Impact of Viloxazine Extended-Release Capsules (Qelbree®) on Select Cytochrome P450 Enzyme Activity and Evaluation of CYP2D6 Genetic Polymorphisms on Viloxazine Pharmacokinetics.

BACKGROUND AND OBJECTIVE: Viloxazine extended-release (ER) [Qelbree®] is a nonstimulant attention-deficit/hyperactivity disorder (ADHD) treatment. In vitro studies suggested potential for viloxazine to inhibit cytochrome 450 (CYP) enzymes 1A2, 2B6, 2D6 and 3A4. This clinical study therefore evaluated viloxazine ER effects on index substrates for CYP1A2, 2D6, and 3A4, and secondarily evaluated the impact of CYP2D6 polymorphisms on viloxazine pharmacokinetics. METHODS: Thirty-seven healthy subjects received a modified Cooperstown cocktail (MCC; caffeine 200 mg, dextromethorphan 30 mg, midazolam 0.025 mg/kg) on Day 1, viloxazine ER 900 mg/day on Days 3-5, and a combination of viloxazine ER 900 mg and MCC on Day 6. Viloxazine ER effects on MCC substrates were evaluated using analysis of variance. The impact of CYP2D6 genetic polymorphisms on steady-state viloxazine plasma concentrations was evaluated using Student's t test assessing pharmacokinetic parameter differences between poor versus extensive metabolizers. RESULTS: The least squares geometric mean ratio [GMR%] (90% CI) of MCC substrate + viloxazine ER/MCC substrate alone for caffeine maximum concentration (Cmax), area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUCt), and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC∞) was 99.11 (95.84-102.49), 436.15 (398.87-476.92), and 583.35 (262.41-1296.80), respectively; 150.76 (126.03-180.35), 185.76 (155.01-222.61), and 189.71 (160.37-224.42) for dextromethorphan Cmax, AUCt, and AUC∞, respectively; and 112.81 (104.71-121.54), 167.56 (153.05-183.45), and 168.91 (154.38-184.80) for midazolam Cmax, AUCt, and AUC∞, respectively. At steady state, viloxazine least squares GMR (90% CI) for poor/extensive CYP2D6 metabolizers were Cmax 120.70 (102.33-142.37) and area under the plasme concentration-time curve from time 0 to 24 hours (AUC0-24 125.66 (105.36-149.87)). CONCLUSION: Viloxazine ER is a strong CYP1A2 inhibitor and a weak CYP2D6 and CYP3A4 inhibitor. CYP2D6 polymorphisms did not meaningfully alter the viloxazine ER pharmacokinetic profile.

Advanced Model-based Approach to Evaluate Human Plasma, Cerebrospinal Fluid, and Neuronal mTORC1 Activation Biomarkers After NV-5138 Administration in Healthy Volunteers.

