Intrinsic anticipatory motives in non-human primate food consumption behavior.

Future-oriented behavior is regarded as a cornerstone of human cognition. One key phenomenon through which future orientation can be studied is the delay of gratification, when consumption of an immediate reward is withstood to achieve a larger reward later. The delays used in animal delay of gratification paradigms are rather short to be considered relevant for studying human-like future orientation. Here, for the first time, we show that rhesus macaques exhibit human-relevant future orientation downregulating their operant food consumption in anticipation of a nutritionally equivalent but more palatable food with an unprecedentedly long delay of approximately 2.5 h. Importantly, this behavior is not a result of conditioning but intrinsic to the animals. Our results show that the cognitive time horizon of primates, when tested in ecologically valid foraging-like experiments, extends much further into the future than previously considered, opening up new avenues for translational biomedical research.

Discovery of Novel Steroid-Based Histamine H3 Receptor Antagonists/Inverse Agonists.

Steroid-based histamine H3 receptor antagonists (d-homoazasteroids) were designed by combining distinct structural elements of HTS hit molecules. They were characterized, and several of them displayed remarkably high affinity for H3 receptors with antagonist/inverse agonist features. Especially, the 17a-aza-d-homolactam chemotype demonstrated excellent H3R activity together with significant in vivo H3 antagonism. Optimization of the chemotype was initiated with special emphasis on the elimination of the hERG and muscarinic affinity. Additionally, ligand-based SAR considerations and molecular docking studies were performed to predict binding modes of the molecules. The most promising compounds (XXI, XXVIII, and XX) showed practically no muscarinic and hERG affinity. They showed antagonist/inverse agonist property in the in vitro functional tests that was apparent in the rat in vivo dipsogenia test. They were considerably stable in human and rat liver microsomes and provided significant in vivo potency in the place recognition and novel object recognition cognitive paradigms.

Optimization of Novel α7 Nicotinic Acetylcholine Receptor Positive Allosteric Modulators and the Discovery of a Preclinical Development Candidate Molecule (RGH-560).

During optimization of a previously identified lead compound, attempts were made to optimize the reactive indole structural element, the suboptimal metabolic stability, as well as the low kinetic solubility. It was concluded that the indole was important for in vitro activity. With the aim of further improvements, more thorough modifications were also carried out. As a result, a new chemotype (the azetidinespirochromone family) was identified, which proved to be 1 order of magnitude less lipophilic retaining the same high level of in vitro potency as the lead series itself, however, with improved metabolic stability and kinetic solubility. Compound 53 showed the most balanced physicochemical and pharmacological profile with significant in vivo efficacy in the scopolamine-induced amnesia test. Based on these promising results, cognitive enhancement through the positive modulation of α7 nAChRs appears to be a viable approach. Compound 53 was selected to be a preclinical development candidate (as RGH-560).

Response-related sensorimotor rhythms under scopolamine and MK-801 exposures in the touchscreen visual discrimination test in rats.

The human mu rhythm has been suggested to represent an important function in information processing. Rodent homologue rhythms have been assumed though no study has investigated them from the cognitive aspect yet. As voluntary goal-directed movements induce the desynchronization of mu rhythm, we aimed at exploring whether the response-related brain activity during the touchscreen visual discrimination (VD) task is suitable to detect sensorimotor rhythms and their change under cognitive impairment. Different doses of scopolamine or MK-801 were injected subcutaneously to rats, and epidural electroencephalogram (EEG) was recorded during task performance. Arciform ~ 10 Hz oscillations appeared during visual processing, then two characteristic alpha/beta desynchronization-resynchronization patterns emerged mainly above the sensorimotor areas, serving presumably different motor functions. Beyond causing cognitive impairment, both drugs supressed the touch-related upper alpha (10-15 Hz) reactivity for desynchronization. Reaction time predominantly correlated positively with movement-related alpha and beta power both in normal and impaired conditions. These results support the existence of a mu homologue rodent rhythm whose upper alpha component appeared to be modulated by cholinergic and glutamatergic mechanisms and its power change might indicate a potential EEG correlate of processing speed. The VD task can be utilized for the investigation of sensorimotor rhythms in rats.

