Wheel running leads to sex-specific effects on Western diet-associated glucose homeostasis and brain insulin signaling without altering food-related impulsive choice.

OBJECTIVES: There is a clear association between obesity and impulsivity. While exercise can suppress weight gain and decrease impulsive choice (IC), the relationship between impulsivity, the consumption of palatable, energy dense diets, and exercise is unclear. We examined IC before and after Western diet (WD) exposure in rats of both sexes and whether exercise would rescue any diet-mediated increases in IC. Our hypotheses were twofold: first, increased impulsivity would be associated with higher WD preference in a positive feedback loop and second, increased WD consumption would impair both peripheral and central insulin signaling, both of which exercise would attenuate. METHODS: Following baseline assessment of IC through a delay discounting task, rats were divided into naïve, sedentary (Sed), or wheel running (WR) groups for a 5-week WR and two-diet choice period after which rats underwent an oral glucose (OGTT) and insulin tolerance test (ITT) in addition to a re-test of IC. Insulin induced Akt-GSK3ß signaling in the brain was examined using western blot. RESULTS: All Sed rats preferred the WD diet, and all WR rats initially avoided the WD but subsequently reversed their avoidance to preference with females reversing earlier than males. Exercise suppressed weight gain and adiposity to a greater extent in males than females. Only WR males showed improved glucose clearance during OGTT, but both male and female WR rats had a faster recovery of hypoglycemia during ITT. Furthermore, WR rescued WD-induced deficits in hypothalamic Akt-GSK3ß signaling in males but not females. In the prefrontal cortex, however, WD and WR both reduced Akt-GSK3ß signaling in males but not females. There were no sex differences in IC at baseline, and all rats made more impulsive choices during the re-test independent of diet, sex, or exercise. DISCUSSION: The results suggest that while exercise may have a greater efficacy at attenuating diet-mediated metabolic dysregulation in males, it has some beneficial effects for females and highlights the need to develop sex-specific interventions for restoring energy balance.

Ecological momentary assessment and cue-elicited drug craving as primary endpoints: study protocol for a randomized, double-blind, placebo-controlled clinical trial testing the efficacy of a GLP-1 receptor agonist in opioid use disorder.

BACKGROUND: Despite continuing advancements in treatments for opioid use disorder (OUD), continued high rates of relapse indicate the need for more effective approaches, including novel pharmacological interventions. Glucagon-like peptide 1 receptor agonists (GLP-1RA) provide a promising avenue as a non-opioid medication for the treatment of OUD. Whereas GLP-1RAs have shown promise as a treatment for alcohol and nicotine use disorders, to date, no controlled clinical trials have been conducted to determine if a GLP-1RA can reduce craving in individuals with OUD. The purpose of the current protocol was to evaluate the potential for a GLP-1RA, liraglutide, to safely and effectively reduce craving in an OUD population in residential treatment. METHOD: This preliminary study was a randomized, double-blinded, placebo-controlled clinical trial designed to test the safety and efficacy of the GLP-1RA, liraglutide, in 40 participants in residential treatment for OUD. Along with taking a range of safety measures, efficacy for cue-induced craving was evaluated prior to (Day 1) and following (Day 19) treatment using a Visual Analogue Scale (VAS) in response to a cue reactivity task during functional near-infrared spectroscopy (fNIRS) and for craving. Efficacy of treatment for ambient craving was assessed using Ecological Momentary Assessment (EMA) prior to (Study Day 1), across (Study Days 2-19), and following (Study Days 20-21) residential treatment. DISCUSSION: This manuscript describes a protocol to collect clinical data on the safety and efficacy of a GLP-1RA, liraglutide, during residential treatment of persons with OUD, laying the groundwork for further evaluation in a larger, outpatient OUD population. Improved understanding of innovative, non-opioid based treatments for OUD will have the potential to inform community-based interventions and health policy, assist physicians and health care professionals in the treatment of persons with OUD, and to support individuals with OUD in their effort to live a healthy life. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04199728. Registered 16 December 2019, https://clinicaltrials.gov/study/NCT04199728?term=NCT04199728 . PROTOCOL VERSION: 10 May 2023.

Prefrontal cortical response to natural rewards and self-reported anhedonia are associated with greater craving among recently withdrawn patients in residential treatment for opioid use disorder.