PURPOSE: NV-5138 ([S]-2-amino-5,5-difluoro-4,4-dimethylpentanoic acid) is an orally bioavailable, small-molecule activator of the mechanistic target of rapamycin complex 1 (mTORC1) pathway in development for treatment-resistant depression. The authors established a model to describe the relationship between plasma and cerebrospinal fluid (CSF) concentrations of NV-5138 and between CSF concentrations and potential biomarkers thought to be associated with mTORC1 activity (ie, orotic acid, N-acetylmethionine, and N-formylmethionine). METHODS: Data were collected from a randomized, double-blind, placebo-controlled, tolerability, and pharmacokinetic (PK) parameter study of 5 ascending (400, 800, 1600, 2400, and 3000 mg), once-daily oral doses of NV-5138 in healthy subjects. NV-5138 plasma PK parameter samples were collected at 15 time points over 24 hours on days 1 and 7, and at pre dose on days 2-6 for all doses. NV-5138 CSF PK parameter and CSF biomarker samples were collected on days 1 and 7 at pre dose and 4, 8, and 12 hours post dose for all doses except 3000 mg. A model-based approach was used to develop and validate a model that describes the relationship between NV-5138 in CSF and biomarker concentrations. FINDINGS: Twenty-four of the 42 enrolled subjects had simultaneous plasma and CSF measurements of NV-5138 and CSF biomarker concentrations and were included in the PK parameter and pharmacodynamic (PD) analyses. A 2-compartment plasma and CSF PK parameter, with indirect PD effects, model was developed and validated. NV-5138 plasma concentrations were positively correlated with those in CSF, although CSF concentrations lagged slightly behind those in plasma, as indicated by a counterclockwise hysteresis effect. Similarly, the relationship between the PD measures of mTORC1 activation and NV-5138 was also characterized by counterclockwise hysteresis, when the increase in CSF biomarker concentrations lagged behind those of NV-5138, consistent with a signaling intermediary/cascade, such as mTORC1. Maximal biomarker activation was achieved at NV-5138 CSF concentrations of approximately 3 µg/mL, which were associated with daily doses of 1600 mg NV-5138. The safety profile analysis (n = 42) found that most of the reported adverse events were mild in severity, with no severe, serious, unusual, or unexpected adverse events or any dissociative effects; 2 subjects (400-mg cohort) discontinued due to adverse events that were judged to be unrelated to study medication. IMPLICATIONS: The model will be used for designing future efficacy and tolerability studies. Consecutive daily doses of NV-5138 were well tolerated in this healthy volunteer study.

Functional Impairments Associated With ADHD in Adulthood and the Impact of Pharmacological Treatment.

OBJECTIVE: Among untreated adults, functional impairments associated with ADHD are widespread and cumulative, and can include social, educational, and professional impairments, increased risk of accidents and mortality, and reduced quality of life. Here, we review the most prominent functional impairments in adults with ADHD and summarize evidence describing the potential role of medication in improving outcomes. METHOD: Articles related to the search terms "ADHD," "adult," and functional impairments were identified through Google Scholar and PubMed and selected for inclusion based on four criteria: strength of evidence, relevance to current challenges in adult ADHD, impact on the field, and recency of the results. RESULTS: We identified 179 papers to support the conclusions on the relationship between ADHD and functional impairments, and the impact of pharmacological therapy on functional impairments. CONCLUSION: This narrative review provides evidence that pharmacological treatment can be effective in minimizing not only the symptoms of ADHD, but its functional consequences as well.

A Phase III, Randomized, Double-Blind, Placebo-Controlled Trial Assessing the Efficacy and Safety of Viloxazine Extended-Release Capsules in Adults with Attention-Deficit/Hyperactivity Disorder.

