Action initiation and punishment learning differ from childhood to adolescence while reward learning remains stable.

Theoretical and empirical accounts suggest that adolescence is associated with heightened reward learning and impulsivity. Experimental tasks and computational models that can dissociate reward learning from the tendency to initiate actions impulsively (action initiation bias) are thus critical to characterise the mechanisms that drive developmental differences. However, existing work has rarely quantified both learning ability and action initiation, or it has relied on small samples. Here, using computational modelling of a learning task collected from a large sample (N = 742, 9-18 years, 11 countries), we test differences in reward and punishment learning and action initiation from childhood to adolescence. Computational modelling reveals that whilst punishment learning rates increase with age, reward learning remains stable. In parallel, action initiation biases decrease with age. Results are similar when considering pubertal stage instead of chronological age. We conclude that heightened reward responsivity in adolescence can reflect differences in action initiation rather than enhanced reward learning.

Ghrelin Amplifies the Nicotine-Induced Release of Dopamine in the Bed Nucleus of Stria Terminalis (BNST).

Ghrelin is an orexigenic neuropeptide that is known for stimulating the release of growth hormone (GH) and appetite. In addition, ghrelin has been implicated in addiction to drugs such as nicotine. Nicotine is the principal psychoactive component in tobacco and is responsible for the reward sensation produced by smoking. In our previous in vitro superfusion studies, it was demonstrated that ghrelin and nicotine stimulate equally the dopamine release in the rat amygdala, and ghrelin amplifies the nicotine-induced dopamine release in the rat striatum. However, less attention was paid to the actions of ghrelin and nicotine in the bed nucleus of the stria terminalis (BNST). Therefore, in the present study, nicotine and ghrelin were superfused to the BNST of male Wistar rats, and the dopamine release from the BNST was measured in vitro. In order to determine which receptors mediate these effects, mecamylamine, a non-selective nicotinic acetylcholine receptor (nAchR) antagonist, and GHRP-6, a selective growth hormone secretagogue receptor (GHS-R1A) antagonist, were also superfused to the rat BNST. Nicotine significantly increased the release of dopamine, and this effect was significantly inhibited by mecamylamine. Ghrelin increased dopamine release even more significantly than nicotine did, and this effect was significantly inhibited by GHRP-6. Moreover, when administered together, ghrelin significantly amplified the nicotine-induced release of dopamine in the BNST, and this additive effect was reversed partly by mecamylamine and partly by GHRP-6. Therefore, the present study provides a new base of evidence for the involvement of ghrelin in dopamine signaling implicated in nicotine addiction.

Psychophysiological responses to sadness in girls and boys with conduct disorder.

Reduced responsiveness to emotions is hypothesized to contribute to the development of conduct disorder (CD) in children and adolescents. Accordingly, blunted psychophysiological responses to emotions have been observed in boys with CD, but this has never been tested in girls. Therefore, this study compared psychophysiological responses to sadness in girls and boys with and without CD, and different clinical phenotypes of CD: with versus without limited prosocial emotions (LPE), and with versus without comorbid internalizing disorders (INT). Nine-hundred and 27 girls (427 CD, 500 controls) and 519 boys (266 CD, 253 controls) aged 9-18 years participated. Psychophysiological responses were measured while participants watched two validated sad film clips, specifically: heart rate (HR), respiratory sinus arrhythmia (RSA; indexing parasympathetic activity), preejection period (PEP; indexing sympathetic activity). Girls and boys with CD showed larger HR responses to sadness than controls. This effect was rendered nonsignificant, however, after controlling for covariates. We observed aberrant RSA responses to sadness in CD compared with controls. Similarly, we found a significant positive association between RSA responsivity and antisocial behavior when assessed dimensionally. The effects were very small, though. Results were similar for boys and girls. We found no evidence for emotional underresponsiveness in CD in the largest psychophysiological study to date in this field. More research is needed to explore whether this is specific to sadness or generalizes to other emotions. Furthermore, we recommend that studies on emotion processing in CD assess different physiological measures to help disentangle CD-related effects on sympathetic and parasympathetic activity. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Sex differences in psychiatric comorbidity and clinical presentation in youths with conduct disorder.

