αCaMKII controls the establishment of cocaine's reinforcing effects in mice and humans

Although addiction develops in a considerable number of regular cocaine users, molecular risk factors for cocaine dependence are still unknown. It was proposed that establishing drug use and memory formation might share molecular and anatomical pathways. Alpha-Ca²⁺/calmodulin-dependent protein kinase-II (αCaMKII) is a key mediator of learning and memory also involved in drug-related plasticity. The autophosphorylation of αCaMKII was shown to accelerate learning. Thus, we investigated the role of αCaMKII autophosphorylation in the time course of establishing cocaine use-related behavior in mice. We found that αCaMKII autophosphorylation-deficient αCaMKII^T286A mice show delayed establishment of conditioned place preference, but no changes in acute behavioral activation, sensitization or conditioned hyperlocomotion to cocaine (20 mg kg⁻¹, intraperitoneal). In vivo microdialysis revealed that αCaMKII^T286A mice have blunted dopamine (DA) and blocked serotonin (5-HT) responses in the nucleus accumbens (NAcc) and prefrontal cortex after acute cocaine administration (20 mg kg⁻¹, intraperitoneal), whereas noradrenaline responses were preserved. Under cocaine, the attenuated DA and 5-HT activation in αCaMKII^T286A mice was followed by impaired c-Fos activation in the NAcc. To translate the rodent findings to human conditions, several CAMK2A gene polymorphisms were tested regarding their risk for a fast establishment of cocaine dependence in two independent samples of regular cocaine users from Brazil (n=688) and Switzerland (n=141). A meta-analysis across both samples confirmed that CAMK2A rs3776823 TT-allele carriers display a faster transition to severe cocaine use than C-allele carriers. Together, these data suggest that αCaMKII controls the speed for the establishment of cocaine''s reinforcing effects.     

Associations of delay discounting and drinking trajectories from ages 14 to 22

Background

While drinking alcohol, one must choose between the immediate rewarding effects and the delayed reward of a healthier lifestyle. Individuals differ in their devaluation of a delayed reward based on the time required to receive it, i.e., delay discounting (DD). Previous studies have shown that adolescents discount more steeply than adults and that steeper DD is associated with heavier alcohol use in both groups.

Methods

In a large-scale longitudinal study, we investigated whether higher rates of DD are an antecedent or a consequence of alcohol use during adolescent development. As part of the IMAGEN project, 2220 adolescents completed the Monetary Choice Questionnaire as a DD measure, the Alcohol Use Disorders Identification Test, and the Timeline Follow Back interview at ages 14, 16, 18, and 22. Bivariate latent growth curve models were applied to investigate the relationship between DD and drinking. To explore the consequences of drinking, we computed the cumulative alcohol consumption and correlated it with the development of discounting. A subsample of 221 participants completed an intertemporal choice task (iTeCh) during functional magnetic resonance imaging at ages 14, 16, and 18. Repeated-measures ANOVA was used to differentiate between high-risk and low-risk drinkers on the development of neural processing during intertemporal choices.

Results

Overall, high rates of DD at age 14 predicted a greater increase in drinking over 8 years. In contrast, on average, moderate alcohol use did not affect DD from ages 14 to 22. Of note, we found indicators for less brain activity in top-down control areas during intertemporal choices in the participants who drank more.

Conclusions

Steep DD was shown to be a predictor rather than a consequence of alcohol use in low-level drinking adolescents. Important considerations for future longitudinal studies are the sampling strategies to be used and the reliability of the assessments.

     

Oppositional COMT Val158Met effects on resting state functional connectivity in adolescents and adults

Prefrontal dopamine levels are relatively increased in adolescence compared to adulthood. Genetic variation of COMT (COMT Val158Met) results in lower enzymatic activity and higher dopamine availability in Met carriers. Given the dramatic changes of synaptic dopamine during adolescence, it has been suggested that effects of COMT Val158Met genotypes might have oppositional effects in adolescents and adults. The present study aims to identify such oppositional COMT Val158Met effects in adolescents and adults in prefrontal brain networks at rest. Resting state functional connectivity data were collected from cross-sectional and multicenter study sites involving 106 healthy young adults (mean age 24 ± 2.6 years), gender matched to 106 randomly chosen 14-year-olds. We selected the anterior medial prefrontal cortex (amPFC) as seed due to its important role as nexus of the executive control and default mode network. We observed a significant age-dependent reversal of COMT Val158Met effects on resting state functional connectivity between amPFC and ventrolateral as well as dorsolateral prefrontal cortex, and parahippocampal gyrus. Val homozygous adults exhibited increased and adolescents decreased connectivity compared to Met homozygotes for all reported regions. Network analyses underscored the importance of the parahippocampal gyrus as mediator of observed effects. Results of this study demonstrate that adolescent and adult resting state networks are dose-dependently and diametrically affected by COMT genotypes following a hypothetical model of dopamine function that follows an inverted U-shaped curve. This study might provide cues for the understanding of disease onset or dopaminergic treatment mechanisms in major neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder.     