Intranasal Oxytocin Improves Social Behavior in Laboratory Beagle Dogs (Canis familiaris) Using a Custom-Made Social Test Battery.

For a long time, oxytocin has been thought to have a generally positive effect on social cognition and prosocial behavior; however, recent results suggested that oxytocin has beneficial effects only under certain conditions. The aim of the present study was to explore potential associations between social competence and the effect of intranasal oxytocin on the social behavior of laboratory beagle dogs. We expected oxytocin treatment to have a more pronounced positive effect on dogs with lower baseline performance in a social test battery. Thirty-six adult dogs of both sexes received 32 IU intranasal oxytocin and physiological saline (placebo) treatment in a double-blind, cross-over design, with 17-20 days between the two sessions. Forty minutes after the treatment, dogs participated in a social test battery consisting of eight situations. The situations were carried out within one session and took 20-30 min to complete. Principal component analysis on the coded behaviors identified four components (Willingness to interact, Preference for social contact, Non-aversive response to nonsocial threat, and Non-aversive response to social threat). The subjects' behavior during the placebo condition was used to assess their baseline performance. We found that oxytocin treatment had a differential effect on the behavior depending on the baseline performance of the individuals in all components, but only two treatment × baseline performance interactions remained significant in a less sensitive analysis. In accordance with our hypothesis, oxytocin administration increased dogs' contact seeking and affiliative behaviors toward humans but only for those with low baseline performance. Dogs with low baseline performance also showed significantly more positive (friendly) reactions to social threat after oxytocin administration than after placebo, while for dogs with high baseline performance, oxytocin administration led to a more negative (fearful) reaction. These results indicate that similar to those on humans, the effects of oxytocin on dogs' social behavior are not universally positive but are constrained by individual characteristics and the context. Nevertheless, oxytocin administration has the potential to improve the social behavior of laboratory beagle dogs that are socially less proficient when interacting with humans, which could have both applied and animal welfare implications.

Maternal P2X7 receptor inhibition prevents autism-like phenotype in male mouse offspring through the NLRP3-IL-1ß pathway.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition caused by interactions of environmental and genetic factors. Recently we showed that activation of the purinergic P2X7 receptors is necessary and sufficient to convert maternal immune activation (MIA) to ASD-like features in male offspring mice. Our aim was to further substantiate these findings and identify downstream signaling pathways coupled to P2X7 upon MIA. Maternal treatment with the NLRP3 antagonist MCC950 and a neutralising IL-1ß antibody during pregnancy counteracted the development of autistic characteristics in offspring mice. We also explored time-dependent changes of a widespread cytokine and chemokine profile in maternal blood and fetal brain samples of poly(I:C)/saline-treated dams. MIA-induced increases in plasma IL-1ß, RANTES, MCP-1, and fetal brain IL-1ß, IL-2, IL-6, MCP-1 concentrations are regulated by the P2X7/NLRP3 pathway. Offspring treatment with the selective P2X7 receptor antagonist JNJ47965567 was effective in the prevention of autism-like behavior in mice using a repeated dosing protocol. Our results highlight that in addition to P2X7, NLRP3, as well as inflammatory cytokines, may also be potential biomarkers and therapeutic targets of social deficits and repetitive behaviors observed in autism spectrum disorder.

Convergent cross-species pro-cognitive effects of RGH-235, a new potent and selective histamine H3 receptor antagonist/inverse agonist.

The histamine H3 receptor is a favourable target for the treatment of cognitive deficits. Here we report the in vitro and in vivo profile of RGH-235, a new potent, selective, and orally active H3 receptor antagonist/inverse agonist developed by Gedeon Richter Plc. Radioligand binding and functional assays were used for in vitro profiling. Procognitive efficacy was investigated in rodent cognitive tests, in models of attention deficit hyperactive disorder (ADHD) and in cognitive tests of high translational value (rat touch screen visual discrimination test, primate fixed-foreperiod visual reaction time task). Results were supported by pharmacokinetic studies, neurotransmitter release, sleep EEG and dipsogenia. RGH-235 displayed high affinity to H3 receptors (Ki = 3.0-9.2 nM, depending on species), without affinity to H1, H2 or H4 receptors and >100 other targets. RGH-235 was an inverse agonist ([35S] GTPγS binding) and antagonist (pERK1/2 ELISA), showing favourable kinetics, inhibition of the imetit-induced dipsogenia and moderate effects on sleep-wake EEG. RGH-235 stimulated neurotransmitter release both in vitro and in vivo. RGH-235 was active in spontaneously hypertensive rats (SHR), generally considered as a model of ADHD, and revealed a robust pro-cognitive profile both in rodent and primate tests (in 0.3-1 mg/kg) and in models of high translational value (e.g. in a rodent touch screen test and in non-human primates). The multiple and convergent procognitive effects of RGH-235 support the view that beneficial cognitive effects can be linked to antagonism/inverse agonism of H3 receptors.