BACKGROUND: Conduct disorder (CD) rarely occurs alone but is typically accompanied by comorbid psychiatric disorders, which complicates the clinical presentation and treatment of affected youths. The aim of this study was to investigate sex differences in comorbidity pattern in CD and to systematically explore the 'gender paradox' and 'delayed-onset pathway' hypotheses of female CD. METHODS: As part of the FemNAT-CD multisite study, semistructured clinical interviews and rating scales were used to perform a comprehensive phenotypic characterization of 454 girls and 295 boys with CD (9-18 years), compared to 864 sex- and age-matched typically developing controls. RESULTS: Girls with CD exhibited higher rates of current major depression, anxiety disorders, post-traumatic stress disorder and borderline personality disorder, whereas boys with CD had higher rates of current attention-deficit/hyperactivity disorder. In line with the 'gender paradox' hypothesis, relative to boys, girls with CD showed significantly more lifetime psychiatric comorbidities (incl. Alcohol Use Disorder), which were accompanied by more severe CD symptoms. Female and male youths with CD also differed significantly in their CD symptom profiles and distribution of age-of-onset subtypes of CD (i.e. fewer girls with childhood-onset CD). In line with the 'delayed-onset pathway' hypothesis, girls with adolescent-onset CD showed similar levels of dimensional psychopathology like boys with childhood-onset CD, while boys with adolescent-onset CD had the lowest levels of internalizing psychopathology. CONCLUSIONS: Within the largest study of CD in girls performed to date, we found compelling evidence for sex differences in comorbidity patterns and clinical presentation of CD. Our findings further support aspects of the 'gender paradox' and 'delayed-onset pathway' hypotheses by showing that girls with CD had higher rates of comorbid lifetime mental disorders and functional impairments, and they usually developed CD during adolescence. These novel data on sex-specific clinical profiles of CD will be critical in informing intervention and prevention programmes.

Positive and negative parenting in conduct disorder with high versus low levels of callous-unemotional traits.

Less is known about the relationship between conduct disorder (CD), callous-unemotional (CU) traits, and positive and negative parenting in youth compared to early childhood. We combined traditional univariate analyses with a novel machine learning classifier (Angle-based Generalized Matrix Learning Vector Quantization) to classify youth (N = 756; 9-18 years) into typically developing (TD) or CD groups with or without elevated CU traits (CD/HCU, CD/LCU, respectively) using youth- and parent-reports of parenting behavior. At the group level, both CD/HCU and CD/LCU were associated with high negative and low positive parenting relative to TD. However, only positive parenting differed between the CD/HCU and CD/LCU groups. In classification analyses, performance was best when distinguishing CD/HCU from TD groups and poorest when distinguishing CD/HCU from CD/LCU groups. Positive and negative parenting were both relevant when distinguishing CD/HCU from TD, negative parenting was most relevant when distinguishing between CD/LCU and TD, and positive parenting was most relevant when distinguishing CD/HCU from CD/LCU groups. These findings suggest that while positive parenting distinguishes between CD/HCU and CD/LCU, negative parenting is associated with both CD subtypes. These results highlight the importance of considering multiple parenting behaviors in CD with varying levels of CU traits in late childhood/adolescence.

Investigating Sex Differences in Emotion Recognition, Learning, and Regulation Among Youths With Conduct Disorder.

OBJECTIVE: Conduct disorder (CD) is a serious neurodevelopmental disorder marked by notably higher prevalence rates for boys than girls. Converging evidence suggests that CD is associated with impairments in emotion recognition, learning, and regulation. However, it is not known whether there are sex differences in the relationship between CD and emotion dysfunction. Prior studies on emotion functioning in CD have so far been underpowered for investigating sex differences. Therefore, our primary aim was to characterize emotion processing skills in a large sample of girls and boys with CD compared to typically developing controls (TDCs) using a comprehensive neuropsychological test battery. METHOD: We included 542 youths with CD (317 girls) and 710 TDCs (479 girls), 9 to 18 years of age, from a European multisite study (FemNAT-CD). Participants completed three experimental tasks assessing emotion recognition, learning, and regulation, respectively. Data were analyzed to test for effects of group and sex, and group-by-sex interactions, while controlling for potentially confounding factors. RESULTS: Relative to TDCs, youths with CD showed impaired emotion recognition (that was related to more physical and proactive aggression, and higher CU traits), emotional learning (specifically from punishment), and emotion regulation. Boys and girls with CD, however, displayed similar impairments in emotion processing. CONCLUSION: This study provides compelling evidence for a relationship between CD and deficient neurocognitive functioning across three emotional domains that have previously been linked to CD etiology. However, there was no support for sex-specific profiles of emotion dysfunction, suggesting that current neurocognitive models of CD apply equally to both sexes.

