Subanesthetic ketamine with an AMPAkine attenuates motor impulsivity in rats.

The concept of 'impulse control' has its roots in early psychiatry and today has progressed into a well-described, although poorly understood, multidimensional endophenotype underlying many neuropsychiatric disorders (e.g., attention deficit hyperactivity disorder, schizophrenia, substance use disorders). There is mounting evidence suggesting that the cognitive and/or behavioral dimensions underlying impulsivity are driven by dysfunctional glutamate (Glu) neurotransmission via targeted ionotropic Glu receptor (GluR) [e.g., N-methyl-D-aspartate receptor (NMDAR), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)] mechanisms and associated synaptic alterations within key brain nodes. Ketamine, a noncompetitive NMDAR antagonist and FDA-approved for treatment-resistant depression, induces a 'glutamate burst' that drives resculpting of the synaptic milieu, which lasts for several days to a week. Thus, we hypothesized that single and repeated treatment with a subanesthetic ketamine dose would normalize motor impulsivity. Next, we hypothesized that AMPAR positive allosteric modulation, alone or in combination with ketamine, would attenuate impulsivity and provide insight into the mechanisms underlying GluR dysfunction relevant to motor impulsivity. To measure motor impulsivity, outbred male Sprague-Dawley rats were trained on the one-choice serial reaction time task. Rats pretreated with single or repeated (3 days) administration of ketamine (10 mg/kg; i.p.; 24-h pretreatment) or with the AMPAkine HJC0122 (1 or 10 mg/kg; i.p.; 30-min pretreatment) exhibited lower levels of motor impulsivity vs. control. Combination of single or repeated ketamine plus HJC0122 also attenuated motor impulsivity vs. control. We conclude that ligands designed to promote GluR signaling represent an effective pharmacological approach to normalize impulsivity and subsequently, neuropsychiatric disorders marked by aberrant impulse control.

Inherent Motor Impulsivity Associates with Specific Gene Targets in the Rat Medial Prefrontal Cortex.

High impulsivity characterizes a myriad of neuropsychiatric diseases, and identifying targets for neuropharmacological intervention to reduce impulsivity could reveal transdiagnostic treatment strategies. Motor impulsivity (impulsive action) reflects in part the failure of "top-down" executive control by the medial prefrontal cortex (mPFC). The present study profiled the complete set of mRNA molecules expressed from genes (transcriptome) in the mPFC of male, outbred rats stably expressing high (HI) or low (LI) motor impulsivity based upon premature responses in the 1-choice serial reaction time (1-CSRT) task. RNA-sequencing identified expression of 18 genes that was higher in the mPFC of HI vs. LI rats. Functional gene enrichment revealed that biological processes related to calcium homeostasis and G protein-coupled receptor (GPCR) signaling pathways, particularly glutamatergic, were overrepresented in the mPFC of HI vs. LI rats. Transcription factor enrichment identified mothers against decapentaplegic homolog 4 (SMAD4) and RE1 silencing transcription factor (REST) as overrepresented in the mPFC of HI rats relative to LI rats, while in silico analysis predicted a conserved SMAD binding site within the voltage-gated calcium channel subunit alpha1 E (CACNA1E) promoter region. qRT-PCR analyses confirmed that mRNA expression of CACNA1E, as well as expression of leucyl and cystinyl aminopeptidase (LNPEP), were higher in the mPFC of HI vs. LI rats. These outcomes establish a transcriptomic landscape in the mPFC that is related to individual differences in motor impulsivity and propose novel gene targets for future impulsivity research.

Profile of cortical N-methyl-D-aspartate receptor subunit expression associates with inherent motor impulsivity in rats.

