piperidines and Autism-Spectrum-Disorder

Autism spectrum disorders (ASDs) are a group of neurodevelopmental conditions defined by behavioral deficits in social communication and interactions, mental inflexibility and repetitive behaviors. Converging evidence from observational and preclinical studies suggest that excessive repetitive behaviors in people with ASD may be due to elevated histaminergic H3 receptor signaling in the striatum. We hypothesized that systemic administration of pharmacological histamine H3 receptor antagonists would attenuate the expression of repetitive behaviors in the BTBR T+Itpr3tf/J (BTBR) mouse inbred strain, an established mouse model presenting autism-like repetitive behaviors and novelty-induced hyperactivity. We further aimed to investigate whether agonism of the histamine H3 receptor would be sufficient to induce repetitive behaviors in the C57BL/6J control mouse strain.. Different doses of H3 receptor agonists (i.e., (R)-α-methylhistamine and immethridine) and H3 receptor antagonists/inverse agonists (i.e., ciproxifan and pitolisant) were administered via intraperitoneal (i.p.) injection in male mice to characterize the acute effects of these compounds on ASD-related behavioral readouts.. The highly selective H3 receptor agonist immethridine significantly increased the time spent in stereotypic patterns in C57BL/6J mice, but this effect appeared to be driven by general sedative properties of the compound. High doses of pitolisant significantly decreased locomotor hyperactivity in novel environments in BTBR mice, without significant effects on repetitive behaviors.. Based on our findings, we conclude that acute H3 receptor manipulation mainly affected general motor activity levels in novel environments. Small changes in stereotyped behaviors were observed but appeared to be driven by altered general activity levels.

Topics: Animals; Autism Spectrum Disorder; Behavior, Animal; Corpus Striatum; Disease Models, Animal; Grooming; Histamine Agonists; Histamine H3 Antagonists; Humans; Hyperkinesis; Imidazoles; Locomotion; Male; Mice; Mice, Inbred C57BL; Piperidines; Receptors, Histamine H3; Social Behavior; Stereotyped Behavior

Autism spectrum disorder (ASD) is a group of developmental disabilities, the aetiology of which remains elusive. The endocannabinoid (eCB) system modulates neurotransmission and neuronal plasticity. Evidence points to the involvement of this neuromodulatory system in the pathophysiology of ASD. We investigated whether there is a disruption to the eCB system in ASD and whether pharmacological modulation of the eCB system might offer therapeutic potential. We examined three major components of the eCB system-endogenous cannabinoids, their receptors and associated enzymes-in ASD children as well as in the valproic acid (VPA) induced animal model in autism. Furthermore, we specifically increased 2-arachidonoylglycerol (2-AG) levels by administering JZL184, a selective inhibitor of monoacylglycerol lipase which is the hydrolytic enzyme for 2-AG, to examine ASD-like behaviours in VPA-induced rats. Results showed that autistic children and VPA-induced rats exhibited reduced eCB content, increased degradation of enzymes and upregulation of CBRs. We found that repetitive and stereotypical behaviours, hyperactivity, sociability, social preference and cognitive functioning improved after acute and chronic JZL184 treatment. The major efficacy of JZL184 was observed after administration of a dosage regimen of 3 mg kg

Topics: Animals; Anti-Anxiety Agents; Autism Spectrum Disorder; Benzodioxoles; Child; Child, Preschool; Endocannabinoids; Enzyme Inhibitors; Female; Humans; Male; Monoacylglycerol Lipases; Piperidines; Rats; Rats, Wistar; Receptors, Cannabinoid; Up-Regulation

