Pro-social and pro-cognitive effects of LIT-001, a novel oxytocin receptor agonist in a neurodevelopmental model of schizophrenia.

Social and cognitive dysfunctions are the most persistent symptoms of schizophrenia. Since oxytocin (OXT) is known to play a role in social functions and modulates cognitive processes, we investigated the effects of a novel, nonpeptide, selective OXT receptor agonist, LIT-001, in a neurodevelopmental model of schizophrenia. Administration of methylazoxymethanol acetate (MAM; 22 mg/kg) on the 17th day of rat pregnancy is known to cause developmental disturbances of the brain, which lead to schizophrenia-like symptomatology in the offspring. Here, we examined the effects of acutely administered LIT-001 (1, 3, and 10 mg/kg) in MAM-exposed males and females on social behaviour, communication and cognition. We report that MAM-treated adult male and female rats displayed reduced social behaviour, ultrasonic communication and novel object recognition test performance. LIT-001 partially reversed these deficits, increasing the total social interaction time and the number of 'positive', highly-modulated 50 kHz ultrasonic calls in male rats. The compound ameliorated MAM-induced deficits in object discrimination in both sexes. Present results confirm the pro-social activity of LIT-001 and demonstrate its pro-cognitive effects following acute administration.

5-HT6 receptor antagonists. Design, synthesis, and structure-activity relationship of substituted 2-(1-methyl-4-piperazinyl)pyridines.

In this study, we present the discovery and pharmacological characterization of a new series of 6-piperazinyl-7-azaindoles. These compounds demonstrate potent antagonism and selectivity against the 5-HT6 receptor. Our research primarily focuses on optimizing the lead structure and investigating the structure-activity relationship (SAR) of these compounds. Our main objective is to improve their activity and selectivity against off-target receptors. Overall, our findings contribute to the advancement of novel compounds targeting the 5-HT6 receptor. Compound 29 exhibits significant promise in terms of pharmacological, physicochemical, and ADME (Absorption, Distribution, Metabolism, and Excretion) properties. Consequently, it merits thorough exploration as a potential drug candidate due to its favorable activity profile and successful outcomes in a range of in vivo experiments.

Maternal immune activation affects socio-communicative behavior in adult rats.

A wide body of evidence suggests a relationship between maternal immune activation (MIA) and neurodevelopmental disorders such as autism spectrum disorder (ASD). Since social and communicative deficits are included in the first diagnostic criterion of ASD, we aimed to characterize socio-communicative behaviors in the MIA model based on prenatal exposure to poly(I:C). Our previous studies demonstrated impaired socio-communicative functioning in poly(I:C)-exposed adolescent rats. Therefore, the current study sought to clarify whether these changes would persist beyond adolescence. For this purpose, we analyzed behavior during the social interaction test and recorded ultrasonic vocalizations (USVs) accompanying interactions between adult poly(I:C) rats. The results demonstrated that the altered pattern of social behavior in poly(I:C) males was accompanied by the changes in acoustic parameters of emitted USVs. Poly(I:C) males also demonstrated an impaired olfactory preference for social stimuli. While poly(I:C) females did not differ from controls in socio-positive behaviors, they displayed aggression during the social encounter and were more reactive to somatosensory stimulation. Furthermore, the locomotor pattern of poly(I:C) animals were characterized by repetitive behaviors. Finally, poly(I:C) reduced parvalbumin and GAD67 expression in the cerebellum. The results showed that prenatal poly(I:C) exposure altered the pattern of socio-communicative behaviors of adult rats in a sex-specific manner.

Impact of the Substitution Pattern at the Basic Center and Geometry of the Amine Fragment on 5-HT6 and D3R Affinity in the 1H-Pyrrolo[3,2-c]quinoline Series.

