Diminished Myoinositol in Ventromedial Prefrontal Cortex Modulates the Endophenotype of Impulsivity.

Maladaptive impulsivity manifests in a variety of disorders, including attention-deficit hyperactivity disorder (ADHD), depression, and substance use disorder. However, the etiological mechanisms of impulsivity remain poorly understood. In the present study, we used in-vivo proton magnetic resonance spectroscopy (1H-MRS) to investigate neurometabolite content in the prefrontal cortex (PFC) and striatum of rats exhibiting low- versus high-impulsive (LI, HI) behavior on a visual attentional task. We validated our 1H-MRS findings using regionally resolved ex-vivo mass spectroscopy, transcriptomics, and site-directed RNA interference in the ventromedial PFC. We report a significant reduction in myoinositol levels in the PFC but not the striatum of HI rats compared with LI rats. Reduced myoinositol content was localized to the infralimbic (IL) cortex, where significant reductions in transcript levels of key proteins involved in the synthesis and recycling of myoinositol (IMPase1) were also present. Knockdown of IMPase1in the IL cortex increased impulsivity in nonimpulsive rats when the demand on inhibitory response control was increased. We conclude that diminished myoinositol levels in ventromedial PFC causally mediate a specific form of impulsivity linked to vulnerability for stimulant addiction in rodents. Myoinositol and related signaling substrates may thus offer novel opportunities for treating neuropsychiatric disorders comorbid with impulsive symptomology.

Ventral Striatal D2/3 Receptor Availability Is Associated with Impulsive Choice Behavior As Well As Limbic Corticostriatal Connectivity.

Background: Low dopamine D2/3 receptor availability in the nucleus accumbens shell is associated with highly impulsive behavior in rats as measured by premature responses in a cued attentional task. However, it is unclear whether dopamine D2/3 receptor availability in the nucleus accumbens is equally linked to intolerance for delayed rewards, a related form of impulsivity. Methods: We investigated the relationship between D2/3 receptor availability in the nucleus accumbens and impulsivity in a delay-discounting task where animals must choose between immediate, small-magnitude rewards and delayed, larger-magnitude rewards. Corticostriatal D2/3 receptor availability was measured in rats stratified for high and low impulsivity using in vivo [18F]fallypride positron emission tomography and ex vivo [3H]raclopride autoradiography. Resting-state functional connectivity in limbic corticostriatal networks was also assessed using fMRI. Results: Delay-discounting task impulsivity was inversely related to D2/3 receptor availability in the nucleus accumbens core but not the dorsal striatum, with higher D2/3 binding in the nucleus accumbens shell of high-impulsive rats compared with low-impulsive rats. D2/3 receptor availability was associated with stronger connectivity between the cingulate cortex and hippocampus of high- vs low-impulsive rats. Conclusions: We conclude that delay-discounting task impulsivity is associated with low D2/3 receptor binding in the nucleus accumbens core. Thus, two related forms of waiting impulsivity-premature responding and delay intolerance in a delay-of-reward task-implicate an involvement of D2/3 receptor availability in the nucleus accumbens shell and core, respectively. This dissociation may be causal or consequential to enhanced functional connectivity of limbic brain circuitry and hold relevance for attention-deficit/hyperactivity disorder, drug addiction, and other psychiatric disorders.

Differences in trait impulsivity do not bias the response to pharmacological drug challenge in the rat five-choice serial reaction time task.

RATIONALE: Maladaptive impulsivity is symptomatic of several neuropsychiatric disorders including schizophrenia, attention-deficit hyperactivity disorder (ADHD), and substance abuse disorders; paradigms designed to assess the underlying neurobiology of this behavior are essential for the discovery of novel therapeutic agents. Various models may be used to assess impulsivity as measured by the five-choice serial reaction time task (5-CSRTT), including variable inter-trial interval (ITI) sessions, the selection of extreme high and low impulsivity phenotypes from a large outbred population of rats, as well as pharmacological challenges. OBJECTIVES: The aim of this study is to evaluate if pharmacological challenge models for impulsivity are biased by underlying differences in impulsivity phenotype. METHODS: Extreme high and low impulsivity phenotypes were selected in the 5-CSRTT, and dose-dependent effects of various pharmacological challenges, namely MK-801, yohimbine, and cocaine, were evaluated on task performance, specifically accuracy and premature responses. RESULTS: All three compounds increased premature responding, while a decrease in attentional performance occurred following MK-801 and yohimbine administration. No differences in drug-induced impulsivity between rats selected for high or low impulsivity or in parameters indicative of attentional performance could be determined. CONCLUSIONS: Our findings indicate that different pharmacological challenges increase impulsivity on the 5-CSRTT, with modest effects on attention. These effects were not influenced by underlying differences in impulsivity phenotype, which is an important prerequisite to reliably use these challenge models to screen and profile compounds with putative anti-impulsive characteristics.

