Behavioral effects of chronic adolescent stress are sustained and sexually dimorphic

Evidence suggests that women are more susceptible to stress-related disorders than men. Animal studies demonstrate a similar female sensitivity to stress and have been used to examine the underlying neurobiology of sex-specific effects of stress. Although our understanding of the sex-specific effects of chronic adolescent stress has grown in recent years, few studies have reported the effects of adolescent stress on depressive-like behavior. The purpose of this study was to determine if a chronic mixed modality stressor (consisting of isolation, restraint, and social defeat) during adolescence (PND 37-49) resulted in differential and sustained changes in depressive-like behavior in male and female Wistar rats. Female rats exposed to chronic adolescent stress displayed decreased sucrose consumption, hyperactivity in the elevated plus maze, decreased activity in the forced swim test, and a blunted corticosterone response to an acute forced swim stress compared to controls during both adolescence (PND 48-57) and adulthood (PND 96-104). Male rats exposed to chronic adolescent stress did not manifest significant behavioral changes at either the end of adolescence or in adulthood. These data support the proposition that adolescence may be a stress sensitive period for females and exposure to stress during adolescence results in behavioral effects that persist in females. Studies investigating the sex-specific effects of chronic adolescent stress may lead to a better understanding of the sexually dimorphic incidence of depressive and anxiety disorders in humans and ultimately improve prevention and treatment strategies.     

Transgenic mice expressing a human mutant beta1 thyroid receptor are hyperactive, impulsive, and inattentive

Attention deficit hyperactivity disorder (ADHD) is the most commonly diagnosed childhood psychiatric disorder. We have found that a transgenic mouse bearing a human mutant thyroid receptor (TRbeta1) expresses all of the defining symptoms of ADHD--inattention, hyperactivity, and impulsivity--as well as a 'paradoxical' response to methylphenidate (MPH). As with ADHD, the behavioral phenotypes expressed by the TRbeta transgenic mice are dynamic and sensitive to changes in environmental conditions, stress, and reinforcement. TRbeta transgenic mice are euthyroid except for a brief period during postnatal development, but the behavioral phenotypes, elevated dopamine turnover, and paradoxical response to MPH persist into adulthood. Thus, like the vast majority of children with ADHD, the TRbeta transgenic mice exhibit the symptoms of ADHD in the complete absence of thyroid abnormalities. This suggests that even transient perturbations in developmental thyroid homeostasis can have long-lasting behavioral and cognitive consequences, including producing the full spectrum of symptoms of ADHD.     

Adolescent exposure to oxytocin,but not the selective oxytocin receptor agonist TGOT,increases social behavior and plasma oxytocin in adulthood

There are indications that exposing adolescent rodents to oxytocin (OT) may have positive “trait-changing” effects resulting in increased sociability and decreased anxiety that last well beyond acute drug exposure and into adulthood. Such findings may have relevance to the utility of OT in producing sustained beneficial effects in human psychiatric conditions. The present study further examined these effects using an intermittent regime of OT exposure in adolescence, and using Long Evans rats, that are generally more sensitive to the acute prosocial effects of OT. As OT has substantial affinity for the vasopressin V1a receptor (V1aR) in addition to the oxytocin receptor (OTR), we examined whether a more selective peptidergic OTR agonist – [Thr4, Gly7]-oxytocin (TGOT) – would have similar lasting effects on behavior. Male Long Evans rats received OT or TGOT (0.5–1 mg/kg, intraperitoneal), once every three days, for a total of 10 doses during adolescence (postnatal day (PND) 28–55). Social and anxiety-related behaviors were assessed during acute administration as well as later in adulthood (from PND 70 onwards). OT produced greater acute behavioral effects than TGOT, including an inhibition of social play and reduced rearing, most likely reflecting primary sedative effects. In adulthood, OT but not TGOT pretreated rats displayed lasting increases in social interaction, accompanied by an enduring increase in plasma OT. These findings confirm lasting behavioral and neuroendocrine effects of adolescent OT exposure. However, the absence of such effects with TGOT suggests possible involvement of the V1aR as well as the OTR in this example of developmental neuroplasticity.     