Both anhedonia and craving are common among patients with opioid use disorder (OUD), and are associated with vulnerability to relapse. Although these constructs are theoretically linked relatively few studies have examined them together. In the current study, recently withdrawn patients (N = 71) in residential treatment for prescription OUD underwent a cue reactivity paradigm while being monitored with functional near-infrared spectroscopy (fNIRS). Patients also self-reported symptoms of anhedonia via the Snaith-Hamilton Pleasure Scale (SHAPS), while smartphone-based ecological momentary assessments (EMA) were used to measure craving levels. On average, lower right prefrontal cortex (PFC) activity in response to positive social stimuli was associated with higher craving (ß = - 2.87; S.E. = 1.23; p = 0.02). Self-reported anhedonia moderated the association between PFC activity and craving (ß = - 1.02; S.E. = 0.48; p = 0.04), such that patients with two or more anhedonic symptoms had a significant and stronger negative association between PFC activation to hedonically positive images and craving, compared to patients with fewer than two anhedonic symptoms, among whom the association was not significant. This finding provides evidence that higher levels of anhedonia among patients in residential treatment for OUD are associated with a stronger link between lower PFC response to positive social experiences and higher levels of craving, potentially increasing overall vulnerability to relapse.

Dose titration with the glucagon-like peptide-1 agonist, liraglutide, reduces cue- and drug-induced heroin seeking in high drug-taking rats.

Opioid use disorder (OUD), like other substance use disorders (SUDs), is widely understood to be a disorder of persistent relapse. Despite the use of three FDA-approved medications for OUD, typically in conjunction with behavioral treatments, relapse rates remain unacceptably high. Whereas medication assisted therapy (MAT) reduces the risk of opioid overdose mortality, the benefits of MAT are negated when people discontinue the medications. Currently approved medications present barriers to efficient use, including daily visits to a treatment center or work restrictions. With spiking increases in opioid relapse and death, it is imperative to identify new treatments that can reduce the risk of relapse. Recent evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1RAs), currently FDA-approved to treat obesity and type two diabetes, may be promising candidates to reduce relapse. GLP-1RAs have been shown to reduce relapse in rats, whether elicited by cues, drug, and/or stress. However, GLP-1RAs also can cause gastrointestinal malaise, and therefore, in humans, the medication typically is titrated up to full dose when initiating treatment. Here, we used a rodent model to test whether cue- and drug-induced heroin seeking can be reduced by the GLP-1RA, liraglutide, when the dose is titrated across the abstinence period and prior to test. The results show this titration regimen is effective in reducing both cue-induced heroin seeking and drug-induced reinstatement of heroin seeking, particularly in rats with a history of high drug-taking. Importantly, this treatment regimen had no effect on either circulating glucose or insulin. GLP-1RAs, then, appear strong candidates for the non-opioid prevention of relapse to opioids.

Reregulation of cortisol levels and sleep in patients with prescription opioid use disorder during long-term residential treatment.

OBJECTIVE: Research has demonstrated that hypothalamic-pituitary-adrenal (HPA) axis function and sleep patterns are dysregulated in patients diagnosed with opioid use disorder (OUD). It is unclear whether and/or when cortisol and sleep might re-regulate over time, and, whether re-regulation is associated with abstinence following discharge from residential treatment. The current study evaluated changes in sleep and basal cortisol levels in prescription OUD patients in residential treatment, and the association between these measures and treatment outcome following discharge. METHOD: As part of a larger study, 55 participants with prescription OUD provided two days of salivary cortisol samples and 12 consecutive nights of sleep actigraphy between days 19-30 of residential treatment (Time Point 1; TP1). Thirteen of the original 55 participants remained in residence and repeated the measures between days 60-72 (Time Point 2; TP2). Thirty-seven healthy controls (HC) provided baseline measures (TP1) of salivary cortisol and sleep. Treatment outcome data, abstinence vs relapse, were established at 120 days following discharge. RESULTS: Prescription OUD patients had higher cortisol levels and lower total sleep time (TST) than HC at TP1. At TP2, TST and cortisol levels no longer differed from HCs in the subgroup of patients who remained abstinent following discharge after TP2. Individuals whose cortisol and TST did not change from TP1 to TP2 were more likely to relapse following discharge from residential treatment. CONCLUSION: Re-regulation of TST and cortisol levels while in residential treatment was associated with better treatment outcome following discharge for prescription OUD patients.

Overexpression of DeltaFosB is associated with attenuated cocaine-induced suppression of saccharin intake in mice.