Contribution of analog signaling to neurotransmitter interactions and behavior: Role of transporter-mediated nonquantal dopamine release.

Neuronal networks cause changes in behaviorally important information processing through the vesicular release of neurotransmitters governed by the rate and timing of action potentials (APs). Herein, we provide evidence that dopamine (DA), nonquantally released from the cytoplasm, may exert similar effects in vivo. In mouse slice preparations, (+/-)-3,4-methylenedioxy-methamphetamine (MDMA, or ecstasy) and ß-phenylethylamine (ß-PEA)-induced DA release in the striatum and nucleus accumbens (NAc), two regions of the brain involved in reward-driven and social behavior and inhibited the axonal stimulation-induced release of tritiated acetylcholine ([3 H]ACh) in the striatum. The DA transporter (DAT) inhibitor (GBR-12909) prevented MDMA and ß-PEA from causing DA release. GBR-12909 could also restore some of the stimulated acetylcholine release reduced by MDMA or ß-PEA in the striatum confirming the fundamental role of DAT. In addition, hypothermia could prevent the ß-PEA-induced release in the striatum and in the NAc. Sulpiride, a D2 receptor antagonist, also prevented the inhibitory effects of MDMA or ß-PEA on stimulated ACh release, suggesting they act indirectly via binding of DA. Reflecting the neurochemical interactions in brain slices at higher system level, MDMA altered the social behavior of rats by preferentially enhancing passive social behavior. Similar to the in vitro effects, GBR-12909 treatment reversed specific elements of the MDMA-induced changes in behavior, such as passive social behavior, while left others including social play unchanged. The changes in behavior by the high level of extracellular DA-- a significant amount originating from cytoplasmic release--suggest that in addition to digital computation through synapses, the brain also uses analog communication, such as DA signaling, to mediate some elements of complex behaviors, but in a much longer time scale.

Cariprazine alleviates core behavioral deficits in the prenatal valproic acid exposure model of autism spectrum disorder.

RATIONALE: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and interaction and restricted, repetitive behaviors. The unmet medical need in ASD is considerable since there is no approved pharmacotherapy for the treatment of these deficits in social communication, interaction, and behavior. Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist, is already approved for the treatment of schizophrenia and bipolar I disorder in adults; investigation in patients with ASD is warranted. OBJECTIVES: The aim of this study was to investigate the effects of cariprazine, compared with risperidone and aripiprazole, in the rat prenatal valporic acid (VPA) exposure model on behavioral endpoints representing the core and associated symptoms of ASD. METHODS: To induce the ASD model, time-mated Wistar rat dams were treated with VPA during pregnancy. Male offspring were assigned to groups and studied in a behavioral test battery at different ages, employing social play, open field, social approach-avoidance, and social recognition memory tests. Animals were dosed orally, once a day for 8 days, with test compounds (cariprazine, risperidone, aripiprazole) or vehicle before behavioral assessment. RESULTS: Cariprazine showed dose-dependent efficacy on all behavioral endpoints. In the social play paradigm, only cariprazine was effective. On the remaining behavioral endpoints, including the reversal of hyperactivity, risperidone and aripiprazole displayed similar efficacy to cariprazine. CONCLUSIONS: In the present study, cariprazine effectively reversed core behavioral deficits and hyperactivity present in juvenile and young adult autistic-like rats. These findings indicate that cariprazine may be useful in the treatment of ASD symptoms.

