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The adenosine A2A receptor ( ADORA2A) is linked to the dopamine neurotransmitter system and is also implicated in the regulation of alertness, suggesting a potential association with attention-deficit hyperactivity disorder ( ADHD) traits. Furthermore, animal studies suggest that the ADORA2A may influence ADHD-like behavior. For that reason, the ADORA2A gene emerges as a promising candidate for studying the etiology of ADHD traits. The aim of this study was to examine the relationship between ADORA2A gene polymorphisms and ADHD traits in a large population-based sample. This study was based on the Child and Adolescent Twin Study in Sweden ( CATSS), and included 1747 twins. Attention-deficit hyperactivity disorder traits were assessed through parental reports, and samples of DNA were collected. Associations between six single nucleotide polymorphisms ( SNPs) and ADHD traits were examined, and results suggested a nominal association between ADHD traits and three of these SNPs: rs3761422, rs5751876 and rs35320474. For one of the SNPs, rs35320474, results remained significant after correction for multiple comparisons. These results indicate the possibility that the ADORA2A gene may be involved in ADHD traits. However, more studies replicating the present results are warranted before this association can be confirmed. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to assess cardiac event incidence and trends by sex and age in young patients on psychopharmacological treatment in Sweden., Methods: This nationwide incidence study encompassed data from Swedish registers (2006-2018). Patients aged 5-30 years were exposed to one or more psychotropic medications (attention deficit hyperactivity disorder medications, antihistamines, selective serotonin reuptake inhibitors, other antidepressants, anxiolytics, antipsychotics, hypnotics/sedatives). Annual incidences, trends and mean incidences of cardiac events (cardiac arrest, arrhythmias, fainting/collapse, sudden death) and recurrent events were calculated., Results: Among those exposed (n = 875 430, 2 647 957 patient-years, 55% female), 26 750 cardiac events were identified. The mean annual incidence of cardiac events and first-ever events were 0.99% and 0.80%, respectively, showing significant upward annual trends of 4.26% and 2.48%, respectively (P < .001). The highest incidences were among females aged 15-19 years (1.50%) and those exposed to polypharmacy (1.63%), anxiolytics (1.53%) or antihistamines (1.27%). The mean annual incidences of cardiac arrest and arrythmias, for both sexes, were 0.01% and 0.51%, respectively. Fainting/collapse accounted for about half of all events, occurring more often in females. The pattern of rising annual incidence remained after excluding fainting/collapse. In all, 21.1% of events were recurrent. Death, including sudden death, occurred in 13 patients., Conclusions: The mean annual incidence of cardiac events among young patients receiving psychopharmacological treatment was low, 0.99%, with an upward trend of 4.26% annually. Incidence was highest in adolescent females and patients exposed to polypharmacy. Our study highlights the need for more knowledge regarding the possible association between exposure to psychopharmacological treatment and cardiac events., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Internalizing disorders, such as anxiety and depressive disorders, are common mental disorders in young people, but a detailed understanding of the symptom continuity from childhood to adolescence that additionally includes a variety of neurodevelopmental disorder (NDD) symptoms is lacking. We therefore aimed to assess the extent to which parent-reported anxiety, depression, and NDD symptoms in childhood predict parent-reported internalizing symptoms in adolescence., Methods: We used the nation-wide population-based Child and Adolescent Twin Study in Sweden, comprising 4492 twins born in Sweden between 1998 and 2003 that were assessed at age 9, and then again at age 15. Linear regression in a structural equation modelling framework was used to analyze the data., Results: Overall, our results indicate that 15.9% of the variance in internalizing symptoms at age 15 can be predicted by anxiety, depression, and NDD symptoms at age 9. Anxiety and NDD symptoms in childhood predicted the largest amount of internalizing symptoms in adolescence., Conclusions: Adolescent internalizing symptoms are modestly affected by childhood symptoms of anxiety, depression, and NDDs, suggesting that they may represent different constructs across age. Future studies should further empirically investigate differences in etiology and trajectories of childhood versus adolescent internalizing symptoms., (© 2022. The Author(s).)