Salt bridge (SB, double-charge-assisted hydrogen bonds) formation is one of the strongest molecular non-covalent interactions in biological systems, including ligand-receptor complexes. In the case of G-protein-coupled receptors, such an interaction is formed by the conserved aspartic acid (D3.32) residue and the basic moiety of the aminergic ligand. This study aims to determine the influence of the substitution pattern at the basic nitrogen atom and the geometry of the amine moiety at position 4 of 1H-pyrrolo[3,2-c]quinoline on the quality of the salt bridge formed in the 5-HT6 receptor and D3 receptor. To reach this goal, we synthetized and biologically evaluated a new series of 1H-pyrrolo[3,2-c]quinoline derivatives modified with various amines. The selected compounds displayed a significantly higher 5-HT6R affinity and more potent 5-HT6R antagonist properties when compared with the previously identified compound PZ-1643, a dual-acting 5-HT6R/D3R antagonist; nevertheless, the proposed modifications did not improve the activity at D3R. As demonstrated by the in silico experiments, including molecular dynamics simulations, the applied structural modifications were highly beneficial for the formation and quality of the SB formation at the 5-HT6R binding site; however, they are unfavorable for such interactions at D3R.

Effects of ketamine optical isomers, fluoxetine and naloxone on timing in differential reinforcement of low-rate response (DRL) 72-s task in rats.

(S)-ketamine-induced rapid-acting antidepressant effects have revolutionized the pharmacotherapy of major depression; however, this medication also produces psychotomimetic effects such as timing distortion. While (R)-ketamine produces fewer dissociative effects, its antidepressant actions are less studied. Depression is associated with time overestimation (i.e., subjectively, time passes slowly). Our recent report suggests that while (S)-ketamine induces an opposite effect, i.e., time underestimation, the (R)-isomer does not affect timing. It has been suggested that opioid receptors are involved in the antidepressant effect of ketamine. In the present study we tested (R)- and (S)-ketamine, and fluoxetine as a positive control in the differential-reinforcement-of-low-rate (DRL) 72-s schedule of reinforcement in male rats following naloxone pretreatment. DRL classic metrics as well as peak deviation analyses served to determine antidepressant-like actions and those associated with timing. We report antidepressant-like effects of (S)-ketamine (30-60 mg/kg) that resemble fluoxetine's (2.5-10 mg/kg), as both compounds increased reinforcement rate and peak location (suggesting increased performance), reduced premature responses (suggesting time underestimation) and decreased Weber's fraction (suggesting increased timing precision). (R)-ketamine (30, but not 60 mg/kg) increased only the reinforcement rate and peak location but did not affect timing. Only fluoxetine decreased burst responses, suggesting decreased impulsivity. Naloxone pretreatment did not block ketamine enantiomers' actions, but unexpectedly, increased fluoxetine' performance. Thus, while all three medications produced antidepressant-like effects in DRL 72-s, fluoxetine- and (S)- but not (R)- ketamine-induced time underestimation (the subject experiences the time as passing quickly). The potentiation of DRL performance of fluoxetine by naloxone was unexpected and warrants clinical studies.

Effects of ketamine on rat social behavior as analyzed by DeepLabCut and SimBA deep learning algorithms.

Traditional methods of rat social behavior assessment are extremely time-consuming and susceptible to the subjective biases. In contrast, novel digital techniques allow for rapid and objective measurements. This study sought to assess the feasibility of implementing a digital workflow to compare the effects of (R,S)-ketamine and a veterinary ketamine preparation Vetoquinol (both at 20 mg/kg) on the social behaviors of rat pairs. Historical and novel videos were used to train the DeepLabCut neural network. The numerical data generated by DeepLabCut from 14 video samples, representing various body parts in time and space were subjected to the Simple Behavioral Analysis (SimBA) toolkit, to build classifiers for 12 distinct social and non-social behaviors. To validate the workflow, previously annotated by the trained observer historical videos were analyzed with SimBA classifiers, and regression analysis of the total time of social interactions yielded R 2 = 0.75, slope 1.04; p < 0.001 (N = 101). Remarkable similarities between human and computer annotations allowed for using the digital workflow to analyze 24 novel videos of rats treated with vehicle and ketamine preparations. Digital workflow revealed similarities in the reduction of social behavior by both compounds, and no substantial differences between them. However, the digital workflow also demonstrated ketamine-induced increases in self-grooming, increased transitions from social contacts to self-grooming, and no effects on adjacent lying time. This study confirms and extends the utility of deep learning in analyzing rat social behavior and highlights its efficiency and objectivity. It provides a faster and objective alternative to human workflow.