Methylphenidate and if-then plans are comparable in modulating the P300 and increasing response inhibition in children with ADHD

A disturbed functioning of the prefrontal cortex, the anterior cingulate cortex, and an accordingly reduced P300 presumably underlies executive function deficits of children with attention deficit hyperactivity disorder (ADHD). Using a combined classification and Go/NoGo task paradigm, the present study investigated whether medication with methylphenidate (MPH) modulates the P300 as measured by a high-density electroencephalogram (EEG) and facilitates response inhibition in children with ADHD. Further, effects of MPH were compared with effects of self-regulation by if-then plans (Gollwitzer in Am Psychol 54: 493-503, 1999). MPH as well as if-then plans modulated the P300 and improved inhibition of an unwanted response on a Go/NoGo task to the same level observed in children without ADHD. Importantly, self-regulation strategies might be a valuable alternative to medication with MPH in children with ADHD.     

Effects of Acute or Chronic Ethanol Exposure during Adolescence on Behavioral Inhibition and Efficiency in a Modified Water Maze Task

Ethanol is well known to adversely affect frontal executive functioning, which continues to develop throughout adolescence and into young adulthood. This is also a developmental window in which ethanol is misused by a significant number of adolescents. We examined the effects of acute and chronic ethanol exposure during adolescence on behavioral inhibition and efficiency using a modified water maze task. During acquisition, rats were trained to find a stable visible platform onto which they could escape. During the test phase, the stable platform was converted to a visible floating platform (providing no escape) and a new hidden platform was added in the opposite quadrant. The hidden platform was the only means of escape during the test phase. In experiment 1, adolescent animals received ethanol (1.0g/kg) 30min before each session during the test phase. In experiment 2, adolescent animals received chronic intermittent ethanol (5.0g/kg) for 16 days (PND30 To PND46) prior to any training in the maze. At PND72, training was initiated in the same modified water maze task. Results from experiment 1 indicated that acute ethanol promoted behavioral disinhibition and inefficiency. Experiment 2 showed that chronic intermittent ethanol during adolescence appeared to have no lasting effect on behavioral disinhibition or new spatial learning during adulthood. However, chronic ethanol did promote behavioral inefficiency. In summary, results indicate that ethanol-induced promotion of perseverative behavior may contribute to the many adverse behavioral sequelae of alcohol intoxication in adolescents and young adults. Moreover, the long-term effect of adolescent chronic ethanol exposure on behavioral efficiency is similar to that observed after chronic exposure in humans.     

Effects of Age and Acute Ethanol on Glutamatergic Neurotransmission in the Medial Prefrontal Cortex of Freely Moving Rats Using Enzyme-Based Microelectrode Amperometry

Ethanol abuse during adolescence may significantly alter development of the prefrontal cortex which continues to undergo structural remodeling into adulthood. Glutamatergic neurotransmission plays an important role during these brain maturation processes and is modulated by ethanol. In this study, we investigated glutamate dynamics in the medial prefrontal cortex of freely moving rats, using enzyme-based microelectrode amperometry. We analyzed the effects of an intraperitoneal ethanol injection (1 g/kg) on cortical glutamate levels in adolescent and adult rats. Notably, basal glutamate levels decreased with age and these levels were found to be significantly different between postnatal day (PND) 28-38 vs PND 44-55 (p<0.05) and PND 28-38 vs adult animals (p<0.001). We also observed spontaneous glutamate release (transients) throughout the recordings. The frequency of transients (per hour) was significantly higher in adolescent rats (PND 28-38 and PND 44-55) compared to those of adults. In adolescent rats, post-ethanol injection, the frequency of glutamate transients decreased within the first hour (p<0.05), it recovered slowly and in the third hour there was a significant rebound increase of the frequency (p<0.05). Our data demonstrate age-dependent differences in extracellular glutamate levels in the medial prefrontal cortex and suggest that acute ethanol injections have both inhibitory and excitatory effects in adolescent rats. These effects of ethanol on the prefrontal cortex may disturb its maturation and possibly limiting individuals´ control over addictive behaviors.     