Rodents suppress intake of saccharin when it is paired with a drug of abuse (Goudie, Dickins, & Thornton, 1978; Risinger & Boyce, 2002). By the authors' account, this phenomenon, referred to as reward comparison, is thought to be mediated by anticipation of the rewarding properties of the drug (P. S. Grigson, 1997; P. S. Grigson & C. S. Freet, 2000). Although a great deal has yet to be discovered regarding the neural basis of reward and addiction, it is known that overexpression of DeltaFosB is associated with an increase in drug sensitization and incentive. Given this, the authors reasoned that overexpression of DeltaFosB should also support greater drug-induced devaluation of a natural reward. To test this hypothesis, NSE-tTA x TetOp-DeltaFosB mice (Chen et al., 1998) with normal or overexpressed DeltaFosB in the striatum were given access to a saccharin cue and then injected with saline, 10 mg/kg cocaine, or 20 mg/kg cocaine. Contrary to the original prediction, overexpression of DeltaFosB was associated with attenuated cocaine-induced suppression of saccharin intake. It is hypothesized that elevation of DeltaFosB not only increases the reward value of drug, but the reward value of the saccharin cue as well.

The Human Transient Receptor Potential Melastatin 2 Ion Channel Modulates ROS Through Nrf2.

Transient receptor potential melastatin channel subfamily member 2 (TRPM2) has an essential role in protecting cell viability through modulation of oxidative stress. TRPM2 is highly expressed in cancer. When TRPM2 is inhibited, mitochondria are dysfunctional, ROS levels are increased, and cell viability is reduced. Here, the importance of NF-E2-related factor (Nrf2) in TRPM2-mediated suppression of oxidant stress was explored. In TRPM2 depleted cells, antioxidant cofactors glutathione, NADPH, and NADH were significantly reduced. Cytoplasmic and nuclear expression of Nrf2 and of IQGAP1, a modulator of Nrf2 stability regulated by intracellular calcium, were decreased. Antioxidant enzymes transcriptionally regulated by Nrf2 and involved in GSH, NADPH, and NADH generation were significantly lower including PRX1 and PRX3, GPX4, GSTP1, GCLC, and MTHFD2. The glutamine pathway leading to GSH production was suppressed, and ATP and GTP levels were impaired. Reconstitution with wild type TRPM2 or Nrf2, but not TRPM2 pore mutant E960D, rescued expression of enzymes downstream of Nrf2 and restored GSH and GTP. Cell viability, ROS, NADPH, NADH, and ATP levels were fully rescued by TRPM2 and partially by Nrf2. These data show that TRPM2 maintains cell survival following oxidative stress through modulation of antioxidant pathways and cofactors regulated by Nrf2.

Heroin-induced suppression of saccharin intake in OPRM1 A118G mice.

The single nucleotide polymorphism of the µ-opioid receptor, OPRM1 A118G, has been associated with greater drug and alcohol use, increased sensitivity to pain, and reduced sensitivity to the antinociceptive effects of opiates. In the present studies, we employed a 'humanized' mouse model containing the wild-type (118AA) or variant (118GG) allele to examine behavior in a model of heroin-induced devaluation of an otherwise palatable saccharin cue when repeated saccharin-heroin pairings occurred every 24h (Experiment 1) or every 48h (Experiment 2). The results showed that, while both the 118AA and 118GG mice demonstrated robust avoidance of the heroin-paired saccharin cue following daily taste-drug pairings, only the 118AA mice suppressed intake of the heroin-paired saccharin cue when 48h elapsed between each taste-drug pairing. Humanized 118GG mice, then, defend their intake of the sweet cue despite saccharin-heroin pairings and this effect is illuminated by the use of spaced, rather than massed, trials. Given that this pattern of strain difference is not evident with saccharin-cocaine pairings (Freet et al., 2015), reduced avoidance of the heroin-paired saccharin cue by the 118GG mice may be due to an interaction between the opiate and the subjects' drive for the sweet or, alternatively, to differential downstream sensitivity to the aversive kappa mediated properties of the drug. These alternative hypotheses are addressed.

Lewis rats are more sensitive than Fischer rats to successive negative contrast, but less sensitive to the anxiolytic and appetite-stimulating effects of chlordiazepoxide.