HTS-based discovery and optimization of novel positive allosteric modulators of the α7 nicotinic acetylcholine receptor.

HTS campaign of the corporate compound collection resulted in a novel, oxalic acid diamide scaffold of α7 nACh receptor positive allosteric modulators. During the hit expansion, several derivatives, such as 4, 11, 17 demonstrated not only high in vitro potency, but also in vivo efficacy in the mouse place recognition test. The advanced hit molecule 11 was further optimized by the elimination of the putatively mutagenic aromatic-amine building block that resulted in a novel, aminomethylindole compound family. The most balanced physico-chemical and pharmacological profile was found in case of compound 55. Docking study revealed an intersubunit binding site to be the most probable for our compounds. 55 demonstrated favorable cognitive enhancing profile not only in scopolamine-induced amnesia (place recognition test in mice) but also in natural forgetting (novel object recognition test in rats). Compound 55 was, furthermore, active in a cognitive paradigm of high translational value, namely in the rat touch screen visual discrimination test. Therefore, 55 was selected as a lead compound for further optimization. Based on the obtained favorable results, the invented aminomethylindole cluster may provide a viable approach for cognitive enhancement through positive allosteric modulation of α7 nAChRs.

Discovery of novel positive allosteric modulators of the α7 nicotinic acetylcholine receptor: Scaffold hopping approach.

The paper focuses on the scaffold hopping-based discovery and characterization of novel nicotinic alpha 7 receptor positive modulator (α7 nAChR PAM) ligands around the reference molecule (A-867744). First, substantial efforts were carried out to assess the importance of the various pharmacophoric elements on the in vitro potency (SAR evaluation) by chemical modifications. Subsequently, several new derivatives with versatile, heteroaromatic central cores were synthesized and characterized. A promising, pyrazole-containing new chemotype with good physicochemical and in vitro parameters was identified. Retrospective analysis based on homology modeling was also carried out. Besides its favorable in vitro characteristics, the most advanced derivative 69 also showed in vivo efficacy in a rodent model of cognition (scopolamine-induced amnesia in the mouse place recognition test) and acceptable pharmacokinetic properties. Based on the in vivo data, the resulting molecule with advanced drug-like characteristics has the possibility to improve cognitive performance in a biologically relevant dose range, further strengthening the view of the supportive role of α7 nACh receptors in the cognitive processes.

Cariprazine modulates sleep architecture in rats.

BACKGROUND: Cariprazine is a dopamine D3-preferring D3/D2 receptor partial agonist compound recently introduced to treat schizophrenia and bipolar disorder. Although cariprazine is clinically classified as a low-somnolence drug, to date no detailed polysomnographic study is available on its effect on sleep. AIMS: This study examined the acute systemic effects of cariprazine on the rat sleep architecture and electroencephalography spectral power. METHODS: Sprague Dawley rats were recorded during their normal sleep period for four hours, and their sleep stages were classified. RESULTS: Cariprazine (0.3 mg/kg i.p.) reduced the time spent in rapid eye movement (REM) sleep and increased REM latency. This dose of cariprazine decreased the gamma (40-80 Hz) band frequency oscillations and increased the theta (4-9 Hz) and alpha (9-15 Hz) frequencies during the wake periods but not during slow-wave sleep. The 0.03 mg/kg dose of cariprazine only increased the alpha power during the wake periods, while the 0.003 mg/kg dose was without any effect. CONCLUSION: Taken together, the present results suggest that the REM-suppressing effect of cariprazine may be related to its effectiveness in improving depressive symptoms, as various drugs with similar REM-reducing properties effectively treat the depressive state, whereas the gamma power-reducing effect of cariprazine may be indicative of its efficacy in schizophrenia or mania, as similar effects have been observed with other D2 and 5-HT2 receptor antagonist drugs. These data contribute to our understanding of the complex mechanism of action that may stand behind the clinical efficacy of cariprazine.

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders.