Markers of serotonergic function in the orbitofrontal cortex and dorsal raphé nucleus predict individual variation in spatial-discrimination serial reversal learning.

Dysfunction of the orbitofrontal cortex (OFC) impairs the ability of individuals to flexibly adapt behavior to changing stimulus-reward (S-R) contingencies. Impaired flexibility also results from interventions that alter serotonin (5-HT) and dopamine (DA) transmission in the OFC and dorsomedial striatum (DMS). However, it is unclear whether similar mechanisms underpin naturally occurring variations in behavioral flexibility. In the present study, we used a spatial-discrimination serial reversal procedure to investigate interindividual variability in behavioral flexibility in rats. We show that flexibility on this task is improved following systemic administration of the 5-HT reuptake inhibitor citalopram and by low doses of the DA reuptake inhibitor GBR12909. Rats in the upper quintile of the distribution of perseverative responses during repeated S-R reversals showed significantly reduced levels of the 5-HT metabolite, 5-hydroxy-indoleacetic acid, in the OFC. Additionally, 5-HT2A receptor binding in the OFC of mid- and high-quintile rats was significantly reduced compared with rats in the low-quintile group. These perturbations were accompanied by an increase in the expression of monoamine oxidase-A (MAO-A) and MAO-B in the lateral OFC and by a decrease in the expression of MAO-A, MAO-B, and tryptophan hydroxylase in the dorsal raphé nucleus of highly perseverative rats. We found no evidence of significant differences in markers of DA and 5-HT function in the DMS or MAO expression in the ventral tegmental area of low- vs high-perseverative rats. These findings indicate that diminished serotonergic tone in the OFC may be an endophenotype that predisposes to behavioral inflexibility and other forms of compulsive behavior.

Selective effects of insecticides on nigrostriatal dopaminergic nerve pathways.

A degeneration of the nigrostriatal pathway is a primary component of Parkinson's disease (PD), and we have investigated the actions of insecticides on this pathway. For in vivo exposures, C57BL/6 mice were treated three times over a 2-week period with heptachlor, the pyrethroids deltamethrin and permethrin, or chlorpyrifos. One day after the last treatment, we observed that heptachlor and the pyrethroids increased maximal [3H]dopamine uptake in striatal synaptosomes from treated mice, with dose-dependent changes in Vmax displaying a bell-shaped curve. Western blot analysis confirmed increased levels of dopamine transporter (DAT) protein in the striatum of mice treated with heptachlor and permethrin. In contrast, we observed a small, but statistically significant decrease in dopamine uptake by 100 mg/kg chlorpyrifos. For heptachlor, doses that upregulated DAT expression had little or no effect on serotonin transport. Permethrin did cause an upregulation of serotonin transport, but required a 30-fold greater dose than that effective on dopamine uptake. Other evidence of specificity was found in transmitter release assays, where heptachlor and deltamethrin released dopamine from striatal terminals with greater potency than other transmitter types. These findings confirm that insecticides possess specificity for effects on striatal dopaminergic neurotransmission.

Discovery of non-zwitterionic GABA(A) receptor full agonists and a superagonist.

Numerous previous studies of GABA(A) receptor ligands have suggested that GABA(A) receptor agonists must be zwitterionic and feature an intercharge separation similar to that of GABA (approx. 4.7-6A). In this communication we demonstrate that appropriately functionalized GABA amides are partial, full, or superagonists, despite their non-zwitterionic structure.

Selective effects of cyclodiene insecticides on dopamine release in mammalian synaptosomes.

Cyclodiene insecticides release labeled neurotransmitter in striatal and cortical synaptosome preparations under nondepolarizing conditions, typically showing half-maximal potencies for release in the low micromolar range. This level of potency is similar to those reported for inhibition of 36Cl- influx at the gamma-aminobutyric acid (GABA)(A) receptor, their consensus target site. A wide variety of other GABA(A) antagonists, including picrotoxinin and bicuculline, did not cause significant dopamine release, which obviated direct involvement of the GABA(A) receptor as a possible site of action. Release assays with different transmitters indicated that striatal dopaminergic terminals are severalfold more sensitive to release than other neurotransmitter types. The selective sensitivity of nigrostriatal dopaminergic nerve terminals to insecticidal organochlorines provides biochemical evidence supporting an epidemiological linkage between exposure to environmental toxicants and Parkinsonism.