, we investigated the role of both mGlu7 receptor NAMs in animal models of schizophrenia. Behavioral tests commonly used in antipsychotic drug discovery were conducted. Both tested compounds dose-dependently inhibited MK-801-induced hyperactivity (MMPIP at 15 mg/kg; ADX at 5 and 15 mg/kg) and DOI-induced head twitches (MMPIP at 5, 10, 15 mg/kg; ADX at 2.5, 5, 10 mg/kg). Moreover, the same effects were noticed in novel object recognition test, where MMPIP (5, 10, 15 mg/kg) and ADX71743 (1, 5, 15 mg/kg) reversed MK-801-induced disturbances. In the social interaction test, antipsychotic activity was observed only for ADX71743 (5, 15 mg/kg). ADX71743 at the dose 2.5 mg/kg reversed MK-801-induced disruption in prepulse inhibition while MMPIP at 10 mg/kg reversed MK-801-induced disruption in spatial delayed alternation. The present studies showed that mGlu7 receptor may be considered as a putative target for antipsychotic drugs, though more studies are needed due to limited number of available ligands.

Search for a 5-CT alternative. In vitro and in vivo evaluation of novel pharmacological tools: 3-(1-alkyl-1H-imidazol-5-yl)-1H-indole-5-carboxamides, low-basicity 5-HT7 receptor agonists.

Close structural analogues of 5-carboxamidotryptamine (5-CT) based on the newly discovered indole-imidazole scaffold were synthesized and evaluated to search for a 5-HT7 receptor agonist of higher selectivity. In vitro drug-likeness studies and in vivo pharmacological evaluation of potent and selective low-basicity 5-HT7 receptor agonists, previously published 7 (3-(1-ethyl-1H-imidazol-5-yl)-1H-indole-5-carboxamide, AH-494) and 13 (3-(1-methyl-1H-imidazol-5-yl)-1H-indole-5-carboxamide), have supported their usefulness as pharmacological tools. Comprehensive in vitro comparison studies between 7, 13 and the commonly used 5-CT showed their very similar ADMET properties. Compound 7 at 1 mg kg-1 reversed MK-801-induced disruption in novel object recognition in mice and alleviated stress-induced hyperthermia (SIH) at high doses. Taking into account both in vitro and in vivo data, 7 and 13 may be considered as alternatives to 5-CT as pharmacological tools with important additional benefit associated with their low-basicity: high selectivity over 5-HT1AR.

Mutual activation of glutamatergic mGlu4 and muscarinic M4 receptors reverses schizophrenia-related changes in rodents.

RATIONALE: Metabotropic glutamate receptors and muscarinic M4 receptors have been proposed as novel targets for various brain disorders, including schizophrenia. Both receptors are coupled to Go/i proteins and are expressed in brain circuits that are important in schizophrenia. Therefore, their mutual activation may be an effective treatment and allow minimizing the doses of ligands required for optimal activity. OBJECTIVES: In the present studies, subactive doses of mGlu4 and M4 activators (LSP4-2022 and VU152100, respectively) were administered to investigate the mutual interaction between mGlu4 and M4 receptors in animal models of schizophrenia. METHODS: The behavioral tests used were MK-801-induced hyperactivity, (±)-2.5-dimethoxy-4-iodoamphetamine hydrochloride (DOI)-induced head twitches, the modified forced swim test, and MK-801-induced disruptions of social interactions and novel object recognition. DOI-induced spontaneous excitatory postsynaptic currents (sEPSCs) in brain slices and positron emission tomography (PET) in were used to establish the ability of these compounds to modulate the glutamatergic and dopaminergic systems. Rotarod was used to assess putative adverse effects. RESULTS: The mutual administration of subactive doses of LSP4-2022 and VU152100 exerted similar antipsychotic-like efficacy in animals as observed for active doses of both compounds, indicating their additive actions. VU152100 inhibited the DOI-induced frequency (but not amplitude) of sEPSCs in the frontal cortex, confirming presynaptic regulation of glutamate release. Both compounds reversed amphetamine-induced decrease in D2 receptor levels in the striatum, as measured with [18F]fallypride. The compounds did not induce any motor impartments when measured in rotarod test. CONCLUSIONS: Based on our results, the simultaneous activation of M4 and mGlu4 receptors is beneficial in reversing MK-801- and amphetamine-induced schizophrenia-related changes in animals.

