Discordance between assessments of food cue responsiveness: Implications for assessment in youth with overweight/obesity.

Food cue responsiveness (FCR), broadly defined as behavioral, cognitive, emotional and/or physiological responses to external appetitive cues outside of physiological need, contributes to overeating and obesity among youth and adults. A variety of measures purportedly assess this construct, ranging from youth- or parent-report surveys to objective eating tasks. However, little research has assessed their convergence. It is especially important to evaluate this in children with overweight/obesity (OW/OB), as reliable and valid assessments of FCR are essential to better understand the role of this critical mechanism in behavioral interventions. The present study examined the relationship between five measures of FCR in a sample of 111 children with OW/OB (mean age = 10.6, mean BMI percentile = 96.4; 70% female; 68% white; 23% Latinx). Assessments included: objectively measured eating in the absence of hunger (EAH), parasympathetic activity when exposed to food, parent reported food responsiveness subscale from the Child Eating Behavior Questionnaire (CEBQ-FR), child self-reported Power of Food total score (C-PFS), and child self-reported Food Cravings Questionnaire total score (FCQ-T). Statistically significant spearman correlations were found between EAH and CEBQ-FR (ρ = 0.19, p < 0.05) and parasympathetic reactivity to food cues with both C-PFS (ρ = -0.32, p = 0.002) and FCQ-T (ρ = -0.34, p < 0.001). No other associations were statistically significant. These relationships remained significant in subsequent linear regression models controlling for child age and gender. The lack of concordance between measures assessing highly conceptually related constructs is of concern. Future studies should seek to elucidate a clear operationalization of FCR, examine the associations between FCR assessments in children and adolescents with a range of weight statuses, and evaluate how to best revise these measures to accurately reflect the latent construct being assessed.

Psychometric properties of the Eating in the Absence of Hunger Questionnaire in treatment-seeking adults with overweight and obesity.

Understanding eating behaviors that contribute to overweight and obesity (OW/OB) is an important public health objective. One eating behavior known to contribute to overeating is eating in the absence of hunger (EAH). The Eating in the Absence of Hunger Questionnaire for Children was developed to assess external events and internal experiences that lead children to overeat. Despite the measure's adaptation for use with adults (i.e., EAH-A), its psychometric properties within this population have not been explored. This study assessed the psychometric properties of the EAH-A in sample of 311 treatment-seeking adults with OW/OB (mean BMI = 34.5 [5.1]; mean age = 46.3 [12.1]; 81.7% female; 20.6% Latinx, 59.2% white). The EAH-A contains 14 items and assesses three domains: negative affect eating (EAH-NAE), external eating, and fatigue/boredom eating, through two parallel sets of items assessing initiating EAH and continuing EAH. Exploratory Factor Analysis was performed with promax rotation and maximum likelihood factor extraction. Results supported a unitary factor of EAH, with scale responses driven by EAH-NAE items. Results may be explained in part by scale structure and domain imbalance favoring EAH-NAE items, or the true internal structure of EAH may consist of a singular latent construct. Follow-up analyses indicated redundancy of the scale's parallel sections. If researchers are primarily interested in EAH-NAE, only the three "start eating" or "keep eating" items may be needed. This study highlights the importance of validating the psychometric properties of a measure within intended populations to ensure interpretations are valid.

Family-based treatment program contributors to child weight loss.

BACKGROUND: Multicomponent family-based behavioral treatment (FBT) program for pediatric obesity includes nutrition and physical activity education, as well as behavior therapy techniques. Studies suggest that parent weight loss is the best predictor of child weight loss in FBT. However, given the important role that parents play in the implementation of FBT for their child, isolating the effects of specific FBT treatment component requires consideration of parent influences over time. METHODS: The following treatment components were assessed: stimulus control (high/low-fat food items in home), nutrition knowledge, energy intake, physical activity, and parental monitoring, as well as weekly anthropometric measures. Adjusted models of interest using inverse probability weights were used to evaluate the effect of specific FBT components on time-varying child weight loss rate, adjusting for time-varying influence of parent weight loss. RESULTS: One hundred thirty-seven parent-child dyads (CHILD: mean BMI = 26.4 (3.7) and BMIz = 2.0 (0.3); mean age = 10.4 (1.3); 64.1% female; ADULT: mean BMI = 31.9 (6.3); mean age = 42.9 (6.5); 30.1% Hispanic parents; 87.1% female) participated in an FBT program. In traditional model, adult BMI change (b = 0.08; p < 0.01) was the most significant predictor of child weight loss rates and no other treatment components were significant (p's > 0.1). In models that accounted for potential influences from parental weight loss and differential attendance during treatment period, lower availability of high-fat items (b = 1.10, p < 0.02), higher availability of low-fat items (b = 3.73; p < 0.01), and higher scores on parental monitoring practices (b = 1.10, p < 0.01) were associated with greater rates of weight loss, respectively. CONCLUSION: Results suggest that outside of parent weight change, changes in stimulus control strategies at home and improved parental-monitoring practices are important FBT components for child weight loss.