Comparison of iSeq and MiSeq as the two platforms for 16S rRNA sequencing in the study of the gut of rat microbiome.

Amplicon-based next-generation sequencing (NGS) of the 16S ribosomal RNA (16S) regions is a culture-free method used to identify and analyze Procaryota occurring within a given sample. The prokaryotic 16S rRNA gene contains conserved regions and nine variable regions (V1-V9) frequently used for phylogenetic classification of genus or species in diverse microbial populations. This work compares the accuracy and efficacy of two platforms, iSeq and MiSeq from Illumina, used in sequencing 16S rRNA. The most important similarities and differences of 16S microbiome sequencing in 20 fecal rat samples were described. Genetic libraries were prepared according to 16S Metagenomic Sequencing Library Preparation (Illumina) for the V3 and V4 regions of the 16S. The species richness obtained using iSeq technology was lower compared to MiSeq. At the second taxonomy level (L2), the abundance of taxa was comparable for both platforms. At the L7, the taxa abundance was significantly different, and the number of taxa was higher for the MiSeq. The alpha diversity was lower for iSeq than for MiSeq, starting from the order to the species level. The beta diversity estimation revealed statistically significant differences in microbiota diversity starting from the class level to the species level in samples sequenced on two investigated platforms. This work disclosed that the iSeq platform could be used to evaluate the bacterial profile of the samples to characterize the overall profile. The MiSeq System seems to be better for a detailed analysis of the differences in the microbiota composition. KEY POINTS: • iSeq platform allows to shorten the sequencing time three times compared to the MiSeq. • iSeq can only be used for an initial and quick microbiome assessment. • MiSeq is better for a detailed analysis of the differences in the microbiota composition.

The Effects of Positive Allosteric Modulators of α7-nAChR on Social Play Behavior in Adolescent Rats Prenatally Exposed to Valproic Acid.

There is still no effective treatment that addresses the core symptoms of autism spectrum disorders (ASD), including social and communication deficits. A comprehensive body of evidence points to the cholinergic system, including alpha7-nicotinic acetylcholine receptors (α7-nAChRs), as a potential target of pharmacotherapy. A promising approach is based on positive allosteric modulators (PAMs) of these receptors due to their advantages over direct agonists. Nevertheless, α7 n-AChR ligands have not been widely studied in the context of autism. Therefore, using one of the most widely used rodent models of ASD, that is, prenatal exposure to valproic acid (VPA), we examined the impact of α7-nAChR PAMs (PNU-120596 and CCMI) on socio-communicative behavior during social play in adolescent male and female rats. The current study demonstrated that PAM treatment affected certain aspects of socio-communicative behavior in adolescent rats. Accordingly, PNU-120596 ameliorated deficient play abilities in VPA-exposed males, as revealed by increased play time during a social encounter. In addition, this compound enhanced the emission of ultrasonic vocalizations that accompanied playful interactions. Moreover, we observed the overall effect of PNU-120596 on non-playful forms of social behavior (i.e., social exploration) and acoustic parameters (i.e., the duration) of emitted calls. The present results suggest the ability of α7-nAChR PAMs to facilitate socio-communicative behavior in adolescent rats.

Effects of ketamine optical isomers, psilocybin, psilocin and norpsilocin on time estimation and cognition in rats.