["Risk factors of childhood depression" research grant - past, present, future].

The authors summarize the last 10 years of an ongoing collaborative study between the Universities of Szeged and Pittsburgh on early onset major depression. First, the "Risk factors of childhood depression" grant is presented briefly as an initial research study in which the subjects of the current studies were recruited. This is a prominently large clinical sample in the field of child psychiatry even on an international level. In addition to the follow-up of the prognosis of the disorder, recent studies continue to explore the early onset depression in two directions. On the one hand, two studies investigate the role of biobehavioral inflexibility markers in the development of major depression ("Biobehavioral inflexibility and risk for juvenile-onset depression" and "Biobehavioral inflexibility and risk for juvenile-onset depression - renewal grant"). On the other hand, the authors would like to have a better understanding of the possible relationship between the major depression and cardiovascular diseases ("Pediatric depression and subsequent cardiac risk factors: a longitudinal study"). The most significant aims of the three studies will be demonstrated, as well as how the studies were prepared and organized along with the already existing experience concerning research management and involvement of new collaborating partners and experts.

Emotion Regulation Among Adolescents With Pediatric Depression As a Function of Anxiety Comorbidity.

Background: Both depression and anxiety (two of the most common internalizing psychopathologies among youths) are associated with difficulties in emotion regulation (ER). Little is known about whether anxiety as a comorbid condition has an effect on the habitual use of different ER strategies in youngsters with depression histories. We aimed 1) to compare ER in adolescents with histories of childhood onset major depressive disorder (MDD) with and without comorbid anxiety and 2) to examine whether certain ER response clusters (Cognitive, Social, and Behavioral/Physical) characterize comorbid children and adolescents. Methods: We analyzed data on 217 youth (11-18 years old) with depression history: 85 subjects with lifetime anxiety comorbidity (comorbid group) and 132 without lifetime anxiety (non-comorbid group). Psychiatric diagnosis was established by a comprehensive Diagnostic and Statistical Manual of Mental Disorders (DSM) IV-based diagnostic procedure. ER strategies were examined via the self-rated "Feelings and Me" Child version questionnaire (FAM-C). Results: The comorbid group used maladaptive ER strategies significantly more frequently than the non-comorbid youngsters. The Behavioral/Physical and Social ER skills, especially those reflecting social withdrawal and self-harm, were responsible for the higher maladaptive scores. Limitations: Because our study is a cross-sectional analysis, we have no information about the development or the onset of maladaptive ER strategies. Therefore, we were unable to examine whether maladaptive ER was a risk factor or a consequence of the internalizing psychopathology and comorbidity. Conclusions: Comorbid anxiety worsens the impaired use of ER strategies in depression-prone youths. Further longitudinal research is needed to explore the causal role of dysfunctional ER in the development of internalizing psychopathology.

Relational Aggression in Adolescents with Conduct Disorder: Sex Differences and Behavioral Correlates.

As most research on conduct disorder (CD) has been conducted on male participants, it has been suggested that female-specific symptoms may be underestimated based on current DSM-5 criteria. In particular, relational aggression, i.e. the hurtful, often indirect, manipulation of relationships with the intention of damaging the other's social position, has been proposed as a characteristic of CD that is more common in females. In addition, sex-specific studies on correlates of relational aggressive behavior are lacking. Relational aggression may be strongly related to the correlates of proactive aggression, namely low affective empathy, and high levels of callous-unemotional (CU) traits and relational victimization. Thus, the present study investigated sex differences in relational aggression, and associations between relational aggression and correlates of proactive aggression in 662 adolescents with CD (403 females) and 849 typically-developing controls (568 females) aged 9-18 years (M = 14.74, SD = 2.34) from the European multi-site FemNAT-CD study. Females with CD showed significantly higher levels of relational aggression compared to males with CD, whereas no sex differences were seen in controls. Relational aggression was only partly related to correlates of proactive aggression in CD: Independent of sex, CU traits showed a positive association with relational aggression. In females only, cognitive, but not affective empathy, was negatively associated with relational aggression. Relational victimization was more strongly associated with relational aggression in males compared to females. Despite interesting sex specific correlates of relational aggression, effects are small and the potential clinical implications should be investigated in future studies.