BACKGROUND AND OBJECTIVE: Attention-deficit/hyperactivity disorder is a neurodevelopmental disorder that typically begins in childhood and often persists into adulthood. Recent phase III trials have demonstrated the efficacy and safety of viloxazine extended-release capsules (viloxazine ER; Qelbree®) in pediatrics (6-17 years of age). The aim of this study was to evaluate the efficacy and safety of viloxazine ER in adults with attention-deficit/hyperactivity disorder. METHODS: This was a phase III, randomized, double-blind, placebo-controlled, two-arm trial in adults (18-65 years of age) with attention-deficit/hyperactivity disorder. Eligible subjects were randomized 1:1 to viloxazine ER (flexible dose of 200-600 mg/day) or matched placebo. The primary efficacy endpoint was the change from baseline at end of study (week 6) in the Adult ADHD Investigator Symptom Rating Scale (AISRS) total score. The key secondary endpoint was the change from baseline at end of study in the Clinical Global Impressions-Severity of Illness (CGI-S) score. Additional secondary outcome measures included the AISRS Inattention and Hyperactivity/Impulsivity subscales, the Behavior Rating Inventory of Executive Function-Adult (BRIEF-A), the Generalized Anxiety Disorder-7 Item (GAD-7), and the Clinical Global Impressions-Improvement (CGI-I); each was analyzed at end of study. Responder rates on CGI scales and the AISRS were also assessed. RESULTS: A total of 374 subjects were randomized. At end of study, the mean viloxazine ER dose was 504 mg. The reduction in the change from baseline at end of study AISRS total score (least-square means ± standard error) was significantly greater in subjects treated with viloxazine ER (-15.5 ± 0.91) compared with placebo (-11.7 ± 0.90), p = 0.0040. The reduction in the CGI-S score was also significantly greater in subjects treated with viloxazine ER (-1.4 ± 0.10) compared with placebo (-1.0 ± 0.10), p = 0.0023. The viloxazine ER group demonstrated significantly greater improvements in the AISRS Inattention (p = 0.0015) and Hyperactivity/Impulsivity (p = 0.0380) subscales, the CGI-I (p = 0.0076), and the BRIEF-A Global Executive Composite (p = 0.0468) and Metacognition Index (p = 0.0100). Analysis of categorical secondary endpoints revealed that the viloxazine ER group had a significantly higher AISRS 30% response rate compared with placebo (p = 0.0395); all other comparisons were not significant. Many treatment effects (including the primary and key secondary endpoints) were significant by week 2. The most common treatment-related adverse events that occurred in ≥5% of subjects receiving viloxazine ER were insomnia (14.8%), fatigue (11.6%), nausea (10.1%), decreased appetite (10.1%), dry mouth (9.0%), and headache (9.0%). Viloxazine ER was well tolerated, with a 9.0% discontinuation rate due to adverse events compared with 4.9% in the placebo group. CONCLUSIONS: Treatment with viloxazine ER resulted in a statistically significant improvement in primary and key secondary endpoints, indicating improvements in attention-deficit/hyperactivity disorder symptomology, executive function, and overall clinical illness severity in adults. Viloxazine ER was well tolerated at the tested doses in adults with attention-deficit/hyperactivity disorder. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04016779.

Attention-deficit/hyperactivity disorder (ADHD) is a condition characterized by inattention (difficulty maintaining focus), and/or impulsiveness/hyperactivity. In 2021, a nonstimulant medication called viloxazine ER (brand name: Qelbree^®) received US FDA-approval for ADHD in children and adolescents (aged 6 to 17 years), based on efficacy and safety demonstrated in clinical trials. Here we present results of a phase 3, randomized, double-blind, placebo-controlled, clinical trial that enrolled 374 adults with ADHD. In this trial, half the patients received viloxazine ER, and half received placebo (identical capsule without active ingredient). Medication doses ranged from 200­600 mg/day, based on symptom response and presence of side effects. To reduce bias, patients and investigators did not know which medication the patient was receiving. The primary measure of efficacy was the Adult ADHD Investigator Symptom Rating Scale (AISRS), a standardized questionnaire rating presence and severity of patient-reported ADHD symptoms. At the end of the 6-week trial, participants receiving viloxazine ER showed greater improvement in ADHD symptoms according to AISRS than those receiving placebo. Improvement was seen in both the Inattentive and Impulsive/Hyperactive components of ADHD and in other study measures, including a measure of behaviors called Executive Function. Viloxazine ER was generally safe and well-tolerated in the trial. The most common side effects were insomnia (14.8%), fatigue (11.6%), and nausea (10.1%). Overall, 9.0% of patients receiving viloxazine and 5% receiving placebo left the trial because of side effects. Due to these positive results, the US FDA recently approved viloxazine ER to treat adults with ADHD.

Impact of a High-Fat Meal and Sprinkled Administration on the Bioavailability and Pharmacokinetics of Viloxazine Extended-Release Capsules (QelbreeTM) in Healthy Adult Subjects.