RATIONALE: Ketamine and psilocybin belong to the rapid-acting antidepressants but they also produce psychotomimetic effects including timing distortion. It is currently debatable whether these are essential for their therapeutic actions. As depressed patients report that the "time is dragging," we hypothesized that ketamine and psilocybin-like compounds may produce an opposite effect, i.e., time underestimation, purportedly contributing to their therapeutic properties. OBJECTIVES: Timing was tested following administration of (R)- and (S)-ketamine, and psilocybin, psilocin, and norpsilocin in the discrete-trial temporal discrimination task (TDT) in male rats. Timing related to premature responses, and cognitive and unspecific effects of compounds were tested in the 5-choice serial reaction time task (5-CSRTT) in the standard 1-s, and "easier" 2-s stimulus duration conditions, as well as in the vITI variant promoting impulsive responses. RESULTS: (S)-ketamine (15 but not 3.75 or 7.5 mg/kg) shifted psychometric curve to the right in TDT and reduced premature responses in 5-CSRTT, suggesting expected time underestimation, but it also decreased the accuracy of temporal discrimination and increased response and reward latencies, decreased correct responses, and increased incorrect responses. While (R)-ketamine did not affect timing and produced no unspecific actions, it reduced incorrect responses in TDT and increased accuracy in 5-CSRTT, suggesting pro-cognitive effects. Psilocin and psilocybin produced mainly unspecific effects in both tasks, while norpsilocin showed no effects. CONCLUSIONS: Time underestimation produced by (S)-ketamine could be associated with its antidepressant effects; however, it was accompanied with severe behavioral disruption. We also hypothesize that behavioral disruption produced by psychedelics objectively reflects their psychotomimetic-like actions.

Astroglia in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is an umbrella term encompassing several neurodevelopmental disorders such as Asperger syndrome or autism. It is characterised by the occurrence of distinct deficits in social behaviour and communication and repetitive patterns of behaviour. The symptoms may be of different intensity and may vary in types. Risk factors for ASD include disturbed brain homeostasis, genetic predispositions, or inflammation during the prenatal period caused by viruses or bacteria. The number of diagnosed cases is growing, but the main cause and mechanism leading to ASD is still uncertain. Recent findings from animal models and human cases highlight the contribution of glia to the ASD pathophysiology. It is known that glia cells are not only "gluing" neurons together but are key players participating in different processes crucial for proper brain functioning, including neurogenesis, synaptogenesis, inflammation, myelination, proper glutamate processing and many others. Despite the prerequisites for the involvement of glia in the processes related to the onset of autism, there are far too little data regarding the engagement of these cells in the development of ASD.

Structure-Based Design and Optimization of FPPQ, a Dual-Acting 5-HT3 and 5-HT6 Receptor Antagonist with Antipsychotic and Procognitive Properties.

In line with recent clinical trials demonstrating that ondansetron, a 5-HT3 receptor (5-HT3R) antagonist, ameliorates cognitive deficits of schizophrenia and the known procognitive effects of 5-HT6 receptor (5-HT6R) antagonists, we applied the hybridization strategy to design dual-acting 5-HT3/5-HT6R antagonists. We identified the first-in-class compound FPPQ, which behaves as a 5-HT3R antagonist and a neutral antagonist 5-HT6R of the Gs pathway. FPPQ shows selectivity over 87 targets and decent brain penetration. Likewise, FPPQ inhibits phencyclidine (PCP)-induced hyperactivity and displays procognitive properties in the novel object recognition task. In contrast to FPPQ, neither 5-HT6R inverse agonist SB399885 nor neutral 5-HT6R antagonist CPPQ reversed (PCP)-induced hyperactivity. Thus, combination of 5-HT3R antagonism and 5-HT6R antagonism, exemplified by FPPQ, contributes to alleviating the positive-like symptoms. Present findings reveal critical structural features useful in a rational polypharmacological approach to target 5-HT3/5-HT6 receptors and encourage further studies on dual-acting 5-HT3/5-HT6R antagonists for the treatment of psychiatric disorders.

Repeated treatment with alpha 7 nicotinic acetylcholine receptor ligands enhances cognitive processes and stimulates Erk1/2 and Arc genes in rats.