Dysregulated behavioral responses to hedonic probes among youth with depression histories and their high-risk siblings.

Affect dysregulation in response to rewarding stimuli has been proposed as a vulnerability factor for major depressive disorder (MDD). However, it remains unclear how affective behavioral dynamics may be altered among individuals who are at high risk for depression but not currently depressed. We examined the dynamics of affective facial behavior during hedonic probes among 3 groups of adolescents: remitted probands who had histories of childhood-onset MDD (n = 187), never-depressed siblings of probands (high familial risk; n = 207), and healthy controls (n = 166). Participants' happy and sad facial expressions were coded during 3 hedonic laboratory tasks: receiving a preferred prize, describing a positive autobiographical memory, and watching a humorous film. Happy and sad behavioral dynamics were indexed by mean level- and time-dependent reactivity, variability (mean of the squared successive differences), and inertia (autocorrelation). Relative to controls, probands and siblings exhibited a more rapid decrease in happy behaviors, and probands exhibited higher inertia of sad behaviors during hedonic probes. Both probands and siblings exhibited lower inertia of sad behaviors while receiving a desired prize, which highlights the importance of context variation in testing hypotheses. Overall, our study provides new evidence that hedonic behavioral dysregulation, as reflected in dynamic facial behavior, may highlight depression vulnerability. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Community Violence Exposure and Conduct Problems in Children and Adolescents with Conduct Disorder and Healthy Controls.

Exposure to community violence through witnessing or being directly victimized has been associated with conduct problems in a range of studies. However, the relationship between community violence exposure (CVE) and conduct problems has never been studied separately in healthy individuals and individuals with conduct disorder (CD). Therefore, it is not clear whether the association between CVE and conduct problems is due to confounding factors, because those with high conduct problems also tend to live in more violent neighborhoods, i.e., an ecological fallacy. Hence, the aim of the present study was: (1) to investigate whether the association between recent CVE and current conduct problems holds true for healthy controls as well as adolescents with a diagnosis of CD; (2) to examine whether the association is stable in both groups when including effects of aggression subtypes (proactive/reactive aggression), age, gender, site and socioeconomic status (SES); and (3) to test whether proactive or reactive aggression mediate the link between CVE and conduct problems. Data from 1178 children and adolescents (62% female; 44% CD) aged between 9 years and 18 years from seven European countries were analyzed. Conduct problems were assessed using the Kiddie-Schedule of Affective Disorders and Schizophrenia diagnostic interview. Information about CVE and aggression subtypes was obtained using self-report questionnaires (Social and Health Assessment and Reactive-Proactive aggression Questionnaire (RPQ), respectively). The association between witnessing community violence and conduct problems was significant in both groups (adolescents with CD and healthy controls). The association was also stable after examining the mediating effects of aggression subtypes while including moderating effects of age, gender and SES and controlling for effects of site in both groups. There were no clear differences between the groups in the strength of the association between witnessing violence and conduct problems. However, we found evidence for a ceiling effect, i.e., individuals with very high levels of conduct problems could not show a further increase if exposed to CVE and vice versa. Results indicate that there was no evidence for an ecological fallacy being the primary cause of the association, i.e., CVE must be considered a valid risk factor in the etiology of CD.

Childhood adversity predicts reduced physiological flexibility during the processing of negative affect among adolescents with major depression histories.