BACKGROUND AND OBJECTIVES: Viloxazine extended-release (viloxazine ER) capsules (QelbreeTM) is a novel nonstimulant recently approved as a treatment for attention-deficit/hyperactivity disorder in children and adolescents. Here, we determined whether the pharmacokinetics of viloxazine are impacted by consuming the capsule contents sprinkled on applesauce rather than an intact capsule, and the effect of a high-fat meal on the pharmacokinetics of viloxazine ER. METHODS: This was a randomized, open-label, crossover, three-treatment, three-period study in healthy adults using orally administered single-dose viloxazine ER 200 mg capsules. Subjects consumed: (1) an intact capsule after a 10-h fast (control condition); (2) the capsule contents sprinkled on one tablespoon of applesauce; and (3) an intact capsule with a standard high-fat meal. Blood samples were collected for 48 h post-dosing. Relative bioavailability analyses were performed to assess the impact of each test condition against the control condition (intact capsule, fasting). The absence of an impact was indicated if the 90% confidence interval (CI) for the least-squares geometric mean ratio (LSGMR) of maximal concentration (Cmax), the area under the concentration-time curve from time 0 to the last measurable concentration time (AUClast), and the area under the concentration-time curve from time 0 to infinity (AUCinf) were within the predetermined no-difference limits of 80-125%. RESULTS: Out of 27 enrolled subjects, 25 were included in the pharmacokinetic analysis. The LSGMR (90% CI) for viloxazine ER sprinkled vs. intact were 90.10% (83.35-97.40) for Cmax, 93.71% (89.09-98.57) for AUClast, and 95.37% (89.80-101.28) for AUCinf. The LSGMR (90% CI) for viloxazine ER consumed in the fed state vs. fasting state were 90.86% (84.05-98.21) for Cmax, 89.68% (85.26-94.33) for AUClast, and 92.35% (86.96-98.07) for AUCinf. The 90% CIs of the LSGMRs were within the predetermined no-difference limits of 80-125%. Viloxazine ER was well tolerated, with most adverse events reported as mild. CONCLUSIONS: These data suggest that viloxazine ER can be consumed sprinkled on applesauce or as intact capsules with or without meals without significantly changing its pharmacokinetics.

Population Pharmacokinetics of Viloxazine Extended-Release Capsules in Pediatric Subjects With Attention Deficit/Hyperactivity Disorder.

Viloxazine extended-release capsules (viloxazine ER; Qelbree) is a novel nonstimulant, recently approved by the US Food and Drug Administration for the treatment of ADHD in pediatrics. Here, we characterize the pharmacokinetics (PK) of viloxazine and its major metabolite, 5-HVLX-gluc, using a population PK model and evaluate the impact of 1-4 days of missed viloxazine ER doses on viloxazine PK. Data from 4 phase 3 trials in pediatric subjects treated with viloxazine ER were used to establish the PK model. Covariate analysis was conducted on the final base model. The impact of 1-4 days of missed doses on steady-state viloxazine PK was evaluated using Monte Carlo simulations. A 1-compartmental linear model with first-order absorption and elimination of the parent drug and first-order metabolite formation and elimination properly described the population PK of viloxazine and 5-HVLX-gluc. Body weight impacted the systemic exposure of viloxazine and 5-HVLX-gluc. Predicted PK parameters at steady state (mean ± standard deviation) in children receiving viloxazine ER were determined. Cmax was 1.60 ± 0.70 µg/mL at 100 mg, 2.83 ± 1.31 µg/mL at 200 mg, and 5.61 ± 2.48 µg/mL at 400 mg. AUC0-t was 19.29 ± 8.88 µg·h/mL at 100 mg, 34.72 ± 16.53 µg·h/mL at 200 mg, and 68.00 ± 28.51 µg·h/mL at 400 mg. PK parameters for adolescents receiving viloxazine ER were also determined. Cmax was 2.06 ± 0.90 µg/mL at 200 mg, 4.08 ± 1.67 µg/mL at 400 mg, and 6.49 ± 2.87 µg/mL at 600 mg. AUC0-t was 25.78 ± 11.55 µg·h/mL at 200 mg, 50.80 ± 19.76 µg·h/mL at 400 mg, and 79.97 ± 36.91 µg·h/mL at 600 mg. Simulations revealed that, regardless of the duration of the dosing interruption, viloxazine concentration returned to steady-state levels after approximately 2 days of once-daily dosing of viloxazine ER.