The α7 nicotinic acetylcholine receptor (α7 nAChR) is a potential target for the treatment of cognitive decline in patients with schizophrenia, Alzheimer's disease, and attention-deficit/hyperactivity disorder. Here we examined the promnesic activity of the α7 nAChR agonist (A582941), the type I (CCMI), and the type II (PNU120596) positive allosteric modulators (PAMs) in rats following single and repeated (once daily for seven days) treatment. To determine the neuronal mechanisms underlying the procognitive activity of the tested compounds, levels of the extracellular signal-regulated kinases (Erk1/2) and the activity-regulated cytoskeleton-associated protein (Arc) mRNAs were assessed in the frontal cortical and hippocampal brain regions. Using the novel object recognition test, we demonstrate that the lower doses of A582941 (0.1 mg/kg), CCMI (1 mg/kg), and PNU120596 (0.3 mg/kg) improved recognition memory after repeated but not single administration, suggesting a cumulative effect of repeated dosing. In contrast, the higher doses of A582941 (0.3 mg/kg), CCMI (3 mg/kg) and PNU120596 (1 mg/kg) demonstrated promnesic efficacy following both single and repeated administration. Subsequent in situ hybridization revealed that repeated treatment with A582941 and CCMI, but not PNU120596 enhanced mRNA expression of the Erk1/2 and Arc in the frontal cortex and hippocampus. Present data suggest that both the α7 nAChR agonist and PAMs exhibit procognitive effects after single and repeated administration. The increased level of the Erk1/2 and Arc genes is likely to be at least partially involved in this effect.

The Effect of Maternal Immune Activation on Social Play-Induced Ultrasonic Vocalization in Rats.

Prenatal maternal infection is associated with an increased risk of various neurodevelopmental disorders, including autism spectrum disorders (ASD). Maternal immune activation (MIA) can be experimentally induced by prenatal administration of polyinosinic:polycytidylic acid (poly I:C), a synthetic viral-like double-stranded RNA. Although this MIA model is adopted in many studies, social and communicative deficits, included in the first diagnostic criterion of ASD, are poorly described in the offspring of poly(I:C)-exposed dams. This study aimed to characterize the impact of prenatal poly(I:C) exposure on socio-communicative behaviors in adolescent rats. For this purpose, social play behavior was assessed in both males and females. We also analyzed quantitative and structural changes in ultrasonic vocalizations (USVs) emitted by rats during the play test. Deficits of social play behaviors were evident only in male rats. Males also emitted a significantly decreased number of USVs during social encounters. Prenatal poly(I:C) exposure also affected acoustic call parameters, as reflected by the increased peak frequencies. Additionally, repetitive behaviors were demonstrated in autistic-like animals regardless of sex. This study demonstrates that prenatal poly(I:C) exposure impairs socio-communicative functioning in adolescent rats. USVs may be a useful tool for identifying early autistic-like abnormalities.

2-Phenyl-1H-pyrrole-3-carboxamide as a New Scaffold for Developing 5-HT6 Receptor Inverse Agonists with Cognition-Enhancing Activity.

Serotonin type 6 receptor (5-HT6R) has gained particular interest as a promising target for treating cognitive deficits, given the positive effects of its antagonists in a wide range of memory impairment paradigms. Herein, we report on degradation of the 1H-pyrrolo[3,2-c]quinoline scaffold to provide the 2-phenyl-1H-pyrrole-3-carboxamide, which is devoid of canonical indole-like skeleton and retains recognition of 5-HT6R. This modification has changed the compound's activity at 5-HT6R-operated signaling pathways from neutral antagonism to inverse agonism. The study identified compound 27 that behaves as an inverse agonist of the 5-HT6R at the Gs and Cdk5 signaling pathways. Compound 27 showed high selectivity and metabolic stability and was brain penetrant. Finally, 27 reversed scopolamine-induced memory decline in the novel object recognition test and exhibited procognitive properties in the attentional set-shifting task in rats. In light of these findings, 27 might be considered for further evaluation as a new cognition-enhancing agent, while 2-phenyl-1H-pyrrole-3-carboxamide might be used as a template for designing 5-HT6R inverse agonists.