BACKGROUND: Adversity during early development has been shown to have enduring negative physiological consequences. In turn, atypical physiological functioning has been associated with maladaptive processing of negative affect, including its regulation. The present study therefore explored whether exposure to adverse life events in childhood predicted maladaptive (less flexible) parasympathetic nervous system functioning during the processing of negative affect among adolescents with depression histories. METHODS: An initially clinic-referred, pediatric sample (N=189) was assessed at two time points. At Time 1, when subjects were 10.17years old (SD=1.42), on average, and were depressed, parents reported on adverse life events the offspring experienced up to that point. At Time 2, when subjects were 17.18years old (SD=1.28), and were remitted from depression, parents again reported on adverse life events in their offspring's lives for the interim period. At time 2, subjects' parasympathetic nervous system functioning (quantified as respiratory sinus arrhythmia) also was assessed at rest, during sad mood induction, and during instructed mood repair. RESULTS: Extent of adverse life events experienced by T1 (but not events occurring between T1 and T2) predicted less flexible RSA functioning 7years later during the processing of negative affect. Adolescents with more extensive early life adversities exhibited less vagal withdrawal following negative mood induction and tended to show less physiological recovery following mood repair. CONCLUSIONS: Early adversities appear to be associated with less flexible physiological regulatory control during negative affect experience, when measured later in development. Stress-related autonomic dysfunction in vulnerable youths may contribute to the unfavorable clinical prognosis associated with juvenile-onset depression.

Positive autobiographical memory deficits in youth with depression histories and their never-depressed siblings.

OBJECTIVES: Impaired positive autobiographical memory (AM) is closely linked to emotional disorders. AM impairments are often found in depressed adults and may be related to the difficulties such persons have in regulating their dysphoric mood. By contrast, less is known about AM disturbances among adolescents, or about the functional relationship of AM disturbances to early-onset depression. DESIGN: A high-risk family design served to compare four groups of youth who differed in depression histories and familial depression risk. METHODS: Thirty-one currently depressed probands, 185 remitted probands, 204 never-depressed siblings of probands, and 180 healthy control youth were induced into a negative mood prior to recalling positive AMs via a novel memory elicitation procedure. Several positive AM characteristics were assessed. RESULTS: Relative to control youth, unaffected siblings and probands exhibited consistently impaired positive AMs. Moreover, we also found some evidence that probands were more impaired than siblings, who were in turn more impaired than controls, consistent with a gradient effect. CONCLUSIONS: Positive AM disturbances may not only precede the onset of depression in vulnerable youth, but also continue to persist after remission of a depressive episode. Clinical and basic research implications of the findings are discussed. PRACTITIONER POINTS: Positive AM impairments may be trait-like, persist in the euthymic phase of depression, and may serve as a risk marker for early-onset depression among vulnerable adolescents. Disturbances in positive AM may negatively impact the mood-regulatory functions of positive memory recall and contribute to persistent sadness and anhedonia, which are core features of depression. Our sample of currently depressed youth was relatively small, tempering our conclusions. Although we collected data on some important covariates (e.g., socioeconomic status), we lacked information on other relevant variables such as youths' executive functioning or IQ.

Parasympathetic nervous system activity predicts mood repair use and its effectiveness among adolescents with and without histories of major depression.

Depressive disorders that onset in the juvenile years have been linked to far-reaching adverse consequences, making it imperative to elucidate key mechanisms and contributory factors. Excessive use of regulatory responses that exacerbate sadness (maladaptive mood repair) or insufficient use of regulatory responses that reduce it (adaptive mood repair) may reflect behavioral mechanisms of depression risk. Cardiac vagal control, indexed by patterns of respiratory sinus arrhythmia (RSA), has received attention as a putative physiological risk factor for depression. Although mood repair and RSA are related, the nature of this relationship is not well characterized in the context of depression risk. Therefore, we tested alternative models of the relationships between RSA patterns (at rest and in response to a sad film), trait mood repair, and the effectiveness of a mood repair response in the laboratory (state mood repair) among adolescents with depression histories (n = 210) and emotionally healthy peers (n = 161). In our data, a mediation model best explained the association between the key constructs: Adolescents with normative RSA patterns exhibited lower levels of depression and trait maladaptive mood repair, and benefited more from instructed (state) mood repair in the laboratory. By contrast, adolescents with atypical RSA patterns exhibited higher levels of depression and dispositional maladaptive mood repair, which, in turn, mediated the relations of RSA patterns and depression symptoms. Atypical RSA patterns also predicted reduced benefits from laboratory mood repair.

Familiality of mood repair responses among youth with and without histories of depression.