Impulsivity is a multifaceted behavioral manifestation with implications in several neuropsychiatric disorders. Glutamate neurotransmission through the N-methyl-D-aspartate receptors (NMDARs) in the medial prefrontal cortex (mPFC), an important brain region in decision-making and goal-directed behaviors, plays a key role in motor impulsivity. We discovered that inherent motor impulsivity predicted responsiveness to D-cycloserine (DCS), a partial NMDAR agonist, which prompted the hypothesis that inherent motor impulsivity is associated with the pattern of expression of cortical NMDAR subunits (GluN1, GluN2A, GluN2B), specifically the protein levels and synaptosomal trafficking of the NMDAR subunits. Outbred male Sprague-Dawley rats were identified as high (HI) or low (LI) impulsive using the one-choice serial reaction time task. Following phenotypic identification, mPFC synaptosomal protein was extracted from HI and LI rats to assess the expression pattern of the NMDAR subunits. Synaptosomal trafficking and stabilization for the GluN2 subunits were investigated by co-immunoprecipitation for postsynaptic density 95 (PSD95) and synapse associated protein 102 (SAP102). HI rats had lower mPFC GluN1 and GluN2A, but higher GluN2B and pGluN2B synaptosomal protein expression versus LI rats. Further, higher GluN2B:PSD95 and GluN2B:SAP102 protein:protein interactions were detected in HI versus LI rats. Thus, the mPFC NMDAR subunit expression pattern and/or synaptosomal trafficking associates with high inherent motor impulsivity. Increased understanding of the complex regulation of NMDAR balance within the mPFC as it relates to inherent motor impulsivity may lead to a better understanding of risk factors for impulse-control disorders.

Serotonin 5-HT2C Receptor Cys23Ser Single Nucleotide Polymorphism Associates with Receptor Function and Localization In Vitro.

A non-synonymous single nucleotide polymorphism of the human serotonin 5-HT2C receptor (5-HT2CR) gene that converts a cysteine to a serine at amino acid codon 23 (Cys23Ser) appears to impact 5-HT2CR pharmacology at a cellular and systems level. We hypothesized that the Cys23Ser alters 5-HT2CR intracellular signaling via changes in subcellular localization in vitro. Using cell lines stably expressing the wild-type Cys23 or the Ser23 variant, we show that 5-HT evokes intracellular calcium release with decreased potency and peak response in the Ser23 versus the Cys23 cell lines. Biochemical analyses demonstrated lower Ser23 5-HT2CR plasma membrane localization versus the Cys23 5-HT2CR. Subcellular localization studies demonstrated O-linked glycosylation of the Ser23 variant, but not the wild-type Cys23, may be a post-translational mechanism which alters its localization within the Golgi apparatus. Further, both the Cys23 and Ser23 5-HT2CR are present in the recycling pathway with the Ser23 variant having decreased colocalization with the early endosome versus the Cys23 allele. Agonism of the 5-HT2CR causes the Ser23 variant to exit the recycling pathway with no effect on the Cys23 allele. Taken together, the Ser23 variant exhibits a distinct pharmacological and subcellular localization profile versus the wild-type Cys23 allele, which could impact aspects of receptor pharmacology in individuals expressing the Cys23Ser SNP.

Convergent neural connectivity in motor impulsivity and high-fat food binge-like eating in male Sprague-Dawley rats.

Food intake is essential for survival, but maladaptive patterns of intake, possibly encoded by a preexisting vulnerability coupled with the influence of environmental variables, can modify the reward value of food. Impulsivity, a predisposition toward rapid unplanned reactions to stimuli, is one of the multifaceted determinants underlying the etiology of dysregulated eating and its evolving pathogenesis. The medial prefrontal cortex (mPFC) is a major neural director of reward-driven behavior and impulsivity. Compromised signaling between the mPFC and nucleus accumbens shell (NAcSh) is thought to underlie the cognitive inability to withhold prepotent responses (motor impulsivity) and binge intake of high-fat food (HFF) seen in binge eating disorder. To explore the relationship between motor impulsivity and binge-like eating in rodents, we identified high (HI) and low impulsive (LI) rats in the 1-choice serial reaction time task and employed a rat model of binge-like eating behavior. HFF binge rats consumed significantly greater calories relative to control rats maintained on continual access to standard food or HFF. HI rats repeatedly exhibited significantly higher bingeing on HFF vs. LI rats. Next, we employed dual viral vector chemogenetic technology which allows for the targeted and isolated modulation of ventral mPFC (vmPFC) neurons that project to the NAcSh. Chemogenetic activation of the vmPFC to NAcSh pathway significantly suppressed motor impulsivity and binge-like intake for high-fat food. Thus, inherent motor impulsivity and binge-like eating are linked and the vmPFC to NAcSh pathway serves as a 'brake' over both behaviors.