Chronic Lorcaserin Treatment Reverses the Nicotine Withdrawal-Induced Disruptions to Behavior and Maturation in Developing Neurons in the Hippocampus of Rats.

Preclinical data have shown that treatment with serotonin (5-HT)2C receptor agonists inhibits the behavioral effects of nicotine, including self-administration, reinstatement, and locomotor responses to nicotine. Since the data on the effects of 5-HT2C receptor agonism on nicotine withdrawal signs are limited, we aimed to investigate whether 5-HT2C receptor agonism alleviated the behavioral and neurobiochemical (hippocampal neurogenesis) consequences of nicotine withdrawal in Sprague-Dawley rats. Our data indicate that withdrawal from nicotine self-administration induced locomotor hyperactivity, lengthened immobility time (the forced swim test), induced 'drug-seeking' behavior and deficits in cognition-like behavior (the novel object recognition task). A two-week exposure to the 5-HT2C receptor agonist lorcaserin attenuated locomotor hyperactivity and induced recovery from depression-like behavior. Analyses of brain slices from nicotine-withdrawn animals revealed that lorcaserin treatment recovered the reduced number of doublecortin (DCX)-positive cells, but it did not affect the number of Ki-67- or 5-bromo-2'-deoxyuridine (BrdU)-positive cells or the maturation of proliferating neurons in drug-weaned rats. To summarize, we show that lorcaserin alleviated locomotor responses and depression-like state during nicotine withdrawal. We propose that the modulatory effect of lorcaserin on the 'affective' aspects of nicotine cessation may be linked to the positive changes caused by the compound in hippocampal neurogenesis during nicotine withdrawal.

The effect of ageing and cerebral serotonin deficit on the activity of cytochrome P450 2D (CYP2D) in the brain and liver of male rats.

Brain cytochrome P450 (CYP) contributes to the local metabolism of endogenous substrates and drugs. The aim of present study was to ascertain whether the cytochrome P450 2D (CYP2D) activity changes with ageing and in cerebral serotonin deficit. Kinetics of 5-methoxytryptamine O-demethylation to serotonin was studied and the CYP2D activity was measured in brain and liver microsomes of Dark Agouti wild type (WT) rats (mature 3.5-month-old and senescent 21-month-old rats) and in tryptophan hydroxylase 2 (TPH2)-deficient senescent rats. The CYP2D activity and protein level decreased in the frontal cortex of senescent WT rats, but increased in senescent TPH2-deficient rats (compared to senescent WT). In contrast, in the hippocampus, hypothalamus and striatum the CYP2D activity/protein level increased with ageing, but did not change in senescent TPH2-deficient animals (compared to senescent WT). The activity and protein level of liver CYP2D was lower in senescent WT rats than in the mature animals and further decreased in senescent TPH2-deficient rats. In conclusion, ageing and TPH2-deficit affect the CYP2D activity and protein level, which may have a positive impact on neurotransmitter synthesis in brain structures involved in cognitive, emotional or motor functions, but a negative effect on drug metabolism in the liver.

Valproic acid exposure impairs ultrasonic communication in infant, adolescent and adult rats.

Persistent deficits of social communication are a hallmark of autism spectrum disorders (ASD). Communication disabilities can be experimentally modeled using rodents' ultrasonic vocalizations (USVs). Although prenatal exposure to valproic acid (VPA) is one of the most widely used animal models of ASD, little is known about communication impairments in this model. We performed a longitudinal study to characterize VPA-induced socio-communicative deficits in male and female rats. USVs were recorded in neonatal rats during maternal separation, in adolescent rats during social play, and in adult rats during social interactions. VPA male and female pups emitted a reduced number of USVs. Their calls were shorter and of an elevated peak frequency. Although social play deficits in adolescent rats were restricted to males only, both males and females demonstrated quantitative and qualitative changes in USVs. Altered vocalization also accompanied deficient social interactions in adult VPA males. In contrast to the adolescents, however, these differences were limited to a reduced number of USVs, but not to the call's structure. Present data suggest that ultrasonic vocalization measurement is a useful tool in detecting lifelong communicative disability in a VPA exposure-induced ASD model. We postulate that USV assessment in female rats may be a more sensitive indicator of juvenile autistic-like disturbances than other behavioral measures.