Affect regulation skills develop in the context of the family environment, wherein youths are influenced by their parents', and possibly their siblings', regulatory responses and styles. Regulatory responses to sadness (mood repair) that exacerbate or prolong dysphoria (maladaptive mood repair) may represent one way in which depression is transmitted within families. We examined self-reported adaptive and maladaptive mood repair responses across cognitive, social and behavioural domains in Hungarian 11- to 19-year-old youth and their parents. Offspring included 214 probands with a history of childhood-onset depressive disorder, 200 never depressed siblings and 161 control peers. Probands reported the most problematic mood repair responses, with siblings reporting more modest differences from controls. Mood repair responses of parents and their offspring, as well as within sib-pairs, were related, although results differed as a function of the regulatory response domain. Results demonstrate familiality of maladaptive and adaptive mood repair responses in multiple samples. These familial associations suggest that relationships with parents and siblings within families may impact the development of affect regulation in youth.

Juvenile onset depression alters cardiac autonomic balance in response to psychological and physical challenges.

Cardiac autonomic balance (CAB) indexes the ratio of parasympathetic to sympathetic activation (Berntson, Norman, Hawkley, & Cacioppo, 2008), and is believed to reflect overall autonomic flexibility in the face of environmental challenges. However, CAB has not been examined in depression. We examined changes in CAB and other physiological variables in 179 youth with a history of juvenile onset depression (JOD) and 161 healthy controls, in response to two psychological (unsolvable puzzle, sad film) and two physical (handgrip, and forehead cold pressor) challenges. In repeated measures analyses, controls showed expected reductions in CAB for both the handgrip and unsolvable puzzle, reflecting a shift to sympathetic relative to parasympathetic activation. By contrast, JOD youth showed increased CAB from baseline for both tasks (p's<.05). No effects were found for the forehead cold pressor or sad film tasks, suggesting that CAB differences may arise under conditions requiring greater attentional control or sustained effort.

Mood repair via attention refocusing or recall of positive autobiographical memories by adolescents with pediatric-onset major depression.

BACKGROUND: Impaired emotion regulation is increasingly recognized as a core feature of depressive disorders. Indeed, currently and previously depressed adults both report greater problems in attenuating sadness (mood repair) in daily life than healthy controls. In contrast, studies of various strategies to attenuate sad affect have mostly found that currently or previously depressed adults and controls were similarly successful at mood repair in the laboratory. But few studies have examined mood repair among depression-prone youths or the effects of trait characteristics on mood repair outcomes in the laboratory. METHODS: Adolescents, whose first episode of major depressive disorder (MDD) had onset at age 9, on average (probands), and were either in remission or depressed, and control peers, watched a sad film clip. Then, they were instructed to engage in refocusing attention (distraction) or recalling happy memories. Using affect ratings provided by the youths, we tested two developmentally informed hypotheses about whether the subject groups would be similarly able to attenuate sadness via the two mood repair strategies. We also explored if self-reported habitual (trait) mood repair influenced laboratory performance. RESULTS: Contrary to expectations, attention refocusing and recall of happy memories led to comparable mood benefits across subjects. Control adolescents reported significantly greater reductions in sadness than did depressed (Cohen's d = .48) or remitted (Cohen's d = .32) probands, regardless of mood repair strategy, while currently depressed probands remained the saddest after mood repair. Habitual mood repair styles moderated the effects of instructed (state) mood repair in the laboratory. CONCLUSIONS: Whether depressed or in remission, adolescents with MDD histories are not as efficient at mood repair in the laboratory as controls. But proband-control group differences in mood repair outcomes were modest in scope, suggesting that the abilities that subserve affect regulation have been preserved in probands to some degree. Further information about the nature of mood repair problems among youths with depression histories would help to better understand the clinical course of MDD and to design personalized interventions for depression.

The association between major depressive disorder in childhood and risk factors for cardiovascular disease in adolescence.