Mapping adolescent reward anticipation,receipt, and prediction error during the monetary incentive delay task

The functional neuroanatomy and connectivity of reward processing in adults are well documented, with relatively less research on adolescents, a notable gap given this developmental period's association with altered reward sensitivity. Here, a large sample (n = 1,510) of adolescents performed the monetary incentive delay (MID) task during functional magnetic resonance imaging. Probabilistic maps identified brain regions that were reliably responsive to reward anticipation and receipt, and to prediction errors derived from a computational model. Psychophysiological interactions analyses were used to examine functional connections throughout reward processing. Bilateral ventral striatum, pallidum, insula, thalamus, hippocampus, cingulate cortex, midbrain, motor area, and occipital areas were reliably activated during reward anticipation. Bilateral ventromedial prefrontal cortex and bilateral thalamus exhibited positive and negative activation, respectively, during reward receipt. Bilateral ventral striatum was reliably active following prediction errors. Previously, individual differences in the personality trait of sensation seeking were shown to be related to individual differences in sensitivity to reward outcome. Here, we found that sensation seeking scores were negatively correlated with right inferior frontal gyrus activity following reward prediction errors estimated using a computational model. Psychophysiological interactions demonstrated widespread cortical and subcortical connectivity during reward processing, including connectivity between reward‐related regions with motor areas and the salience network. Males had more activation in left putamen, right precuneus, and middle temporal gyrus during reward anticipation. In summary, we found that, in adolescents, different reward processing stages during the MID task were robustly associated with distinctive patterns of activation and of connectivity.     

Adolescent to young adult longitudinal development of subcortical volumes in two European sites with four waves

Adolescent subcortical structural brain development might underlie psychopathological symptoms, which often emerge in adolescence. At the same time, sex differences exist in psychopathology, which might be mirrored in underlying sex differences in structural development. However, previous studies showed inconsistencies in subcortical trajectories and potential sex differences. Therefore, we aimed to investigate the subcortical structural trajectories and their sex differences across adolescence using for the first time a single cohort design, the same quality control procedure, software, and a general additive mixed modeling approach. We investigated two large European sites from ages 14 to 24 with 503 participants and 1408 total scans from France and Germany as part of the IMAGEN project including four waves of data acquisition. We found significantly larger volumes in males versus females in both sites and across all seven subcortical regions. Sex differences in age-related trajectories were observed across all regions in both sites. Our findings provide further evidence of sex differences in longitudinal adolescent brain development of subcortical regions and thus might eventually support the relationship of underlying brain development and different adolescent psychopathology in boys and girls.     

The interaction of child abuse and rs1360780 of the FKBP5 gene is associated with amygdala resting‐state functional connectivity in young adults

Extensive research has demonstrated that rs1360780, a common single nucleotide polymorphism within the FKBP5 gene, interacts with early‐life stress in predicting psychopathology. Previous results suggest that carriers of the TT genotype of rs1360780 who were exposed to child abuse show differences in structure and functional activation of emotion‐processing brain areas belonging to the salience network. Extending these findings on intermediate phenotypes of psychopathology, we examined if the interaction between rs1360780 and child abuse predicts resting‐state functional connectivity (rsFC) between the amygdala and other areas of the salience network. We analyzed data of young European adults from the general population (N = 774; mean age = 18.76 years) who took part in the IMAGEN study. In the absence of main effects of genotype and abuse, a significant interaction effect was observed for rsFC between the right centromedial amygdala and right posterior insula (p < .025, FWE‐corrected), which was driven by stronger rsFC in TT allele carriers with a history of abuse. Our results suggest that the TT genotype of rs1360780 may render individuals with a history of abuse more vulnerable to functional changes in communication between brain areas processing emotions and bodily sensations, which could underlie or increase the risk for psychopathology.     