Role of appetitive phenotype trajectory groups on child body weight during a family-based treatment for children with overweight or obesity.

OBJECTIVE: Emerging evidence suggests that individual appetitive traits may usefully explain patterns of weight loss in behavioral weight loss treatments for children. The objective of this study was to identify trajectories of child appetitive traits and the impact on child weight changes over time. METHODS: Secondary data analyses of a randomized noninferiority trial conducted between 2011 and 2015 evaluated children's appetitive traits and weight loss. Children with overweight and obesity (mean age = 10.4; mean BMI z = 2.0; 67% girls; 32% Hispanic) and their parent (mean age = 42.9; mean BMI = 31.9; 87% women; 31% Hispanic) participated in weight loss programs and completed assessments at baseline, 3, 6,12, and 24 months. Repeated assessments of child appetitive traits, including satiety responsiveness, food responsiveness and emotional eating, were used to identify parsimonious grouping of change trajectories. Linear mixed-effects models were used to identify the impact of group trajectory on child BMIz change over time. RESULTS: One hundred fifty children and their parent enrolled in the study. The three-group trajectory model was the most parsimonious and included a high satiety responsive group (HighSR; 47.4%), a high food responsive group (HighFR; 34.6%), and a high emotional eating group (HighEE; 18.0%). Children in all trajectories lost weight at approximately the same rate during treatment, however, only the HighSR group maintained their weight loss during follow-ups, while the HighFR and HighEE groups regained weight (adjusted p-value < 0.05). CONCLUSIONS: Distinct trajectories of child appetitive traits were associated with differential weight loss maintenance. Identified high-risk subgroups may suggest opportunities for targeted intervention and maintenance programs.

Evaluating psychometric properties of the Emotional Eating Scale Adapted for Children and Adolescents (EES-C) in a clinical sample of children seeking treatment for obesity: a case for the unidimensional model.

BACKGROUND: The Emotional Eating Scale - Adapted for Children and Adolescents (EES-C) assesses children's urge to eat in response to experiences of negative affect. Prior psychometric studies have demonstrated the high reliability, concurrent validity, and test-retest reliability of theoretically defined subconstructs among non-clinical samples of children and adolescents who were primarily healthy weight; however, no psychometric studies exist investigating the EES-C among clinical samples of children with overweight/obesity (OW/OB). Furthermore, studies conducted in different contexts have suggested a discordant number of subconstructs of emotions related to eating. The purpose of this study was to evaluate the validity of the EES-C in a clinical sample of children seeking weight-loss treatment. METHOD: Using a hierarchical bi-factor approach, we evaluated the validity of the EES-C to measure a single general construct, a set of two separate correlated subconstructs, or a hierarchical arrangement of two constructs, and determined reliability in a clinical sample of treatment-seeking children with OW/OB aged 8-12 years (N = 147, mean age = 10.4 years.; mean BMI z = 2.0; female = 66%; Hispanic = 32%, White and other = 68%). RESULTS: Comparison of factor-extraction methods suggested a single primary construct underlying EES-C in this clinical sample. The bi-factor indices provided clear evidence that most of the reliable variance in the total score (90.8 for bi-factor model with three grouping factors and 95.2 for bi-factor model with five grouping factors) was attributed to the general construct. After adjusting for relationships with the primary construct, remaining correlations among sets of items did not suggest additional reliable constructs. CONCLUSION: Results suggest that the primary interpretive emphasis of the EES-C among treatment-seeking children with overweight or obesity should be placed on a single general construct, not on the 3- or 5- subconstructs as was previously suggested.

Cluster randomized control trial promoting child self-regulation around energy-dense food.