Impact of Paroxetine, a Strong CYP2D6 Inhibitor, on SPN-812 (Viloxazine Extended-Release) Pharmacokinetics in Healthy Adults.

SPN-812 (viloxazine extended-release) is a novel nonstimulant recently approved as a treatment for attention-deficit/hyperactivity disorder in children and adolescents. Given that SPN-812 is metabolized by CYP2D6 and may be coadministered with CYP2D6 inhibitors, this trial investigated the pharmacokinetics and safety of SPN-812 coadministered with the potent CYP2D6 inhibitor paroxetine. In this single-sequence, 3-treatment period study in healthy volunteers, subjects received a single oral dose of 700 mg SPN-812 alone (period 1), 20 mg daily paroxetine (10 days, period 2), followed by concurrent administration of SPN-812 and paroxetine (period 3). Blood samples were collected for 72 hours post-SPN-812 dosing and analyzed for viloxazine and its primary metabolite, 5-HVLX-gluc. Twenty-two healthy adults were enrolled; all completed the trial. The potential for drug interaction between SPN-812 and paroxetine was assessed using analysis of variance on the log-transformed pharmacokinetic parameters Cmax , AUC0-t , and AUCinf . The least-squares geometric mean ratios for viloxazine were (reported as the ratio of combination/SPN-812 alone) Cmax , 116.04%; 90%CI, 109.49%-122.99%; AUC0-t , 134.65%; 90%CI, 127.65-142.03; and AUCinf , 134.80%; 90%CI, 127.94%-142.03%. CYP2D6 inhibition resulted in a modest change (<35%) on viloxazine AUCs with no change in Cmax . All adverse events were mild in severity.

Evaluating the likelihood to be helped or harmed after treatment with viloxazine extended-release in children and adolescents with attention-deficit/hyperactivity disorder.

AIMS: When clinicians evaluate potential medications for their patients, they must weigh the probability of a treatment's benefits against the possible risks. To this end, the present analyses evaluate the novel nonstimulant viloxazine extended-release (viloxazine ER) using measures of effect size to describe the potential benefits of its treatment in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) as well as the risk of discontinuation because of intolerable adverse events. METHODS: These post hoc analyses use pooled data from four pivotal Phase 3 trials in paediatric patients treated with viloxazine ER. The Likelihood to be Helped or Harmed (LHH) effect size measure was calculated to describe the probability of patients benefiting from treatment vs discontinuing. The Number Needed to Treat (NNT) was calculated from frequently used thresholds of response. The Number Needed to Harm (NNH) was calculated using discontinuations because of adverse events. RESULTS: LHH values for viloxazine ER ranged from 5 to 13, suggesting that subjects were 5-13 times more likely to benefit from, rather than discontinue, viloxazine ER treatment. Specifically, NNT values for viloxazine ER treatment ranged from 6 to 7. NNH values for viloxazine ER treatment ranged from 31 to 74. By convention, single-digit NNTs (<10) suggest the intervention is potentially useful, while NNH values ≥10 for adverse events suggest it is potentially safe or tolerable. CONCLUSIONS: These results indicate that patients with ADHD are likely to benefit from treatment with viloxazine ER, and are unlikely to discontinue, as viloxazine ER treatment was associated with favourable LHH, NNT, and NNH values. Clinicaltrials.gov: NCT03247530, NCT03247543, NCT03247517, NCT03247556.

Translating Attention-Deficit/Hyperactivity Disorder Rating Scale-5 and Weiss Functional Impairment Rating Scale-Parent Effectiveness Scores into Clinical Global Impressions Clinical Significance Levels in Four Randomized Clinical Trials of SPN-812 (Viloxazine Extended-Release) in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder.