Glucocorticoid receptor antagonism blocks ethanol-induced place preference learning in mice and attenuates dopamine D2 receptor adaptation in the frontal cortex

The glucocorticoid receptor (GR) plays an important role in alcohol (EtOH) self-administration behaviour by its interaction with the dopaminergic (DA) system in the brain. Here we asked whether the GR is also involved in the establishment of EtOH-induced conditioned place preference (CPP) by an interaction with the DA systems in terminal projection areas. We found that the establishment of an EtOH (2 g/kg, i.p.)-induced CPP was paralleled by a decrease in frontal cortex DA D2 receptor mRNA expression, but not in local D2 gene promoter methylation rate. No effect in other brain areas, nor on DA transporter or DA receptor regulating factor mRNA was found. The GR antagonist, RU486 (20 mg/kg, i.p.) blocked the establishment of EtOH CPP and prevented DA D2 receptor adaptations. These data may suggest a role of glucocorticoid receptor mediated D2 adaptations in the establishment of the reinforcing effects of EtOH.     

The initiation of cannabis use in adolescence is predicted by sex‐specific psychosocial and neurobiological features

Cannabis use initiated during adolescence might precipitate negative consequences in adulthood. Thus, predicting adolescent cannabis use prior to any exposure will inform the aetiology of substance abuse by disentangling predictors from consequences of use. In this prediction study, data were drawn from the IMAGEN sample, a longitudinal study of adolescence. All selected participants (n = 1,581) were cannabis‐naïve at age 14. Those reporting any cannabis use (out of six ordinal use levels) by age 16 were included in the outcome group (N = 365, males n = 207). Cannabis‐naïve participants at age 14 and 16 were included in the comparison group (N = 1,216, males n = 538). Psychosocial, brain and genetic features were measured at age 14 prior to any exposure. Cross‐validated regularized logistic regressions for each use level by sex were used to perform feature selection and obtain prediction error statistics on independent observations. Predictors were probed for sex‐ and drug‐specificity using post‐hoc logistic regressions. Models reliably predicted use as indicated by satisfactory prediction error statistics, and contained psychosocial features common to both sexes. However, males and females exhibited distinct brain predictors that failed to predict use in the opposite sex or predict binge drinking in independent samples of same‐sex participants. Collapsed across sex, genetic variation on catecholamine and opioid receptors marginally predicted use. Using machine learning techniques applied to a large multimodal dataset, we identified a risk profile containing psychosocial and sex‐specific brain prognostic markers, which were likely to precede and influence cannabis initiation.     

KCNJ6 is Associated with Adult Alcohol Dependence and Involved in Gene × Early Life Stress Interactions in Adolescent Alcohol Drinking

Alcohol abuse and dependence have proven to be complex genetic traits that are influenced by environmental factors. Primate and human studies have shown that early life stress increases the propensity for alcohol abuse in later life. The reinforcing properties of alcohol are mediated by dopaminergic signaling; however, there is little evidence to indicate how stress alters alcohol reinforcement. KCNJ6 (the gene encoding G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2)) is a brain expressed potassium channel with inhibitory effects on dopaminergic tone. The properties of GIRK2 have been shown to be enhanced by the stress peptide corticotrophin-releasing hormone. Therefore, we sought to examine the role of KCNJ6 polymorphisms in adult alcohol dependence and stress-related alcohol abuse in adolescents. We selected 11 SNPs in the promoter region of KCNJ6, which were genotyped in 1152 adult alcohol dependents and 1203 controls. One SNP, rs2836016, was found to be associated with alcohol dependence (p=0.01, false discovery rate). We then assessed rs2836016 in an adolescent sample of 261 subjects, which were characterized for early life stress and adolescent hazardous drinking, defined using the Alcohol Use Disorders Identification Test (AUDIT), to examine gene–environment interactions. In the adolescent sample, the risk genotype of rs2836016 was significantly associated with increased AUDIT scores, but only in those individuals exposed to high levels of psychosocial stress in early life (p=0.01). Our findings show that KCNJ6 is associated with alcohol dependence and may moderate the effect of early psychosocial stress on risky alcohol drinking in adolescents. We have identified a candidate gene for future studies investigating a possible functional link between the response to stress and alcohol reinforcement.