Children with lower inhibitory control have greater weight gain over time and consume more snack food. Our goal was to test whether a pilot program based on enhancing self-regulation in preschool children could decrease consumption of energy-dense foods. Ninety-two preschool children were randomized to the intervention or control group. The intervention was a three-week, play-based program that focused on enhancing executive function skills and decreasing consumption of energy dense snack foods. Controls met for a similar length of time, but focused on dental hygiene, good sleep habits/routines, and physical activity. Primary outcome included calories consumed during the post-intervention "Eating in the Absence of Hunger" paradigm, controlling for baseline calories consumed. Inhibitory control was assessed using the "Day/Night" and "Less is More" tasks. There were no differences in post-intervention calories consumed between groups (p = 0.42). However, post-hoc analysis revealed a significant interaction between group and weight status (p = 0.04). In the intervention group, overweight/obese and healthy weight children consumed a similar number of calories (118.0 kcals vs. 124.1 kcals respectively, p = 0.64). However, in the control group, overweight/obese children consumed more than normal weight children (155.9 kcals vs. 103.6 kcals respectively; p = 0.01). With regards to inhibitory control, post-hoc analysis revealed a significant interaction between group and age (p = 0.03), with younger children in the intervention group scoring higher than younger children in the control group (0.93 vs 0.78 respectively, p = 0.007). No differences were observed between groups among older children (0.93 vs 0.96, p = 0.42). These types of programs for preschool children may help to temper consumption of excess calories among overweight/obese children. Further development and investigation of pediatric programs that prevent consumption of excess calories are warranted. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02077387.

Exploring relationships among appetitive traits, negative affect, and binge eating in adults with overweight or obesity.

Binge eating (BE) is a significant public health concern due to its prevalence and impact on mental and physical health. While research has suggested both negative affect and appetitive traits are associated with BE, few studies have investigated these constructs concurrently. Structural equation modeling (SEM) evaluated relationships between negative affect, reward-related appetitive traits, and BE among 293 adults with overweight or obesity (OW/OB) seeking treatment for BE, overeating, and weight management (m age = 46.6; m body mass index[BMI] = 34.5; 81.2 % female; 20.1 % Latinx, 60.8 % White non-Latinx). BE was related to negative affect (ß = 0.53; p < 0.01) and appetitive traits (ß = 1.53; p < 0.001). Negative affect and appetitive traits were related to one another (r = 0.42; p < 0.001), and the full model accounted for 77 % of the variance in BE. In an exploratory follow-up analysis, multigroup SEM evaluated the above relationships in models stratified by sex. Exploratory findings demonstrated both negative affect and appetitive traits were related to BE across sex, particularly when examining BE cognitions and behaviors. However, relationships in men depended upon BE assessment tool. These findings highlight that both negative affect and appetitive traits are related to BE, and jointly may represent significant risk and maintenance factors, particularly in adults with OW/OB. Our findings also highlight the importance of future investigation of sex differences in BE and the potential impact of assessment method.

Development and validation of the food cue responsivity scale.

Food cues are ubiquitous in today's environment; however, there is heterogeneity as to the extent to which these cues impact eating behavior among individuals. This study examines the validity and reliability of the Food Cue Responsivity Scale (FCRS) to assess responsivity to distinct types of food cues. Items gathered from existing measures were combined in the FCRS to reflect two subdomains, uncontrolled eating behavior and cognitive rumination. The criterion validity of the FCRS was established using a paradigm that assesses psychophysiological responsivity to a craved food among adults with overweight or obesity. Higher overall FCRS scores were associated with greater physiological responsivity to food exposures. These findings may help identify specific phenotypes of individuals with overweight or obesity with high responsivity to food cues, which could be used to understand overeating and response to weight-loss programs.

Design of the FRESH-DOSE study: A randomized controlled noninferiority trial evaluating a guided self-help family-based treatment program for children with overweight or obesity.