Repetitive behaviors (e.g., stereotypic movements, compulsions, rituals) are common features of a number of neurodevelopmental disorders. Clinical and animal model studies point to the importance of cortical-basal ganglia circuitry in the mediation of repetitive behaviors. In the current study, we tested whether a drug cocktail (dopamine D2 receptor antagonist + adenosine A2A receptor agonist + glutamate mGlu5 positive allosteric modulator) designed to activate the indirect basal ganglia pathway would reduce repetitive behavior in C58 mice after both acute and sub-chronic administration. In addition, we hypothesized that sub-chronic administration (i.e. 7 days of twice-daily injections) would increase the functional activation of the subthalamic nucleus (STN), a key node of the indirect pathway. Functional activation of STN was indexed by dendritic spine density, analysis of GABA, glutamate, and synaptic plasticity genes, and cytochrome oxidase activity. The drug cocktail used significantly reduced repetitive motor behavior in C58 mice after one night as well as seven nights of twice-nightly injections. These effects did not reflect generalized motor behavior suppression as non-repetitive motor behaviors such as grooming, digging and eating were not reduced relative to vehicle. Sub-chronic drug treatment targeting striatopallidal neurons resulted in significant changes in the STN, including a four-fold increase in brain-derived neurotrophic factor (BDNF) mRNA expression as well as a significant increase in dendritic spine density. The present findings are consistent with, and extend, our prior work linking decreased functioning of the indirect basal ganglia pathway to expression of repetitive motor behavior in C58 mice and suggest novel therapeutic targets.

Topics: Adenosine; Animals; Autism Spectrum Disorder; Basal Ganglia; Behavior, Animal; Benzamides; Compulsive Behavior; Corpus Striatum; Disease Models, Animal; Indoles; Male; Mice; Mice, Inbred Strains; Neural Pathways; Neurons; Phenethylamines; Piperidines; Pyrazoles; Stereotyped Behavior; Subthalamic Nucleus

Currently, there are no medications that effectively treat the core symptoms of Autism Spectrum Disorder (ASD). We recently found that the bacterial species Lactobacillus (L.) reuteri reverses social deficits in maternal high-fat-diet offspring. However, whether the effect of L. reuteri on social behavior is generalizable to other ASD models and its mechanism(s) of action remains unknown. Here, we found that treatment with L. reuteri selectively rescues social deficits in genetic, environmental, and idiopathic ASD models. Interestingly, the effects of L. reuteri on social behavior are not mediated by restoring the composition of the host's gut microbiome, which is altered in all of these ASD models. Instead, L. reuteri acts in a vagus nerve-dependent manner and rescues social interaction-induced synaptic plasticity in the ventral tegmental area of ASD mice, but not in oxytocin receptor-deficient mice. Collectively, treatment with L. reuteri emerges as promising non-invasive microbial-based avenue to combat ASD-related social dysfunction.

Topics: Action Potentials; Animals; Autism Spectrum Disorder; Benzoxazines; Capillary Permeability; Central Nervous System Stimulants; Disease Models, Animal; Dopamine Plasma Membrane Transport Proteins; Exploratory Behavior; Gastrointestinal Microbiome; Humans; Interpersonal Relations; Limosilactobacillus reuteri; Male; Mice; Mice, Transgenic; Microfilament Proteins; Nerve Tissue Proteins; Picrotoxin; Piperidines; Receptors, Oxytocin; Smell; Social Behavior Disorders; Valproic Acid

Mutations of the. We investigated the behavior of mice with a conventional or conditional deletion of. Conventional heterozygous

Topics: Animals; Anxiety; Autism Spectrum Disorder; Dioxoles; Gamma Rhythm; Haploinsufficiency; Male; Membrane Transport Modulators; Memory; Mice; Mice, Inbred C57BL; NAV1.2 Voltage-Gated Sodium Channel; Phenotype; Piperidines; Prefrontal Cortex; Psychomotor Agitation; Social Behavior

Social deficit is a core clinical feature of autism spectrum disorder (ASD) but the underlying neural mechanisms remain largely unclear. We demonstrate that structural and functional impairments occur in glutamatergic synapses in the pyramidal neurons of the anterior cingulate cortex (ACC) in mice with a mutation in Shank3, a high-confidence candidate ASD gene. Conditional knockout of Shank3 in the ACC was sufficient to generate excitatory synaptic dysfunction and social interaction deficits, whereas selective enhancement of ACC activity, restoration of SHANK3 expression in the ACC, or systemic administration of an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-positive modulator improved social behavior in Shank3 mutant mice. Our findings provide direct evidence for the notion that the ACC has a role in the regulation of social behavior in mice and indicate that ACC dysfunction may be involved in social impairments in ASD.