Childhood ADHD and Risk for Substance Dependence in Adulthood: A Longitudinal,Population-Based Study

Background

Adolescents with attention-deficit/hyperactivity disorder (ADHD) are known to be at significantly greater risk for the development of substance use disorders (SUD) compared to peers. Impulsivity, which could lead to higher levels of drug use, is a known symptom of ADHD and likely accounts, in part, for this relationship. Other factors, such as a biologically increased susceptibility to substance dependence (addiction), may also play a role.

Objective

This report further examines the relationships between childhood ADHD, adolescent- onset SUD, and substance abuse and substance dependence in adulthood.

Method

Individuals with childhood ADHD and non-ADHD controls from the same population-based birth cohort were invited to participate in a prospective outcome study. Participants completed a structured neuropsychiatric interview with modules for SUD and a psychosocial questionnaire. Information on adolescent SUD was obtained retrospectively, in a previous study, from medical and school records. Associations were summarized using odds ratios (OR) and 95% CIs estimated from logistic regression models adjusted for age and gender.

Results

A total of 232 ADHD cases and 335 non-ADHD controls participated (mean age, 27.0 and 28.6 years, respectively). ADHD cases were more likely than controls to have a SUD diagnosed in adolescence and were more likely to have alcohol (adjusted OR 14.38, 95% CI 1.49–138.88) and drug (adjusted OR 3.48, 95% CI 1.38–8.79) dependence in adulthood. The subgroup of participating ADHD cases who did not have SUD during adolescence were no more likely than controls to develop new onset alcohol dependence as adults, although they were significantly more likely to develop new onset drug dependence.

Conclusions

Our study found preliminary evidence that adults with childhood ADHD are more susceptible than peers to developing drug dependence, a disorder associated with neurological changes in the brain. The relationship between ADHD and alcohol dependence appears to be more complex.     

Long lasting complex nocturnal hallucinations during Osmotic Release Oral System (OROS) methylphenidate treatment in a 7-year old girl

We report a case of a girl with Attention deficit hyperactivity disorder (ADHD) and Oppositional defiant disorder (ODD) who experienced a 3-hour episode of nocturnal complex bizarre visual hallucinations when treated with 18 mg Osmotic Release Oral System (OROS) methylphenidate (MPH). Nocturnal polysomnography performed two weeks later revealed REM sleep reduction (17%) and fragmentation . Two episodes of confusional arousals were recorded. This finding is typical of parasomnia associated with NREM sleep - disorder of arousal. We hypothesize that this preexisting sleep impairment represents a factor of vulnerability to MPH sleep side effects. In our search of literature, we found no report of nocturnal hallucination alone during treatment with stimulants.     

Effect of methylphenidate on dopamine/DARPP signalling in adult, but not young, mice

Methylphenidate (MPH), a dopamine uptake inhibitor, is the most commonly prescribed drug for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children. We examined the effect of MPH on dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa (DARPP-32) phosphorylation at Thr34 (PKA-site) and Thr75 (Cdk5-site) using neostriatal slices from young (14-15- and 21-22-day-old) and adult (6-8-week-old) mice. MPH increased DARPP-32 Thr34 phosphorylation and decreased Thr75 phosphorylation in slices from adult mice. The effect of MPH was blocked by a dopamine D1 antagonist, SCH23390. In slices from young mice, MPH did not affect DARPP-32 phosphorylation. As with MPH, cocaine stimulated DARPP-32 Thr34 phosphorylation in slices from adult, but not from young mice. In contrast, a dopamine D1 agonist, SKF81297, regulated DARPP-32 phosphorylation comparably in slices from young and adult mice, as did methamphetamine, a dopamine releaser. The results suggest that dopamine synthesis and the dopamine transporter are functional at dopaminergic terminals in young mice. In contrast, the lack of effect of MPH in young mice is likely attributable to immature development of the machinery that regulates vesicular dopamine release.     