Dopamine (DA), as one of the major neurotransmitters in the central nervous system (CNS) and periphery, exerts its actions through five types of receptors which belong to two major subfamilies such as D1-like (i.e., D1 and D5 receptors) and D2-like (i.e., D2, D3 and D4) receptors. Dopamine D3 receptor (D3R) was cloned 30 years ago, and its distribution in the CNS and in the periphery, molecular structure, cellular signaling mechanisms have been largely explored. Involvement of D3Rs has been recognized in several CNS functions such as movement control, cognition, learning, reward, emotional regulation and social behavior. D3Rs have become a promising target of drug research and great efforts have been made to obtain high affinity ligands (selective agonists, partial agonists and antagonists) in order to elucidate D3R functions. There has been a strong drive behind the efforts to find drug-like compounds with high affinity and selectivity and various functionality for D3Rs in the hope that they would have potential treatment options in CNS diseases such as schizophrenia, drug abuse, Parkinson's disease, depression, and restless leg syndrome. In this review, we provide an overview and update of the major aspects of research related to D3Rs: distribution in the CNS and periphery, signaling and molecular properties, the status of ligands available for D3R research (agonists, antagonists and partial agonists), behavioral functions of D3Rs, the role in neural networks, and we provide a summary on how the D3R-related drug research has been translated to human therapy.

Acute blockade of NR2C/D subunit-containing N-methyl-D-aspartate receptors modifies sleep and neural oscillations in mice.

N-methyl-d-aspartate receptors (NMDARs) play an important role in excitatory neurotransmission and have been associated with psychiatric conditions including schizophrenia and major depressive disorder. NMDARs are composed of two NR1 and two NR2 subunits. The type of NR2 subunit determines electrophysiological and pharmacological properties of the receptor. As the precise role of NR2C/D subunit-containing NMDARs is poorly understood in vivo, we have performed behavioural, quantitative electroencephalographic (qEEG) and polysomnographic analysis following acute pharmacological blockade of these receptor subtypes in adult male CD1 mice. We found that NR2C/D blockade impaired motor coordination and decreased the amount of gross movement. Moreover, EEG power in multiple frequency bands including theta and sigma were found to decrease significantly together with a decrease of theta oscillation frequency. Changes of these qEEG measures were accompanied by a decrease in time spent in slow-wave and rapid eye movement sleep, but an increase of time spent in quiet wakefulness. Furthermore, there was a significant decrease of sleep spindle oscillation density. These findings highlight the importance of NR2C/D-containing NMDARs and take a step towards establishing a link between electrophysiological correlates of psychiatric disorders and underlying synaptic dysfunctions.

Delay-dependent cholinergic modulation of visual short-term memory in rhesus macaques.

Cholinergic neuromodulation is known to play a key role in visual working memory (VWM) - keeping relevant stimulus representations available for cognitive processes for short time periods (up to a few minutes). Despite the growing body of evidence on how the neural and cognitive mechanisms of VWM dynamically change over retention time, there is mixed evidence available on cholinergic effects as a function of VWM delay period in non-human primates. Using the delayed matching to sample VWM task in rhesus macaques (N = 6), we aimed to characterize VWM maintenance in terms of performance changes as a function of delay duration (across a wide range of delays from 1 to 76 s). Then, we studied how cholinergic neuromodulation influences VWM maintenance using the muscarinic receptor antagonist scopolamine administered alone as transient amnestic treatment, and in combination with two doses of the acetylcholinesterase inhibitor donepezil, a widely used Alzheimer's medication probing for the reversal of scopolamine-induced impairments. Results indicate that scopolamine-induced impairments of VWM maintenance are delay-dependent and specifically affect the 15-33 s time range, suggesting that scopolamine worsens the normal decay of VWM with the passage of time. Donepezil partially rescued the observed scopolamine-induced impairments of VWM performance. These results provide strong behavioral evidence for the role of increased cholinergic tone and muscarinic neuromodulation in the maintenance of VWM beyond a few seconds, in line with our current knowledge on the role of muscarinic acetylcholine receptors in sustained neural activity during VWM delay periods.

Converging Evidence on D-Amino Acid Oxidase-Dependent Enhancement of Hippocampal Firing Activity and Passive Avoidance Learning in Rats.