Topics: Animals; Autism Spectrum Disorder; Dioxoles; Disease Models, Animal; Glutamic Acid; Grooming; Gyrus Cinguli; Interpersonal Relations; Mice; Mice, Inbred C57BL; Mice, Knockout; Microfilament Proteins; Mutation; Nerve Tissue Proteins; Optogenetics; Piperidines; Pyramidal Cells; Receptors, AMPA; Social Behavior; Synapses

Topics: Adult; Autism Spectrum Disorder; Humans; Illicit Drugs; Male; Piperidines; Serotonin Agents; Serotonin Syndrome; Tryptamines

Restricted and repetitive behaviors are a defining feature of autism, which can be expressed as a cognitive flexibility deficit or stereotyped, motor behaviors. There is limited knowledge about the underlying neuropathophysiology contributing to these behaviors. Previous findings suggest that central 5HT

Topics: Animals; Autism Spectrum Disorder; Autistic Disorder; Cognition Disorders; Corpus Striatum; Disease Models, Animal; Exploratory Behavior; Fluorobenzenes; Grooming; Male; Mice; Mice, Inbred Strains; Neostriatum; Piperidines; Prefrontal Cortex; Receptor, Serotonin, 5-HT2A; Reversal Learning; Serotonin 5-HT2 Receptor Antagonists; Stereotyped Behavior

Individuals with autism spectrum disorder (ASD) exhibit social-communication deficits along with restricted interests and repetitive behaviors (RRBs). To date, there is a lack of effective treatments to alleviate RRBs. A recent study found that treatment with the 5HT2A receptor antagonist M100907 attenuates a reversal learning deficit in the BTBR mouse model of autism. The BTBR mouse also exhibits elevated grooming behavior which may model stereotyped motor behaviors also observed in ASD. The present study examined whether 5HT2A receptor blockade with M100907 at either 0.01 or 0.1mg/kg can reduce repetitive grooming in BTBR mice compared to that of vehicle-treated BTBR and C57BL6/J (B6) mice. M100907 at 0.1mg/kg, but not 0.01mg/kg, significantly attenuated repetitive grooming in BTBR mice compared to that of vehicle-treated BTBR mice. M100907 at either dose did not affect grooming behavior in B6 mice. To determine whether 0.1mg/kg M100907 had a more general effect on activity in BTBR mice, a second experiment determined whether M100907 at 0.1mg/kg affected locomotor activity in BTBR mice. M100907 treatment in BTBR and B6 mice did not alter locomotor activity compared to that of vehicle-treated BTBR and B6 mice. The present findings taken together with past results suggest that treatment with a 5HT2A receptor antagonist may be effective in ameliorating RRBs in ASD.

Topics: Animals; Autism Spectrum Disorder; Fluorobenzenes; Grooming; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Motor Activity; Piperidines; Serotonin 5-HT2 Receptor Antagonists; Stereotyped Behavior

Marijuana exerts profound effects on human social behavior, but the neural substrates underlying such effects are unknown. Here we report that social contact increases, whereas isolation decreases, the mobilization of the endogenous marijuana-like neurotransmitter, anandamide, in the mouse nucleus accumbens (NAc), a brain structure that regulates motivated behavior. Pharmacological and genetic experiments show that anandamide mobilization and consequent activation of CB1 cannabinoid receptors are necessary and sufficient to express the rewarding properties of social interactions, assessed using a socially conditioned place preference test. We further show that oxytocin, a neuropeptide that reinforces parental and social bonding, drives anandamide mobilization in the NAc. Pharmacological blockade of oxytocin receptors stops this response, whereas chemogenetic, site-selective activation of oxytocin neurons in the paraventricular nucleus of the hypothalamus stimulates it. Genetic or pharmacological interruption of anandamide degradation offsets the effects of oxytocin receptor blockade on both social place preference and cFos expression in the NAc. The results indicate that anandamide-mediated signaling at CB1 receptors, driven by oxytocin, controls social reward. Deficits in this signaling mechanism may contribute to social impairment in autism spectrum disorders and might offer an avenue to treat these conditions.

Topics: Analysis of Variance; Animals; Arachidonic Acids; Autism Spectrum Disorder; Benzamides; Benzodiazepines; Camphanes; Carbamates; Clozapine; Cocaine; Endocannabinoids; Immunohistochemistry; Infusions, Intraventricular; Lipids; Male; Mice; Mice, Inbred C57BL; Nucleus Accumbens; Oxytocin; Piperazines; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptors, Cannabinoid; Reward; Signal Transduction; Social Behavior