Effects of prenatal exposure to valproic acid or poly(I:C) on ultrasonic vocalizations in rat pups: The role of social cues.

Sociocommunicative deficits commonly observed in autism spectrum disorder (ASD) can be experimentally modeled using rodents' ultrasonic vocalizations (USVs). For example, USVs emitted by pups, separated from their mothers and nest, serve as a useful tool to identify autistic-like behaviors during the early period of development. Being sensitive to social context, these neonatal calls may help to reveal reduced social attachment or abnormal processing of social information. The aim of the present study was to characterize quantitative and structural changes in USVs emitted during isolation by male and female rat pups prenatally exposed to either valproic acid (VPA) or poly(I:C). To determine whether those pups differed from controls in sensitivity to social stimuli, isolation-induced USVs were recorded under two bedding conditions, i.e., novel bedding and soiled bedding from their home cages. Our results demonstrated early communication deficits in both models of autism. We reported a reduced number of USVs emitted by both VPA- and poly(I:C)-exposed males and females. Moreover, compared to the controls, VPA (but not poly(I:C)) pups emitted shorter calls with a higher peak frequency. While VPA offspring demonstrated fewer USVs on the "safe" bedding imbued with maternal/nest odors, this calming effect was not observed in poly(I:C) males, suggesting a more specific deficit in social communication. The present results demonstrate that qualitative along with quantitative analyses of neonatal vocalizations are a useful tool for assessing early sociocommunicative deficits in ASD models. Notably, more specific changes in USV emission may be detected when introducing social context.

Distinct cognitive and discriminative stimulus effects of ketamine enantiomers in rats.

Although (S)-ketamine was approved for use in treatment-resistant depression in 2019, new preclinical findings suggest that (R)-ketamine might produce better efficacy and tolerability relative to (S)-ketamine. Here we evaluated the effects of (R)-, (S)-, and (R,S)-ketamine on executive functions as measured in the attentional set shifting task (ASST) and on their discriminative stimulus effects in rats. Earlier data demonstrated that cognitive flexibility is compromised by (R,S)-ketamine, but the effects of enantiomers in rats are unknown. Separate cohorts of rats were tested in ASST and trained to discriminate either (R,S)-ketamine, (S)-ketamine, or (R)-ketamine (all at 10 mg/kg) from saline; in order to maintain the discrimination, a higher (R)-ketamine dose (17.5 mg/kg) was subsequently instituted. In ASST, all three forms increased the trials to criterion measure at reversal learning and extra-dimensional set-shifting phases. However, in contrast to (R)- and (S)-ketamine, (R,S)-ketamine prolonged the mean time to complete a single trial during early stages, suggesting increased reaction time, and/or unspecific side-effects related to motor or motivational impairments. In the drug discriminations, all rats acquired their respective discriminations between drug and saline. In (R,S)-ketamine-trained rats, (R)-ketamine and (S)-ketamine only partially substituted for the training dose of (R,S)-ketamine. Further, (R)-ketamine did not fully substitute in rats trained to (S)-ketamine. The data suggest more serious cognitive deficits produced by (R,S)-ketamine than its enantiomers. Furthermore, (R,S)-ketamine and its isomers share overlapping but not isomorphic discriminative stimulus effects predicting distinct subjective responses to (R)- vs. (S)-ketamine in humans.

Correction to: Desformylflustrabromine, a positive allosteric modulator of α4ß2-containing nicotinic acetylcholine receptors, enhances cognition in rats.

The original article can be found online.