Background: Attention deficit hyperactivity disorder (ADHD) is a common childhood behavioral condition that globally affects an average of around 5% of children and is associated with several adverse life outcomes. Comorbidity with autism spectrum disorder (ASD) is highly prevalent. Pharmacological treatment for ADHD symptoms has been shown to be effective. However, the prevailing perception is that children with ADHD and concomitant ASD symptoms report poorer efficacy and more side effects. This has been supported by studies on this population, but prospective studies directly comparing children with ADHD and different levels of ASD symptoms are lacking. We aimed to assess if children with ADHD and concomitant ASD symptoms differ regarding effects and side-effects of pharmacological ADHD treatment compared to children with ADHD without ASD traits. This is to our knowledge the second study to directly compare the effect of ADHD medication between ADHD patients with different levels of ASD symptoms., Methods: In a non-randomized, observational, prospective cohort study, 323 patients aged 6 to 17 years who were diagnosed with ADHD and starting pharmacological treatment were divided into two groups: one with high level of ASD symptoms (ASD group, N=71) and one with low level of ASD symptoms (non-ASD group, N = 252). Treatment outcome was measured as ADHD symptoms, and evaluated using the Swanson, Nolan and Pelham Teacher and Parent ADHD rating scale-version IV (SNAP-IV). Side-effects were evaluated using the Pediatric Side Effects Checklist (P-SEC), at 3 months follow-up., Results: From baseline to 3 months, there was no significant difference in neither treatment effect nor number of clinically significant adverse events experienced between the ASD group and the non-ASD group., Conclusions: Our results did not implicate that ADHD patients with concomitant ASD symptoms have decreased treatment effect of ADHD medication than patients with ADHD without concomitant ASD symptoms. Neither did the results support that ADHD patients with ASD symptoms experienced significantly more side-effects than ADHD patients without ASD symptoms. Although, we did not analyze different medications separately, this is in line with the only previous study directly comparing methylphenidate treatment in children with or without ASD., Trial Registration: NCT02136147 , May 12, 2014., (© 2022. The Author(s).)

Background: Clinical studies found that medication for attention-deficit/hyperactivity disorder (ADHD) is effective in coexisting autism spectrum disorder (ASD), but current research is based on small clinical studies mainly performed on children or adolescents. We here use register data to examine if individuals with ADHD and coexisting ASD present differences in the prescribing patterns of ADHD medication when compared to individuals with pure ADHD., Methods: Data with information on filled prescriptions and diagnoses was retrieved from the Swedish Prescribed Drug Register and the National Patient Register. We identified 34,374 individuals with pure ADHD and 5012 individuals with ADHD and coexisting ASD, aged between 3 and 80 years. The first treatment episode with ADHD medications (≥ 2 filled prescriptions within 90 days) and daily doses of methylphenidate during a 3-year period was measured. Odds ratios (ORs) were calculated for the likelihood of being prescribed ADHD medication in individuals with and without ASD and Wilcoxon rank-sum test was used to compare group differences in dose per day., Results: Individuals with ADHD and coexisting ASD were less likely to start continuous treatment with ADHD medication (ADHD 80.5%; ADHD with ASD 76.2%; OR, 0.80; 95% confidence interval, 0.75-0.86), were less likely to be prescribed methylphenidate, and were more commonly prescribed second line treatments such as dexamphetamine, amphetamine, or modafinil. No group difference was observed for atomoxetine. In adults with ADHD and coexisting ASD, methylphenidate was prescribed in lower daily doses over three years as compared to individuals with pure ADHD., Conclusions: The findings indicate that there are differences in the medical treatment of individuals with or without ASD. If these differences are due to different medication responses in ASD or due to other factors such as clinicians' perceptions of medication effects in patients with ASD, needs to be further studied.

Background: Previous research has noted trends of increasing internalizing problems (e.g., symptoms of depression and anxiety), particularly amongst adolescent girls. Cross-cohort comparisons using identical assessments of both anxiety and depression in youth are lacking, however., Methods: In this large twin study, we examined trends in internalizing symptoms in samples of 9 year old children and 15 year old adolescents, gathered from successive birth cohorts from 1998 to 2008 (age 9) and 1994-2001 (age 15). Assessments at age 9 were parent-rated, and at age 15 self- and parent-rated. We examined (i) the relation between birth cohorts and internalizing symptoms using linear regressions, and (ii) whether percentages of participants exceeding scale cut-off scores changed over time, using Cochrane Armitage Trend Tests., Results: Among 9 year old children, a significantly increasing percentage of participants (both boys and girls) had scores above cut-off on anxiety symptoms, but not on depressive symptoms. At age 15, a significantly increasing percentage of participants (both boys and girls) had scores above cut-off particularly on self-reported internalizing symptoms. On parent-reported internalizing symptoms, only girls demonstrated a corresponding trend., Conclusion: In line with previous studies, we found small changes over sequential birth cohorts in frequencies of depression and anxiety symptoms in children. Further, these changes were not exclusive to girls.