Adolescent binge drinking leads to changes in alcohol drinking, anxiety, and amygdalar corticotropin releasing factor cells in adulthood in male rats

Heavy episodic drinking early in adolescence is associated with increased risk of addiction and other stress-related disorders later in life. This suggests that adolescent alcohol abuse is an early marker of innate vulnerability and/or binge exposure impacts the developing brain to increase vulnerability to these disorders in adulthood. Animal models are ideal for clarifying the relationship between adolescent and adult alcohol abuse, but we show that methods of involuntary alcohol exposure are not effective. We describe an operant model that uses multiple bouts of intermittent access to sweetened alcohol to elicit voluntary binge alcohol drinking early in adolescence (~postnatal days 28-42) in genetically heterogeneous male Wistar rats. We next examined the effects of adolescent binge drinking on alcohol drinking and anxiety-like behavior in dependent and non-dependent adult rats, and counted corticotropin-releasing factor (CRF) cell in the lateral portion of the central amygdala (CeA), a region that contributes to regulation of anxiety- and alcohol-related behaviors. Adolescent binge drinking did not alter alcohol drinking under baseline drinking conditions in adulthood. However, alcohol-dependent and non-dependent adult rats with a history of adolescent alcohol binge drinking did exhibit increased alcohol drinking when access to alcohol was intermittent. Adult rats that binged alcohol during adolescence exhibited increased exploration on the open arms of the elevated plus maze (possibly indicating either decreased anxiety or increased impulsivity), an effect that was reversed by a history of alcohol dependence during adulthood. Finally, CRF cell counts were reduced in the lateral CeA of rats with adolescent alcohol binge history, suggesting semi-permanent changes in the limbic stress peptide system with this treatment. These data suggest that voluntary binge drinking during early adolescence produces long-lasting neural and behavioral effects with implications for anxiety and alcohol use disorders.     

Long-term effects of postnatal exposure to diethylstilbestrol on uterine estrogen receptor and growth.

Diethylstilbestrol (DES) treatment of female rats on postnatal days (PND) 1-5 reduces uterine growth, estrogen receptor (ER) level and gland number by PND 25, while daily DES treatment on PND 1-25 increases uterine growth 4-fold, further reduces ER level and completely suppresses gland formation. We now report the persistence of these effects in adults. By PND 60, uterine weight was 70% of controls in rats injected with DES on PND 1-5 but only 10% of controls in rats injected PND 1-10 or longer. In fact, uterine weights were the same on PND 10 and 60. Uterine gland numbers were reduced to 30% of controls in all DES-treated rats regardless of exposure length; however, luminal and glandular epithelial cell heights were reduced to less than 50 and 70%, respectively, of controls when DES was given on PND 1-25 but not when given on PND 1-5. Ovariectomy 7 days prior to sacrifice on PND 60 reduced uterine weight in controls by 67% and in rats injected with DES on PND 1-5 by 53%, but had no effect in rats injected with DES on PND 1-10. DES exposure at either PND 1-5 or 1-10 lowered ER levels by 35-50% at both 60 and 90 days. Treatment with a high dose of estradiol (E2) 1 week before sacrifice significantly down-regulated ER to the same concentration in all treatment groups at PND 60 and 90. Following E2 treatment, all groups also showed increased uterine weight at PND 60 and 90. These data show there is a short period of development (PND 5-10) in which further DES exposure indirectly inhibits uterine growth.     