Antidepressant-like activity of the neuropeptide Y Y5 receptor antagonist Lu AA33810: behavioral, molecular, and immunohistochemical evidence.

RATIONALE: It has recently been found that chronic treatment with the highly selective, brain-penetrating Y5 receptor antagonist, Lu AA33810 [N-[[trans-4-[(4,5-dihydro [1] benzothiepino[5,4-d] thiazol-2-yl) amino] cyclohexyl]methyl]-methanesulfonamide], produces antidepressant-like effects in the rat chronic mild stress model. OBJECTIVE: In the present study, we investigated the possible antidepressant-like activity of Lu AA33810 in rats subjected to glial ablation in the prefrontal cortex (PFC) by the gliotoxin L-AAA, which is an astroglial degeneration model of depression. RESULTS: We observed that Lu AA33810 administered intraperitoneally at a single dose of 10 mg/kg both reversed depressive-like behavioral changes in the forced swim test (FST) and prevented degeneration of astrocytes in the mPFC. The mechanism of antidepressant and glioprotective effects of Lu AA33810 has not been studied, so far. We demonstrated the contribution of the noradrenergic rather than the serotonergic pathway to the antidepressant-like action of Lu AA33810 in the FST. Moreover, we found that antidepressant-like effect of Lu AA33810 was connected with the influence on brain-derived neurotrophic factor (BDNF) protein expression. We also demonstrated the antidepressant-like effect of Lu AA33810 in the FST in rats which did not receive the gliotoxin. We found that intracerebroventricular injection of the selective MAPK/ERK inhibitor U0126 (5 µg/2 µl) and the selective PI3K inhibitor LY294002 (10 nmol/2 µl) significantly inhibited the anti-immobility effect of Lu AA33810 in the FST in rats, suggesting that MAPK/ERK and PI3K signaling pathways could be involved in the antidepressant-like effect of Lu AA33810. CONCLUSION: Our results indicate that Lu AA33810 exerts an antidepressant-like effect and suggest the Y5 receptors as a promising target for antidepressant therapy.

Neurochemical and behavioral studies on the 5-HT1A-dependent antipsychotic action of the mGlu4 receptor agonist LSP4-2022.

LSP4-2022 is a novel, orthosteric agonist of mGlu4 receptor that induces antipsychotic-like activity in animal studies. In the present study, the involvement of 5-HT1A receptors in LSP4-2022-induced antipsychotic actions and the neurochemical background of that interaction were investigated. In several behavioral tests the actions of effective doses of the compound (0.5-2 mg/kg) were antagonized via the administration of the 5-HT1A antagonist WAY100635 (0.1 mg/kg). The co-administration of sub-effective dose of the 5-HT1A agonist (R)-(S)-8-OH-DPAT (0.01 mg/kg) intensified the activity of ineffective doses of LSP4-2022, having no influence on the efficacy of the active doses. The co-administration of effective doses of both compounds did not intensify each other's action. In the microdialysis in vivo tests, MK-801 (0.6 mg/kg) induced an enhancement of the release of dopamine, serotonin, glutamate and GABA in the prefrontal cortex. Administration of LSP4-2022 (2 mg/kg) abolished this MK-801-induced effect on neurotransmitter release. Co-administration with WAY100635 (0.1 mg/kg), a 5-HT1A antagonist, completely (dopamine, serotonin) or partially (glutamate, GABA) counteracted this LSP4-2022-induced effect. Subsequently, the patch-clamp recordings of spontaneous EPSCs were performed. sEPSCs were evoked in slices from the mouse prefrontal cortex by DOI (10 µM). LSP4-2022 (2.5; 5 and 10 µm) reversed DOI-induced changes in both the frequency and amplitude of the sEPSCs, but the more robust effect on the frequency was observed. The administration of WAY100635 had no effect on the LSP4-2022-induced effects on sEPSCs, indicating that the mGlu4-5-HT1A interaction does not occur via single-neuron signaling but involves neuronal circuits that regulate neurotransmitter release. This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'.