OBJECTIVE: Depression in adults is associated with risk factors for cardiovascular disease (CVD). It is unclear, however, when the association between clinical depression and cardiac risk factors develops or how early in life this association can be detected. METHODS: In an ongoing study of pediatric depression, we compared CVD risk factors including smoking, obesity, physical activity level, sedentary behavior, and parental history of CVD across three samples of adolescents: probands with established histories of childhood-onset major depressive disorder (n = 210), never-depressed siblings of probands (n = 195), and controls with no history of any major psychiatric disorder (n = 161). RESULTS: When assessed during adolescence, 85% of the probands were not in a major depressive episode. Nevertheless, at that assessment, probands had a higher prevalence of regular smoking (odds ratio [OR] = 12.54, 95% confidence interval [CI] = 4.36-36.12) and were less physically active than controls (OR = 0.59, CI = 0.43-0.81) and siblings (OR = 0.70, CI = 0.52-0.94) and had a higher rate of obesity than did controls (OR = 3.67, CI = 1.42-9.52). Parents of probands reported high rates of CVD (significantly higher than did parents of controls), including myocardial infarction and CVD-related hospitalization (ORs = 1.62-4.36, CIs = 1.03-15.40). Differences in CVD risk factors between probands and controls were independent of parental CVD. CONCLUSIONS: Major depression in childhood is associated with an unfavorable CVD risk profile in adolescence, and risks for pediatric depression and CVD may coincide in families. Effective prevention and treatment of childhood depression may be a means to reduce the incidence of adult CVD.

Ligand-specific regulation of the endogenous mu-opioid receptor by chronic treatment with mu-opioid peptide agonists.

Since the discovery of the endomorphins (EM), the postulated endogenous peptide agonists of the mu-opioid receptors, several analogues have been synthesized to improve their binding and pharmacological profiles. We have shown previously that a new analogue, cis-1S,2R-aminocyclohexanecarboxylic acid(2)-endomorphin-2 (ACHC-EM2), had elevated mu-receptor affinity, selectivity, and proteolytic stability over the parent compound. In the present work, we have studied its antinociceptive effects and receptor regulatory processes. ACHC-EM2 displayed a somewhat higher (60%) acute antinociceptive response than the parent peptide, EM2 (45%), which peaked at 10 min after intracerebroventricular (icv) administration in the rat tail-flick test. Analgesic tolerance developed to the antinociceptive effect of ACHC-EM2 upon its repeated icv injection that was complete by a 10-day treatment. This was accompanied by attenuated coupling of mu-sites to G-proteins in subcellular fractions of rat brain. Also, the density of mu-receptors was upregulated by about 40% in the light membrane fraction, with no detectable changes in surface binding. Distinct receptor regulatory processes were noted in subcellular fractions of rat brains made tolerant by the prototypic full mu-agonist peptide, DAMGO, and its chloromethyl ketone derivative, DAMCK. These results are discussed in light of the recently discovered phenomenon, that is, the "so-called biased agonism" or "functional selectivity".

Ghrelin amplifies the nicotine-induced dopamine release in the rat striatum.

The orexigenic peptide ghrelin plays a prominent role in the regulation of energy balance and in the mediation of reward mechanisms and reinforcement for addictive drugs, such as nicotine. Nicotine is the principal psychoactive component in tobacco, which is responsible for addiction and relapse of smokers. Nicotine activates the mesencephalic dopaminergic neurons via nicotinic acetylcholine receptors (nAchR). Ghrelin stimulates the dopaminergic neurons via growth hormone secretagogue receptors (GHS-R1A) in the ventral tegmental area and the substantia nigra pars compacta resulting in the release of dopamine in the ventral and dorsal striatum, respectively. In the present study an in vitro superfusion of rat striatal slices was performed, in order to investigate the direct action of ghrelin on the striatal dopamine release and the interaction of ghrelin with nicotine through this neurotransmitter release. Ghrelin increased significantly the dopamine release from the rat striatum following electrical stimulation. This stimulatory effect was reversed by both the selective nAchR antagonist mecamylamine and the selective GHS-R1A antagonist GHRP-6. Nicotine also increased significantly the dopamine release under the same conditions. This stimulatory effect was antagonized by mecamylamine, but not by GHRP-6. Ghrelin further stimulated the nicotine-induced dopamine release and this effect was abolished by mecamylamine and was partially inhibited by GHRP-6. The present results demonstrate that ghrelin stimulates directly the dopamine release and amplifies the nicotine-induced dopamine release in the rat striatum. We presume that striatal cholinergic interneurons also express GHS-R1A, through which ghrelin can amplify the nicotine-induced dopamine release in the striatum. This study provides further evidence of the impact of ghrelin on the mesolimbic and nigrostriatal dopaminergic pathways. It also suggests that ghrelin signaling may serve as a novel pharmacological target for treatment of addictive and neurodegenerative disorders.