BACKGROUND: N-methyl-D-aspartate (NMDA) receptor activation requires the binding of a co-agonist on the glycine-binding site. D-serine is the main endogenous co-agonist of NMDA receptors, and its availability significantly depends on the activity of the metabolic enzyme D-amino acid oxidase (DAAO). Inhibition of DAAO increases the brain levels of D-serine and modulates a variety of physiological functions, including cognitive behavior. METHODS: Here, we examined the effects of a novel 4-hydroxypyridazin-3(2H)-one derivative DAAO inhibitor, Compound 30 (CPD30), on passive avoidance learning and on neuronal firing activity in rats. RESULTS: D-serine administration was applied as reference, which increased cognitive performance and enhanced hippocampal firing activity and responsiveness to NMDA after both local and systemic application. Similarly to D-serine, CPD30 (0.1 mg/kg) effectively reversed MK-801-induced memory impairment in the passive avoidance test. Furthermore, local iontophoretic application of CPD30 in the vicinity of hippocampal pyramidal neurons significantly increased firing rate and enhanced their responses to locally applied NMDA. CPD30 also enhanced hippocampal firing activity after systemic administration. In 0.1- to 1.0-mg/kg doses, CPD30 increased spontaneous and NMDA-evoked firing activity of the neurons. Effects of CPD30 on NMDA responsiveness emerged faster (at 10 minutes post-injection) when a 1.0-mg/kg dose was applied compared with the onset of the effects of 0.1 mg/kg CPD30 (at 30 minutes post-injection). CONCLUSIONS: The present results confirm that the inhibition of DAAO enzyme is an effective strategy for cognitive enhancement. Our findings further facilitate the understanding of the cellular mechanisms underlying the behavioral effects of DAAO inhibition in the mammalian brain.

Measuring sociability of mice using a novel three-chamber apparatus and algorithm of the LABORAS™ system.

BACKGROUND: The social approach and social novelty tests utilizing the three-chamber apparatus are widely accepted to measure social behavior of rodents. The LABORAS™ system offers a possibility to assess sociability of mice in a reliable and objective manner. NEW METHOD: We assessed the capability of the LABORAS™ sociability cage and algorithm (2.6.6) to detect social behaviors in mice. Furthermore, we investigated whether the system is able to detect various levels of sociability due to genetic background or after pharmacological treatments. RESULTS: By comparing manual scoring with various detection zone settings of the automated registration, the most fitting algorithm with a detection zone radius of 90 mm was identified. When different strains were investigated, C57Bl/6 J and NMRI mice proved to be social, while CD1 mice were found asocial. The system was able to detect the sociability increasing effect of R-baclofen (0.5 mg/kg i.p.) and oxytocin (12 ng i.c.v.) in asocial CD1 mice. The negative control PCP impaired social behavior of C57Bl/6 J mice (1 mg/kg i.p.) and increased social avoidance in CD1 mice (0.3 mg/kg i.p.). COMPARISON WITH EXISTING METHOD(S): This setup, in contrast to video frame analysis softwares, determines signal changes caused by movements of rodents allowing accurate detection and analysis of trajectories. Parallel automated measurements also allow replacing time and labor intensive, highly subjective human observational work. CONCLUSIONS: The set-up provides a fast and reliable method to examine social behavior of mice in the three-chamber apparatus. The system is capable of detecting pro or antisocial activity of pharmacological agents.

Dissociating cholinergic influence on alertness and temporal attention in primates in a simple reaction time paradigm.

The ability to promptly respond to behaviourally relevant events depends on both general alertness and phasic changes in attentional state driven by temporal expectations. Using a variable foreperiod simple reaction time (RT) task in four adult male rhesus macaques, we investigated the role of the cholinergic system in alertness and temporal expectation. Foreperiod effects on RT reflect temporal expectation, while alertness is quantified as overall response speed. We measured these RT parameters under vehicle treatment and systemic administration of the muscarinic receptor antagonist scopolamine. We also investigated whether and to what extent the effects of scopolamine were reversed by donepezil, a cholinesterase inhibitor widely used for the treatment of dementia. In the control condition, RT showed a continuous decrease as the foreperiod duration increased, which clearly indicated the effect of temporal expectation on RT. This foreperiod effect was mainly detectable on the faster tail of the RT distribution and was eliminated by scopolamine. Furthermore, scopolamine treatment slowed down the average RT. Donepezil treatment was efficient on the slower tail of the RT distribution and improved scopolamine-induced impairments only on the average RT reflecting a general beneficial effect on alertness without any improvement in temporal expectation. The present results highlight the role of the cholinergic system in temporal expectation and alertness in primates and help delineate the efficacy and scope of donepezil and other cholinomimetic agents as cognitive enhancers in present and future clinical practice.