Low-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol.

A series of 5-aryl-1-alkylimidazole derivatives was synthesized using the van Leusen multicomponent reaction. The chemotype is the first example of low-basicity scaffolds exhibiting high affinity for 5-HT7 receptor together with agonist function. The chosen lead compounds 3-(1-ethyl-1H-imidazol-5-yl)-5-iodo-1H-indole (AGH-107, 1o, K i 5-HT7 = 6 nM, EC50 = 19 nM, 176-fold selectivity over 5-HT1AR) and 1e (5-methoxy analogue, K i 5-HT7 = 30 nM, EC50 = 60 nM) exhibited high selectivity over related CNS targets, high metabolic stability and low toxicity in HEK-293 and HepG2 cell cultures. A rapid absorption to the blood, high blood-brain barrier permeation and a very high peak concentration in the brain (Cmax = 2723 ng/g) were found for 1o after i.p. (5 mg/kg) administration in mice. The compound was found active in novel object recognition test in mice, at 0.5, 1 and 5 mg/kg. Docking to 5-HT7R homology models indicated a plausible binding mode which explain the unusually high selectivity over the related CNS targets. Halogen bond formation between the most potent derivatives and the receptor is consistent with both the docking results and SAR. 5-Chlorine, bromine and iodine substitution resulted in a 13, 27 and 89-fold increase in binding affinities, respectively, and in enhanced 5-HT1AR selectivity.

Involvement of GABAB Receptor Signaling in Antipsychotic-like Action of the Novel Orthosteric Agonist of the mGlu4 Receptor, LSP4-2022.

Considering that ligands of metabotropic glutamate and GABA receptors may exert beneficial effects on schizophrenia, we assessed the actions of the first mGlu>4-selective orthosteric agonist, LSP4-2022, in several tests reflecting positive, negative, and cognitive symptoms of schizophrenia. Moreover, we investigated the possible involvement of GABAB receptors in LSP4-2022-induced actions. Hyperactivity induced by MK-801 or amphetamine and DOI-induced head twitches in mice were used as the models of positive symptoms. The social interaction test, modified forced swim test (FST), and novel object recognition (NOR) test were used as the models of negative and cognitive symptoms of schizophrenia. LSP4-2022 inhibited hyperactivity (in a dose-dependent manner, 0.5-2 mg/kg) induced by MK-801 or amphetamine and DOI-induced head twitches. In mGlu4 receptor knockout mice, LSP4-2022 was not effective. However, it reversed MK-801-induced impairment in the social interaction test and the MK-801-induced increase of immobility in the modified FST. In the NOR test, LSP4-2022 was active at a dose of 2 mg/kg. GABAB receptor antagonist, CGP55845 (10 mg/kg), reversed LSP4-2022-induced effects in hyperactivity and head twitch tests. At the same time, the simultaneous administration of subeffective doses of LSP4-2022 (0.1 mg/kg) and a positive allosteric modulator of GABAB receptor PAM, GS39783 (0.1 mg/kg), induced clear antipsychotic-like effects in those two tests. Such an interaction between mGlu4 and GABAB receptors was not observed in the social interaction and NOR tests. Therefore, we suggest that the activation of the mGlu4 receptor is a promising approach facilitating the discovery of novel antipsychotic drugs, and that the interplay between mGlu4 and GABAB receptors may become the basis for a novel therapy for schizophrenic patients with predomination of positive symptoms.