Lewis rats show greater anticipatory contrast effects than Fischer 344 rats. Specifically, relative to Fischer rats, Lewis rats exhibit greater avoidance of a saccharin cue when it predicts the future availability of a preferred sucrose reward [Grigson, P.S., Freet, C.S. The suppressive effects of sucrose and cocaine, but not lithium chloride, are greater in Lewis than in Fischer rats: evidence for the reward comparison hypothesis. Behav Neurosci 2000;114:353-363.]. Experiment 1 was designed to determine whether Lewis rats also would demonstrate greater contrast in another paradigm, successive negative contrast (SNC). The results demonstrated a tendency for greater SNC in Lewis rats and then slower recovery from the unexpected loss of reward relative to the Fischer rats. Pretreatment with the anxiolytic agent, chlordiazepoxide (CDP), effectively eliminated contrast in the Fischer rats, but served to prolong recovery from contrast in the Lewis rats. Finally, the results of Experiment 2 demonstrated that Fischer rats, but not Lewis rats, increase consumption of a 0.1 M sucrose solution following pretreatment with CDP. Together, the results show that, while both Lewis and Fischer rats demonstrate SNC, the effect is more sustained in the Lewis rats and these rats are insensitive to both the anxiolytic and the appetite-stimulating effects of CDP.

Increased intravenous morphine self-administration following Roux-en-Y gastric bypass in dietary obese rats.

Roux-en-Y gastric bypass (RYGB) surgery is a commonly performed and very effective method to achieve significant, long-term weight loss. Opioid analgesics are primarily used to manage postoperative pain as fewer alternative medication options are available for bariatric surgery patients than for the general population. Recent clinical studies support a greater risk for substance use following bariatric surgery, including an increased use of opioid medications. The present study is the first to study morphine self-administration in a rat model of RYGB. High fat diet-induced obese (HFD-DIO) rats underwent RYGB (n=14) or sham-surgery with ad libitum HFD (SHAM, n=14) or a restricted amount that resulted in weight matched to the RYGB cohort (SHAM-WM, n=8). An additional normal-diet (ND, n=7), intact (no surgery) group of rats was included. Two months after the surgeries, rats were fitted with jugular catheters and trained on a fixed ratio-2 lick task to obtain morphine intravenously. Both morphine-seeking (number of licks on an empty spout to obtain morphine infusion) and consumption (number of infusion) were significantly greater in RYGB than any control group beginning on day 3 and reached a two-fold increase over a period of two weeks. These findings demonstrate that RYGB increases motivation for taking morphine and that this effect is independent of weight loss. Further research is warranted to reveal the underlying mechanisms and to determine whether increased morphine use represents a risk for opioid addiction following RYGB. Identifying risk factors preoperatively could help with personalized postoperative care to prevent opioid abuse and addiction.

The role of dose and restriction state on morphine-, cocaine-, and LiCl-induced suppression of saccharin intake: A comprehensive analysis.

Rats avoid intake of a taste cue when paired with a drug of abuse or with the illness-inducing agent, lithium chloride (LiCl). Although progress has been made, it is difficult to compare the suppressive effects of abused agents and LiCl on intake of a gustatory conditioned stimulus (CS) because of the cross-laboratory use of different CSs, different unconditioned stimuli (USs), and different doses of the drugs, different conditioning regimens, and different restriction states. Here we have attempted to unify these variables by comparing the suppressive effects of a range of doses of morphine, cocaine, and LiCl on intake of a saccharin CS using a common regimen in non-restricted, food restricted, or water restricted male Sprague-Dawley rats. The results showed that, while the putatively aversive agent, LiCl, was effective in suppressing intake of the taste cue across nearly all doses, regardless of restriction state, the suppressive effects of both morphine and cocaine were greatly reduced when evaluated in either food or water restricted rats. Greater sensitivity to drug was revealed, at very low doses, when testing occurred in the absence of need (i.e., when the rats were non-restricted). Together, these results provide the first uniform and comprehensive analysis of the suppressive effects of morphine, cocaine, and LiCl as a function of dose and restriction state. In the present case, the suppressive effects of morphine and cocaine are found to differ from those of LiCl and, in some respects, from one another as well.

Ceftriaxone attenuates acquisition and facilitates extinction of cocaine-induced suppression of saccharin intake in C57BL/6J mice.