Objectives: Clinical trials in psychiatry frequently report results from lengthy, comprehensive assessments to characterize a subject emotionally, cognitively, and behaviorally before and after treatment. However, the potential treatment implications of these results and how they translate into clinical practice remain unclear. Conversely, the Clinical Global Impressions (CGI) scales are quick, intuitive assessments used to assess the functional impact of a treatment in clinically relevant terms. The objectives of the present analyses are to translate scores from comprehensive assessments of symptom severity and functional impairment into clinically meaningful CGI levels. Methods: These post-hoc analyses use data integrated from four pivotal Phase 3 trials in attention-deficit/hyperactivity disorder (ADHD) in children and adolescents treated with the novel nonstimulant SPN-812 (Viloxazine Extended-Release). In this study, we evaluated the ADHD Rating Scale-5 (ADHD-RS-5) and Weiss Functional Impairment Rating Scale-Parent (WFIRS-P), assessments of symptom severity and functional impairment, respectively, by linking these scales with the CGI scales at baseline and end of study. Results: For participants that improved, a one-level change on the CGI-Improvement (CGI-I) was associated with a 10-15-point change on the ADHD-RS-5, and a 0.2-0.5-point change on the WFIRS-P. On the CGI-I, ratings of much improved and very much improved were associated with a percent score decrease (i.e., improvement) of ∼55% and 80% on the ADHD-RS-5 and ∼40% and 70% on the WFIRS-P, respectively. Differences between children and adolescents were minor and are unlikely to be clinically meaningful. Conclusion: These post-hoc analyses provide clinically meaningful benchmarks for the interpretation of scores on the ADHD-RS-5 and WFIRS-P in terms of CGI evaluations in subjects with ADHD. These results may be useful for physicians seeking to understand a treatment's potential impact on their ADHD patients or for researchers looking to define their study results within a clinically relevant context. Data are from clinical trials NCT03247530, NCT03247543, NCT03247517, and NCT03247556.

Junk Food Exposure Disrupts Selection of Food-Seeking Actions in Rats.

There is growing evidence that repeated consumption of highly palatable, nutritionally poor "junk food" diets can produce deficits in cognition and behavioral control. We explored whether long-term junk-food diet exposure disrupts rats' ability to make adaptive choices about which foods to pursue based on (1) expected reward value (outcome devaluation test) and (2) cue-evoked reward expectations (Pavlovian-to-instrumental test). Rats were initially food restricted and trained on two distinct response-outcome contingencies (e.g., left press chocolate pellets, and right press sweetened condensed milk) and stimulus-outcome contingencies (e.g., white noise chocolate pellets, and clicker sweetened condensed milk). They were then given 6 weeks of unrestricted access to regular chow alone (controls) or chow and either 1 or 24 h access to junk food per day. Subsequent tests of decision making revealed that rats in both junk-food diet groups were impaired in selecting actions based on either expected food value or the presence of food-paired cues. These data demonstrate that chronic junk food consumption can disrupt the processes underlying adaptive control over food-seeking behavior. We suggest that the resulting dysregulation of food seeking may contribute to overeating and obesity.

Pattern of access determines influence of junk food diet on cue sensitivity and palatability.

AIMS: Like drug addiction, cues associated with palatable foods can trigger food-seeking, even when sated. However, whether susceptibility to the motivating influence of food-related cues is a predisposing factor in overeating or a consequence of poor diet is difficult to determine in humans. Using a rodent model, we explored whether a highly palatable 'junk food' diet impacts responses to reward-paired cues in a Pavlovian-to-instrumental transfer test, using sweetened condensed milk (SCM) as the reward. The hedonic impact of SCM consumption was also assessed by analyzing licking microstructure. METHODS: To probe the effects of pattern and duration of junk food exposure, we provided rats with either regular chow ad libitum (controls) or chow plus access to junk food for either 2 or 24 h per day for 1, 3, or 6 weeks. We also examined how individual susceptibility to weight gain related to these measures. RESULTS: Rats provided 24 h access to the junk food diet were insensitive to the motivational effects of a SCM-paired cue when tested sated even though their hedonic experience upon reward consumption was similar to controls. In contrast, rats provided restricted, 2 h access to junk food exhibited a cue generalization phenotype under sated conditions, lever-pressing with increased vigor in response to both a SCM-paired cue, and a cue not previously paired with reward. Hedonic response was also significantly higher in these animals relative to controls. CONCLUSIONS: These data demonstrate that the pattern of junk food exposure differentially alters the hedonic impact of palatable foods and susceptibility to the motivating influence of cues in the environment to promote food-seeking actions when sated, which may be consequential for understanding overeating and obesity.