Overweight and obesity affect 45% of children and increases the risk for several negative health sequelae. Family-Based Behavioral Treatment (FBT) is the most efficacious treatment for child weight management and consists of nutrition and physical activity education, behavior change skills and parenting skills training. FBT is time and staff intensive and can include 20, 60-min separate groups for parents and children, as well as 20-min behavior coaching sessions to help problem solve barriers to implementing the skills learned and individualize the program. Guided self-help (GSH) therapies involve providing families a manual to review independently and brief coaching sessions by an interventionist to facilitate adherence. We developed a GSH version of FBT (gshFBT) which provides a manual to both parents and children and includes 14, 20-min coaching sessions over 6-months. The current study randomized 150 children (mean age = 10.1 years (SD = 1.38); mean BMI% = 97.3% (SD = 2.84); mean BMIz = 2.09 (SD = 0.40); 49% female; 43% Hispanic) and one of their parents (mean age = 41.8 years (SD = 6.52); mean BMI = 32.0 (SD = 7.24); 87.3% female; 43% Hispanic) to either a group-based FBT program or a gshFBT program. Assessments are conducted at baseline, post-treatment (6 months), 6-month follow-up (12 months) and 12-month follow-up (18 months). Primary outcomes are child weight change (BMIz) and cost effectiveness. Recruitment occurred between May 2017 and October 2021 and follow-up assessments are underway. Given the public health concern for children with obesity and the low level of access to FBT, gshFBT could prove extremely useful to provide intervention to a greater proportion of the population.

Exploring the relationship between appetitive behaviours, executive function, and weight status among preschool children.

OBJECTIVE: The goal was to conduct exploratory analysis to determine if executive functions (EFs) and food responsiveness/satiety responsiveness (appetitive behaviours that describe one's tendency to eat in the presence of food or food cues) interact to influence weight status among preschool children participating in a trial promoting self-regulation around energy-dense foods. METHODS: At baseline, parents completed the Behaviour Rating Inventory of Executive Function-Preschool and the Child Eating Behaviour Questionnaire. Children completed anthropometric measurements at the preschool. Spearman's correlation, linear regression, and tests of interaction were conducted. The relationship between weight status and EFs among those who were high vs low in food responsiveness and satiety responsiveness was examined. RESULTS: Children (n = 92) had a mean age of 5.1 years and body mass index (BMI) percentile of 57.6; half (54%) were male. There were significant correlations between food responsiveness and several EFs (emotional control, inhibitory control, working memory, and plan/organize). In the stratified analysis, children with high food responsiveness or low satiety responsiveness had higher BMI percentiles as emotional control skills worsened. BMI percentiles were not elevated among children with low food responsiveness and poor emotional control. CONCLUSION: These results suggest that EFs may be more relevant to weight status if preschool children had high levels of food responsiveness or low levels of satiety responsiveness (ie, increased tendency to be influenced by environmental food cues). This analysis should be replicated with direct measures of executive function and appetitive behaviours in larger samples of young children to examine longitudinal impact on weight status.

Psychometric properties of the Child Eating Behavior Questionnaire (CEBQ) in school age children with overweight and obesity: A proposed three-factor structure.

BACKGROUND: Obesity in youth is a significant public health concern, with eating behaviors being a major contributor. The Child Eating Behavior Questionnaire (CEBQ) was developed to evaluate the appetitive characteristics of young children, across a myriad of eating domains. Despite the breadth of its use, the psychometric properties of the measure in children with overweight/obesity (OW/OB), particularly treatment seeking youth, remains largely unexplored. METHODS: The psychometric properties of the CEBQ were examined in a sample of school age children (8-12) with OW/OB. Parent-child dyads (N = 148) completed assessments prior to beginning a family weight management program. Exploratory factor analysis (EFA) was performed utilizing polychoric correlations, and emerging subscales were assessed to ensure that the range of response scores demonstrated adequate variability. Indices of the number of factors to be retained included acceleration factor (2), optimal coordinates (4), Velicer's MAP (5) and parallel analysis (11). These indices were used in combination with clinical utility to determine the final factor structure. RESULTS: A three-factor structure emerged. The first factor combined many food responsiveness, enjoyment of food, satiety responsiveness and slowness in eating items, with the latter two domains loading negatively. The second factor retained the food fussiness subscale, and the third factor included items from the emotional over- and under-eating subscales. CONCLUSIONS: These results suggest that in children with OW/OB, eating behaviors may be optimally assessed using three domains: reward-based eating, emotional eating and picky eating. Future research should explore how this structure holds in non-treatment-seeking samples and across wider socio-demographic profiles.

Appetitive traits as targets for weight loss: The role of food cue responsiveness and satiety responsiveness.