Growing evidence implicates glutamate homeostasis in a number of behaviors observed in addiction such as acquisition of drug taking, motivation, and reinstatement. To date, however, the role of glutamate homeostasis in the avoidance of natural rewards due to exposure to drugs of abuse has received little attention. The aim of the current study was to evaluate the beta-lactam antibiotic, ceftriaxone, which has been shown to normalize disrupted glutamate homeostasis associated with exposure to drugs of abuse, in cocaine-induced suppression of saccharin intake in C57BL/6J mice. Briefly, C57BL/6J mice received daily injections of either 200mg/kg ceftriaxone or saline. Mice were then given access to 0.15% saccharin for 1h and immediately injected intraperitoneally with either saline or 30 mg/kg cocaine; taste-drug pairings occurred every 24h for 5 trials followed by a final CS only trial. One week following taste-drug pairings, extinction was evaluated in a series of one- and two-bottle saccharin intake tests. Individual differences in cocaine-induced suppression were observed (i.e., low and high suppressors) with differential effects of ceftriaxone. Ceftriaxone delayed suppression of saccharin intake in high suppressors but prevented suppression in low suppressors. In addition, ceftriaxone history facilitated extinction in the high suppressors. These data suggest that changes in glutamate homeostasis may be involved in the formation and expression of cocaine-induced suppression of saccharin intake in mice.

Cocaine-induced suppression of saccharin intake and morphine modulation of Ca²âº channel currents in sensory neurons of OPRM1 A118G mice.

Several studies have shown that human carriers of the single nucleotide polymorphism of the µ-opioid receptor, OPRM1 A118G, exhibit greater drug and alcohol use, increased sensitivity to pain, and reduced sensitivity to the antinociceptive effects of opiates. In the present study, we employed a 'humanized' mouse model containing the wild-type (118AA) or variant (118GG) allele to examine behavior in our model of drug-induced suppression of a natural reward cue and to compare the morphine pharmacological profile in acutely isolated sensory neurons. Compared with 118AA mice, our results demonstrate that homozygous 118GG mice exhibit greater avoidance of the cocaine-paired saccharin cue, a behavior linked to an aversive withdrawal-like state. Electrophysiological recordings confirmed the reduced modulation of Ca(2+) channels by morphine in trigeminal ganglion (TG) neurons from 118GG mice compared to the 118AA control cells. However, repeated cocaine exposure in 118GG mice led to a leftward shift of the morphine concentration-response relationship when compared with 118GG control mice, while a rightward shift was observed in 118AA mice. These results suggest that cocaine exposure of mice carrying the 118G allele leads to a heightened sensitivity of the reward system and a blunted modulation of Ca(2+) channels by morphine in sensory neurons.

Baroreflex and chemoreflex controls of sympathetic activity following intermittent hypoxia.

There is a large amount of evidence linking obstructive sleep apnea (OSA), and the associated intermittent hypoxia that accompanies it, with the development of hypertension. For example, cross-sectional studies demonstrate that the prevalence of hypertension increases with the severity of OSA (Bixler et al., 2000; Grote et al., 2001) and an initial determination of OSA is associated with a three-fold increase for future hypertension (Peppard et al., 2000). Interestingly, bouts of intermittent hypoxia have also been shown to affect sympathetic output associated with the baroreflex and chemoreflex, important mechanisms in the regulation of arterial blood pressure. As such, the possibility exists that changes in the baroreflex and chemoreflex may contribute to the development of chronic hypertension observed in OSA patients. The aim of the current article is to briefly review the response of the baroreflex and chemoreflex to intermittent hypoxic exposure and to evaluate evidence for the hypothesis that modification of these autonomic reflexes may, at least in part, support the comorbidity observed between chronic hypertension and OSA.

Compared with DBA/2J mice, C57BL/6J mice demonstrate greater preference for saccharin and less avoidance of a cocaine-paired saccharin cue.

Rats avoid intake of a saccharin cue when paired with a drug of abuse. While this is true for most subjects, the degree of avoidance of the drug-paired cue depends upon many factors including an individual rat's preference for rewards. That said, the direction of this effect is complex. For example, reward-preferring Lewis rats exhibit greater cocaine-induced avoidance of a saccharin cue relative to Fischer 344 rats; while reward-preferring mice that overexpress ΔFosB (NSE-tTA × TetOp-ΔFosB) exhibit less avoidance of the drug-paired taste cue compared to controls. The aim here was to use two strains of commonly used mice, C57BL/6J and DBA/2J, to determine whether known differences in sensitivity to rewards will facilitate or attenuate drug-induced suppression of intake of a drug-paired taste cue. The results of Experiment 1 demonstrate that C57BL/6J mice, compared with DBA/2J mice, exhibit attenuated suppression of saccharin intake when it is paired with cocaine. The results of Experiment 2 demonstrate that strain differences in impulsivity are not likely to account for these differences. It is proposed that, while the C57BL/6J mice typically are more responsive to drug, they also are more responsive to natural rewards (in this case saccharin), and the stronger preference for saccharin serves to militate against drug.