Phasic mesolimbic dopamine signaling encodes the facilitation of incentive motivation produced by repeated cocaine exposure.

Drug addiction is marked by pathological drug seeking and intense drug craving, particularly in response to drug-related stimuli. Repeated psychostimulant administration is known to induce long-term alterations in mesolimbic dopamine (DA) signaling that are hypothesized to mediate this heightened sensitivity to environmental stimuli. However, there is little direct evidence that drug-induced alteration in mesolimbic DA function underlies this hypersensitivity to motivational cues. In the current study, we tested this hypothesis using fast-scan cyclic voltammetry to monitor phasic DA signaling in the nucleus accumbens core of cocaine-pretreated (6 once-daily injections of 15 mg/kg, i.p.) and drug-naive rats during a test of cue-evoked incentive motivation for food-the Pavlovian-to-instrumental transfer task. We found that prior cocaine exposure augmented both reward seeking and DA release triggered by the presentation of a reward-paired cue. Furthermore, cue-evoked DA signaling positively correlated with cue-evoked food seeking and was found to be a statistical mediator of this behavioral effect of cocaine. Taken together, these findings provide support for the hypothesis that repeated cocaine exposure enhances cue-evoked incentive motivation through augmented phasic mesolimbic DA signaling. This work sheds new light on a fundamental neurobiological mechanism underlying motivated behavior and its role in the expression of compulsive reward seeking.

Differential effects of systemic cholinergic receptor blockade on Pavlovian incentive motivation and goal-directed action selection.

Reward-seeking actions can be guided by external cues that signal reward availability. For instance, when confronted with a stimulus that signals sugar, rats will prefer an action that produces sugar over a second action that produces grain pellets. Action selection is also sensitive to changes in the incentive value of potential rewards. Thus, rats that have been prefed a large meal of sucrose will prefer a grain-seeking action to a sucrose-seeking action. The current study investigated the dependence of these different aspects of action selection on cholinergic transmission. Hungry rats were given differential training with two unique stimulus-outcome (S1-O1 and S2-O2) and action-outcome (A1-O1 and A2-O2) contingencies during separate training phases. Rats were then given a series of Pavlovian-to-instrumental transfer tests, an assay of cue-triggered responding. Before each test, rats were injected with scopolamine (0, 0.03, or 0.1 mg/kg, intraperitoneally), a muscarinic receptor antagonist, or mecamylamine (0, 0.75, or 2.25 mg/kg, intraperitoneally), a nicotinic receptor antagonist. Although the reward-paired cues were capable of biasing action selection when rats were tested off-drug, both anticholinergic treatments were effective in disrupting this effect. During a subsequent round of outcome devaluation testing-used to assess the sensitivity of action selection to a change in reward value--we found no effect of either scopolamine or mecamylamine. These results reveal that cholinergic signaling at both muscarinic and nicotinic receptors mediates action selection based on Pavlovian reward expectations, but is not critical for flexibly selecting actions using current reward values.

Relative response cost determines the sensitivity of instrumental reward seeking to dopamine receptor blockade.