Individuals with overweight or obesity (OW/OB) are at increased risk for significant physical and psychological comorbidities. The current treatment for OW/OB is behavioral weight loss, which provides psychoeducation on nutrition and physical activity, as well as behavior therapy skills. However, behavioral weight loss is not effective for the majority of the individuals who participate. Research suggests that overeating, or eating past nutritional needs, is one of the leading causes of weight gain. Accumulating evidence suggests that appetitive traits, such as food cue responsiveness and satiety responsiveness, are associated with overeating and weight in youth and adults. The following review presents the current literature on the relationship between food cue responsiveness, satiety responsiveness, overeating, and OW/OB. Research suggests that higher food cue responsiveness and lower satiety responsiveness are associated with overeating and OW/OB cross-sectionally and longitudinally. Emerging data suggest that food cue responsiveness and satiety responsiveness may exist along the same continuum and can be targeted to manage overeating and reduce weight. We have developed a treatment model targeting food cue responsiveness and satiety responsiveness to reduce overeating and weight and have preliminary feasibility, acceptability, and efficacy data, with testing currently being conducted in larger trials. Through programs targeting appetitive traits we hope to develop an alternative weight loss model to assist individuals with a propensity to overeat.

Evaluation of dyadic changes of parent-child weight loss patterns during a family-based behavioral treatment for obesity.

BACKGROUND: Family-based treatment (FBT) for children with overweight and obesity is a package that includes nutrition and physical activity education, as well as parenting and behavior therapy skills. To date, the majority of research suggests that one of the best predictors of child weight loss is parent weight loss. However, the bidirectional processes facilitating parent-child weight loss are not well understood. OBJECTIVE: To evaluate the strength and direction of parent-child weight-change patterns during a 6-month intervention with FBT for childhood obesity. METHODS: Parent-child weight change dynamics were evaluated using a bivariate multilevel approach. RESULTS: Significant positive weight reductions throughout treatment were observed among both parents and children (P's < .01 for both parent and child). In the model adjusting for the conditional influence of attendance over time, parents' initial weight loss was associated with subsequent weight loss by their child (B = 0.102, P < .05; d = 0.352) across the first 10 sessions. Child's weight loss also was associated with subsequent weight loss by their parent (B = 0.105, P < .01; d = 0.412) across the first 10 sessions. A small and negative effects of parents' weight loss on children and children's weight loss on parents from sessions 10 to 20 may have been reflective of slowed rates of weight loss as treatment progressed. CONCLUSIONS: Together these data suggest that parent-child dyads mutually influence weight loss in FBT. Future studies should leverage how to make best clinical use of these dynamic effects in the context of family-based interventions.

Evaluating the Acceptability and Feasibility of Providing Egg or Cereal Breakfast during a Family-Based Treatment for Children with Overweight/Obesity: The Families and Breakfast Pilot Trial.

Background: Family-based behavioral treatment (FBT) is the most successful weight-loss treatment for children with overweight and obesity, however, long-term success is only achieved by a third of children over time. The use of foods that induce satiety, such as eggs, could improve adherence to calorically restricted diets in children and improve outcomes. This study explored the consumption of eggs (FBT+egg) or cereal (FBT+cereal) for breakfast as part of an FBT program, when breakfast foods were provided to families. Methods: Fifty 8-12-year-old children with overweight and obesity and their parents were randomized to a 4-month FBT+egg or FBT+cereal treatment program. Families were provided the ingredients for their assigned breakfast at each treatment session, and instructed to consume the breakfast a minimum of 5 days per week. Families attended assessments at baseline, post-treatment, and 4-months post-treatment. Results: Results showed that both treatments were well liked, FBT attendance was similar, and there was high compliance with consumption of the specified breakfast. Children experienced moderate weight loss at post-treatment [-0.11 standardized BMI (BMIz)] through 4-month follow-up (-0.09 BMIz), with no statistically significant differences (mean difference -0.05 BMIz, 95% confidence interval -0.19 to 0.09) observed between egg and cereal conditions across any anthropometric or appetitive measures. Conclusions: The use of eggs for breakfast in children enrolled in FBT was well tolerated, and future studies should include larger samples and longer follow-up periods to assess the potential differential effects of prescribed breakfasts on children's weight and eating behaviors.

Dissociation between duration of action in the forced swim test in mice and nicotinic acetylcholine receptor occupancy with sazetidine, varenicline, and 5-I-A85380.