Fischer rats are more sensitive than Lewis rats to the suppressive effects of morphine and the aversive kappa-opioid agonist spiradoline.

Data have suggested that rats avoid intake of an otherwise palatable saccharin cue when paired with a drug of abuse, at least, in part, because the value of the taste cue pales in anticipation of the availability of the highly rewarding drug. Earlier support for this hypothesis was provided by the finding that, relative to the less sensitive Fischer rats, Lewis rats exhibit greater avoidance of a saccharin cue when paired with a rewarding sucrose or cocaine unconditioned stimulus (US), but not when paired with the aversive agent, lithium chloride. More recent data, however, have shown that Fischer rats actually exhibit greater, not less, avoidance of the same saccharin cue when morphine serves as the US. Therefore, Experiment 1 evaluated morphine-induced suppression of intake of the taste cue in Lewis and Fischer rats when the morphine US was administered subcutaneously, rather than intraperitoneally. Experiment 2 examined the effect of strain on the suppression of intake of the saccharin cue when paired with spiradoline, a selective kappa-opioid receptor agonist. The results confirmed that Fischer rats are more responsive to the suppressive effects of morphine than Lewis rats, and that Fischer rats also exhibit greater avoidance of the saccharin cue when paired with spiradoline, despite the fact that spiradoline is devoid of reinforcing properties. Taken together, the data suggest that the facilitated morphine-induced suppression observed in Fischer rats, compared with Lewis rats, may reflect an increased sensitivity to the aversive, kappa-mediated properties of opiates.

Pontine and thalamic influences on fluid rewards: I. Operant responding for sucrose and corn oil.

The reward strength of orosensory sucrose and corn oil was measured using fixed and progressive ratio operant schedules. Because the orosensory effects of the stimuli were of interest, Experiment 1 compared operant responses for sucrose in sham and real feeding rats. The results demonstrated that rats would work for sucrose solutions without the accompanying postingestive effects. Furthermore, the break points for high concentrations of sucrose (1.0 M or 2.0 M) were significantly higher in sham feeding rats than in real feeding controls. Experiment 2 investigated the role of the parabrachial nucleus (PBN) and of the thalamic orosensory area (TOA) in sucrose and corn oil reward. During free access, rats with PBN lesions (PBNx) licked significantly less sucrose solution than their controls, but both groups ingested a similar volume of corn oil emulsion. When an operant was imposed, these same PBNx rats failed to respond for sucrose and continued only modestly for corn oil. In contrast, the TOA lesioned rats (TOAx) showed no impairment in responding for sucrose or corn oil during either the free access or operant sessions. Furthermore, rats with TOA lesions demonstrated significantly higher break points for sucrose than did their controls. Together, the data imply that the PBN but not the TOA is critical for the perception of, or responding to the reward value of sucrose and corn oil.

Abnormal latent inhibition and impulsivity in coloboma mice, a model of ADHD.

Attention deficit hyperactivity disorder (ADHD) is characterized by hyperactivity, inattention, and impulsivity. The coloboma mouse model of ADHD exhibits profound hyperactivity. To determine whether coloboma mice exhibit other signs of ADHD, we assessed latent inhibition as a test of attention, and impulsivity in a delayed reinforcement paradigm. Latent inhibition was present in control mice but was disrupted in coloboma mice. Coloboma mice also exhibited impaired performance on the delayed reinforcement task and were not able to wait as long as control mice to obtain the greater reinforcer. Because norepinephrine mediates hyperactivity in coloboma mice, we examined the role of norepinephrine in disrupted latent inhibition and impulsivity. Reduction of norepinephrine with DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride) restored latent inhibition but did not ameliorate impulsivity. In summary, coloboma mice exhibit hyperactivity, inattention as determined by latent inhibition, and impulsivity, and norepinephrine mediates hyperactivity and inattention but not impulsivity in these mice.