The novel antipsychotic cariprazine stabilizes gamma oscillations in rat hippocampal slices.

BACKGROUND AND PURPOSE: Gamma oscillations are fast rhythmic fluctuations of neuronal network activity ranging from 30 to 90 Hz that establish a precise temporal background for cognitive processes such as perception, sensory processing, learning, and memory. Alterations of gamma oscillations have been observed in schizophrenia and are suggested to play crucial roles in the generation of positive, negative, and cognitive symptoms of the disease. EXPERIMENTAL APPROACH: In this study, we investigated the effects of the novel antipsychotic cariprazine, a D3 -preferring dopamine D3 /D2 receptor partial agonist, on cholinergically induced gamma oscillations in rat hippocampal slices from treatment-naïve and MK-801-treated rats, a model of acute first-episode schizophrenia. KEY RESULTS: The D3 receptor-preferring agonist pramipexole effectively decreased the power of gamma oscillations, while the D3 receptor antagonist SB-277011 had no effect. In treatment-naïve animals, cariprazine did not modulate strong gamma oscillations but slightly improved the periodicity of non-saturated gamma activity. Cariprazine showed a clear partial agonistic profile at D3 receptors at the network level by potentiating the inhibitory effects when the D3 receptor tone was low and antagonizing the effects when the tone was high. In hippocampal slices of MK-801-treated rats, cariprazine allowed stabilization of the aberrant increase in gamma oscillation power and potentiated resynchronization of the oscillations. CONCLUSION AND IMPLICATIONS: Data from this study indicate that cariprazine stabilizes pathological hippocampal gamma oscillations, presumably by its partial agonistic profile. The results demonstrate in vitro gamma oscillations as predictive biomarkers to study the effects of antipsychotics preclinically at the network level.

Preclinical pharmacodynamic and pharmacokinetic characterization of the major metabolites of cariprazine.

INTRODUCTION: Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, has two major human metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR). The metabolite pharmacology was profiled to understand the contribution to cariprazine efficacy. METHODS: In vitro receptor binding and functional assays, electrophysiology, animal models, microdialysis, and kinetic-metabolism approaches were used to characterize the pharmacology of DCAR and DDCAR. RESULTS: Similar to cariprazine, both metabolites showed high affinity for human D3, D2L, 5-HT1A, 5-HT2A, and 5-HT2B receptors, albeit with higher selectivity than cariprazine for D3 versus D2 receptors. In [35S]GTPγS binding assays, cariprazine and DDCAR were antagonists in membranes from rat striatum and from cells expressing human D2 and D3 receptors, and were partial agonists in membranes from rat hippocampus. In cAMP signaling assays, cariprazine, DCAR, and DDCAR acted as partial agonists at D2 and D3 receptors; cariprazine and DDCAR were full agonists, whereas DCAR was a partial agonist at 5-HT1A receptors. Cariprazine, DCAR, and DDCAR were pure antagonists at human 5-HT2B receptors. Cariprazine and DDCAR increased rat striatal dopamine and reduced cortical serotonin turnover. Cariprazine and DDCAR showed similar in vivo D3 receptor occupancy in rat brain; however, cariprazine was more potent for D2 receptor occupancy. Both cariprazine and DDCAR dose-dependently but partially suppressed the spontaneous activity of midbrain dopaminergic neurons in rats, with the parent compound being more potent but shorter acting than its metabolite. Consistent with the D2 receptor occupancy profile, DDCAR was 3- to 10-fold less potent than cariprazine in rodent models of antipsychotic-like activity. Following acute cariprazine administration, DDCAR was detected in the rodent brain but at much lower levels than cariprazine. CONCLUSION: Overall, in vitro and in vivo pharmacological profiles of DCAR and DDCAR demonstrated high similarity with cariprazine, suggesting that the major metabolites of cariprazine contribute significantly to its clinical efficacy.