RATIONALE: Nicotinic acetylcholine receptor (nAChR) agonists, partial agonists, and antagonists have antidepressant-like effects in rodents and reduce symptoms of depression in humans. OBJECTIVES: The study determined whether the antidepressant-like effect of the nAChR ß2* partial agonist sazetidine-A (sazetidine) in the forced swim test was due to activation or desensitization of ß2* nAChRs. The study also determined if sazetidine's behavioral responses in the forced swim test corresponded to ß2* nAChRs receptor occupancy and drug bioavailability. RESULTS: Acute antidepressant-like effects in the forced swim test were seen with sazetidine and the full ß2* agonist 5-I-A8350 (BALB/cJ mice) and the less selective ß2* partial agonist varenicline in C57BL/6J but not BALB/cJ mice. The role of ß2* nAChRs was confirmed by results showing: (1) reversal of sazetidine's antidepressant-like effects in the forced swim test by nAChR antagonists mecamylamine and dihydro-ß-erythroidine; (2) absence of sazetidine's effect in mice lacking the ß2 subunit of the nAChR; and (3) a high correspondence between behaviorally active doses of sazetidine and ß2* receptor occupancy. ß2* receptor occupancy following acute sazetidine, varenicline, and 5-I-A8350 lasted beyond the duration of action in the forced swim test. Sazetidine's long lasting receptor occupancy did not diminish behavioral efficacy in the forced swim test following repeated dosing. CONCLUSIONS: Results demonstrate that activation of a small population of ß2* nAChRs (10-40%) is sufficient to elicit sazetidine's antidepressant-like actions without producing tolerance and suggest that ligands that activate ß2* nAChRs would be promising targets for the development of a new class of antidepressant.

Selective 5-hydroxytryptamine 2C receptor agonists derived from the lead compound tranylcypromine: identification of drugs with antidepressant-like action.

We report here the design, synthesis, and pharmacological properties of a series of compounds related to tranylcypromine (9), which itself was discovered as a lead compound in a high-throughput screening campaign. Starting from 9, which shows modest activity as a 5-HT(2C) agonist, a series of 1-aminomethyl-2-phenylcyclopropanes was investigated as 5-HT(2C) agonists through iterative structural modifications. Key pharmacophore feature of this new class of ligands is a 2-aminomethyl-trans-cyclopropyl side chain attached to a substituted benzene ring. Among the tested compounds, several were potent and efficacious 5-HT(2C) receptor agonists with selectivity over both 5-HT(2A) and 5-HT(2B) receptors in functional assays. The most promising compound is 37, with 120- and 14-fold selectivity over 5-HT(2A) and 5-HT(2B), respectively (EC(50) = 585, 65, and 4.8 nM at the 2A, 2B, and 2C subtypes, respectively). In animal studies, compound 37 (10-60 mg/kg) decreased immobility time in the mouse forced swim test.

Chemistry and pharmacology of nicotinic ligands based on 6-[5-(azetidin-2-ylmethoxy)pyridin-3-yl]hex-5-yn-1-ol (AMOP-H-OH) for possible use in depression.

AMOP-H-OH (sazetidine-A; 6-[5-(azetidin-2-ylmethoxy)pyridin-3-yl]hex-5-yn-1-ol) and some sulfur-bearing analogues were tested for their activities in vitro against human alpha4beta2-, alpha4beta4-, alpha3beta4*- and alpha1*-nicotinic acetylcholine receptors (nAChRs). AMOP-H-OH was also assessed in an antidepressant efficacy model. AMOP-H-OH and some of its analogues have high potency and selectivity for alpha4beta2-nAChRs over other nAChR subtypes. Effects are manifested as partial agonism, perhaps reflecting selectivity for high sensitivity (alpha4)(3)(beta2)(2)-nAChRs. More prolonged exposure to AMOP-H-OH and its analogues produces inhibition of subsequent responses to acute challenges with full nicotinic agonists, again selectively for alpha4beta2-nAChRs over other nAChR subtypes. The inhibition is mediated either via antagonism or desensitization of nAChR function, but the degree of inhibition of alpha4beta2-nAChRs is limited by the partial agonist activity of the drugs. Certain aspects of the in vitro pharmacology suggest that AMOP-H-OH and some of its analogues have a set of binding sites on alpha4beta2-nAChRs that are distinct from those for full agonists. The in vitro pharmacological profile suggests that peripheral side effects of AMOP-H-OH or its analogues would be minimal and that their behavioral effects would be dominated by central nAChR actions. AMOP-H-OH also has profound and high potency antidepressant-like effects in the forced swim test. The net action of prolonged exposure to AMOP-H-OH or its analogues, as for nicotine, seems to be a selective decrease in alpha4beta2-nAChR function. Inactivation of nAChRs may be a common neurochemical endpoint for nicotine dependence, its treatment, and some of its manifestations, including relief from depression.