1. 2-p-(2-carboxyethylphenethylamino-5'-ethylcarboxamidoadenosine) (CGS 21680) is considered the reference compound to study adenosine A(2A) receptors. However, CGS 21680 binding in the cerebral cortex, where adenosine A(1) receptors are predominant, displays a mixed A(2A)/A(1) receptor pharmacology. We now use adenosine A(1) and A(2A) receptor knockout mice to investigate the characteristics of cortical [(3)H]CGS 21680 binding. 2. [(3)H]CGS 21680 binding to the cerebral cortex was strongly reduced in adenosine A(1) receptor knockout mice, but only slightly reduced in A(2A) receptor knockout mice compared with the corresponding wild-type littermates. 3. Another selective A(2A) receptor ligand, [(3)H]-5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine ([(3)H]SCH 58261), displayed a saturable binding to mouse cortical membranes, albeit with a binding density 20 times lower than that of striatal membranes, and this [(3)H]SCH58261 binding was abolished in both striatal and cortical membranes of A(2A) receptor knockout mice and unchanged in A(1) receptor knockout mice. 4. The presence of A(2A) receptors in cortical neurons was further confirmed by Western blot in mouse cortical nerve terminal membranes. 5. It is concluded that, although A(2A) receptors are present in the cerebral cortex, the purportedly selective A(2A) receptor agonist [(3)H]CGS 21680 binds in the cerebral cortex to an entity that requires the presence of adenosine A(1) receptors. Thus, CGS 21680 should be used with care in all preparations where adenosine A(1) receptors out-number A(2A) receptors.

Background and Purpose: Cerebral hypoxic ischemia (HI) is an important cause of brain injury in the newborn infant. Adenosine is believed to protect against HI brain damage. However, the roles of the different adenosine receptors are unclear, particularly in young animals. We examined the role of adenosine A2A receptors (A2AR) using 7-day-old A2A knockout (A2AR(-/-)) mice in a model of HI., Methods: HI was induced in 7-day-old CD1 mice by exposure to 8% oxygen for 30 minutes after occlusion of the left common carotid artery. The resulting unilateral focal lesion was evaluated with the use of histopathological scoring and measurements of residual brain areas at 5 days, 3 weeks, and 3 months after HI. Behavioral evaluation of brain injury by locomotor activity, rotarod, and beam-walking test was made 3 weeks and 3 months after HI. Cortical cerebral blood flow, assessed by laser-Doppler flowmetry, and rectal temperature were measured during HI., Results: Reduction in cortical cerebral blood flow during HI and rectal temperature did not differ between wild-type (A2AR(+/+)) and knockout mice. In the A2AR(-/-) animals, brain injury was aggravated compared with wild-type mice. The A2AR(-/-) mice subjected to HI displayed increased forward locomotion and impaired rotarod performance in adulthood compared with A2AR(+/+) mice subjected to HI, whereas beam-walking performance was similarly defective in both groups., Conclusions: These results suggest that, in contrast to the situation in adult animals, A2AR play an important protective role in neonatal HI brain injury.

Caffeine is believed to act by blocking adenosine A(1) and A(2A) receptors (A(1)R, A(2A)R), indicating that some A(1) receptors are tonically activated. We generated mice with a targeted disruption of the second coding exon of the A(1)R (A(1)R(-/-)). These animals bred and gained weight normally and had a normal heart rate, blood pressure, and body temperature. In most behavioral tests they were similar to A(1)R(+/+) mice, but A(1)R(-/-) mice showed signs of increased anxiety. Electrophysiological recordings from hippocampal slices revealed that both adenosine-mediated inhibition and theophylline-mediated augmentation of excitatory glutamatergic neurotransmission were abolished in A(1)R(-/-) mice. In A(1)R(+/-) mice the potency of adenosine was halved, as was the number of A(1)R. In A(1)R(-/-) mice, the analgesic effect of intrathecal adenosine was lost, and thermal hyperalgesia was observed, but the analgesic effect of morphine was intact. The decrease in neuronal activity upon hypoxia was reduced both in hippocampal slices and in brainstem, and functional recovery after hypoxia was attenuated. Thus A(1)Rs do not play an essential role during development, and although they significantly influence synaptic activity, they play a nonessential role in normal physiology. However, under pathophysiological conditions, including noxious stimulation and oxygen deficiency, they are important.