Dopamine is a critical mediator of instrumental reward seeking behavior and appears to have a particularly important role in motivating actions that require considerable effort. As with rewards, response costs can be evaluated in both absolute and relative terms. The current study investigated whether the extent to which instrumental performance is dependent on dopamine transmission is influenced by relative or absolute response cost. Three groups of rats were rewarded for lever pressing on different fixed ratio (FR) schedules that required 1 (FR-1), 10 (FR-10), or 20 (FR-20) presses for each food reward. Rats were then injected systemically with flupentixol, a dopamine receptor antagonist, or vehicle before testing all groups on an intermediate-cost (FR-10) schedule, such that only the relative cost of responding differed across groups. Rats experiencing an upshift in cost (group FR-1/FR-10) showed greater response suppression following flupentixol administration than rats experiencing no shift in cost (group FR-10/FR-10), whereas flupentixol treatment had no effect on rats experiencing a downshift in cost (group FR-20/FR-10). A second round of flupentixol tests was conducted using the rats' maintenance schedules, such that only absolute response costs differed across groups. Here, the pattern was reversed among the groups, in line with previous reports. Specifically, flupentixol had a stronger suppressive effect in group FR-20/FR-20 than in group FR-10/FR-10, and had no detectable effect in group FR-1/FR-1. These findings suggest that response costs are evaluated in both absolute and relative terms and that dopamine has a role in overcoming both kinds of cost.

Comparison of single-dose and extended methamphetamine administration on reversal learning in rats.

RATIONALE: Protracted use of methamphetamine (mAMPH) can result in long-term impairments in cognitive function in humans. A previous study reported reversal-specific learning impairments in rats after a binge administration of mAMPH. Several studies show that extended exposure to mAMPH may confer protection against cognitive impairments and the insult to monoamine systems typically observed after larger binge doses. OBJECTIVES: To explore this issue, we compared the effects of escalating and single doses of mAMPH (and saline, SAL) on retention, reversal learning, and post-mortem analysis of dopamine and serotonin transporters, DAT and SERT. METHODS: Rats learned to discriminate equiluminant stimuli and then were treated with either: (1) 4 weeks of mAMPH increasing by 0.3 mg/kg, culminating in 6 mg/kg (mAMPH(escal)); (2) 4 weeks of SAL with a single dose of 6 mg/kg on the last day of treatment (mAMPH(single)); or (3) 4 weeks of SAL. Following treatment, rats were tested on retention and reversal learning, with subsequent analysis of DAT and SERT binding across subregions of the striatum and frontoparietal cortex, respectively. RESULTS: Retention of the pretreatment discrimination was not significantly impaired in either mAMPH treatment group. A significant decrease in ventrolateral striatal DAT binding was observed only in the mAMPH(single) group and frontoparietal SERT was unaffected by either mAMPH treatment. Both treatment groups demonstrated attenuated reversal learning, particularly on measures of accuracy and effort. CONCLUSIONS: These results show that extended and single-dose pretreatment with mAMPH similarly and selectively affect reversal learning, even in the absence of significant DAT or SERT changes.

Work aversion and associated changes in dopamine and serotonin transporter after methamphetamine exposure in rats.

RATIONALE: Methamphetamine (mAMPH) administration in animals can lead to a variety of cognitive and behavioral deficits. We previously reported non-acute reversal learning impairments after a single-day administration of mAMPH, providing evidence of this drug's selective effects on inhibitory control. Effortful decision-making (i.e., how much effort to invest in rewards) is an aspect of cognition that has not yet been explored after mAMPH. OBJECTIVES: Given that frontostriatal circuitry mediating this type of choice is vulnerable to the effects of mAMPH, we tested the hypothesis that mAMPH may also affect decision-making involving effort, another form of cognitive flexibility. METHODS: We examined the non-acute effects of an experimenter-administered single day of mAMPH on effort discounting. In this task, rats previously treated with mAMPH or saline (SAL) could select a high reward at the cost of climbing over a tall barrier or a low reward with no barrier impeding its procurement. RESULTS: Following treatment, mAMPH rats were more work-averse than SAL rats. A control task showed there were no treatment group differences when the high and low rewards involved equal work: all rats chose the high reward preferentially. There were no significant treatment group differences in [(125)I]RTI-55 binding to dopamine and serotonin transporters (DAT, SERT) in any of the regions assayed; however, there were significant correlations of accumbens DAT and cingulate SERT with post-treatment performance. CONCLUSIONS: These findings suggest that even modest dose mAMPH exposure has long-lasting effects on effortful decision-making and may do so through influences on forebrain monoaminergic systems.