Heart rate variability and methylphenidate in children with ADHD

Although an extensive number of studies support the efficacy and tolerability of stimulants in the treatment of attention deficit/hyperactivity disorder (ADHD), in recent years, increasing concerns have been raised about their cardiovascular safety. We investigated whether a time domain analysis of heart rate variability (HRV) recordings in 24-h ECG under medication with stimulants yielded new information about therapy control in ADHD. We analysed the HRV parameter standard deviation of all normal sinus RR intervals over 24 h (SDNN), percentage of successive normal sinus RR intervals > 50 ms (pNN50) and root-mean-square of the successive normal sinus RR interval difference (rMSSD) from 23 children diagnosed by ADHD (19 boys and 4 girls), aged 10.5 ± 2.2 years, who were consecutively referred to our outpatient clinic for paediatric cardiology. Eleven children received medication with methylphenidate (MPH), while twelve children were initially examined without medication. Of these, eight probands were re-examined after therapy with MPH was established. Controls comprised 19 children (10 boys, 9 girls) from our Holter ECG data base without any cardiac or circulatory disease. Compared to healthy controls, the ADHD children with and without MPH treatment showed significantly higher mean heart rates (ADHD without MPH: 94.3 ± 2.2; ADHD with MPH: 90.5 ± 1.8, controls: 84.7 ± 1.8). pNN50 (ADHD without MPH: 6.5 ± 2.7; ADHD with MPH: 14.2 ± 6.9, controls: 21.5 ± 9.0) and rMSSD (ADHD without MPH: 26.1 ± 4.1; ADHD with MPH: 36.7 ± 8.3, controls: 44.5 ± 10.1) were lowest in ADHD children without MPH, middle in ADHD children with MPH and highest in controls. SDNN values were not significantly different. The hourly analysis shows highly significant reduced pNN50 and rMSSD values in untreated ADHD children between 5:00 pm and 6:00 am while the pattern approaches to levels of controls during MPH treatment. Data of this pilot study indicate a decreased vagal tone with significantly diminished HRV and higher heart rates in unmedicated ADHD children. These parameters of autonomic activation are ameliorated by MPH treatment. No evidence for negative impact of MPH on HRV was detected. Further studies will clarify a potential cardio-protective effect of MPH in ADHD.     

Effects of age and weaning on the immature rat uterotrophic assay using ethynylestradiol.

The purpose of this study was to evaluate the most appropriate rat age for the start of administration, and the effect of weaning, in the immature rat uterotrophic assay using ethynylestradiol (EE). Animals weaned on postnatal day (PND) 20 were administered subcutaneously EE at doses of 0.06-6 micrograms/kg/day for 3 days beginning on PND 21, 23 or 25. EE at the same doses was also administered to rats weaned on PND 17 or 20 from PND 21 for 3 days. Although uterine weight was significantly increased in the rats given 0.6-6 micrograms/kg EE in both of the studies, the percentage increase relative to the control in each group given EE from PND 21 and weaned on PND 20 was higher than in those groups given EE from PND 23 or 25, and the group weaned on PND 17.     

Long-lasting, sex- and age-specific effects of social stressors on corticosterone responses to restraint and on locomotor responses to psychostimulants in rats

Many neural systems are undergoing marked development over adolescence, which may heighten an animal's vulnerability to stressors. One consequence may be altered sensitivity to drugs of abuse. We previously reported that social stressors in adolescence increased behavioral sensitization to nicotine in adulthood in female, but not male, rats. Here we examined whether social stressors in adolescence alter the functioning of the hypothalamic-pituitary-adrenal (HPA) axis by examining corticosterone release in response to restraint in adulthood. To further assess effects of social stressors on behavioral sensitivity to psychostimulants, we examined locomotor activity in response to nicotine and to amphetamine. In a second set of experiments, we investigated whether the same procedure of social stressors administered in adulthood produces effects similar to that observed when administered in adolescence. Rats underwent daily 1 h isolation followed by pairing with a new cage mate on either postnatal days 33-48 (pubertal stress: PS) or days 65-80 (adult stress: AS). Three weeks later rats tested for either: (a) corticosterone levels were measured in response to restraint, or (b) locomotor sensitization to nicotine (0.25 mg/kg; 5 days) followed by an amphetamine challenge (0.5 mg/kg) 24 h later. Effects of social stressors were evident only in females. PS females had increased locomotor activity to amphetamine compared to controls, and AS females had increased corticosterone release compared to controls. No effect of the social stressors was found in males at either age except for reduced weight gain during the stress procedure. Thus, females are more susceptible to the enduring effects of these moderate social stressors than are males. However, in terms of behavioral sensitivity to drugs of abuse, females may be more susceptible to stressors during adolescence than adulthood, although the reverse appears to be true for HPA function.     

An Evaluation on the Efficacy and Safety of Treatments for Attention Deficit Hyperactivity Disorder in Children and Adolescents: a Comparison of Multiple Treatments

Attention deficit hyperactivity disorder (ADHD) is one of the most common neurobehavioral disorders. We carried out this comparison of multiple treatments based on sufficient data in attempt to evaluate the efficacy and safety of ADHD medication for children and adolescents. PubMed, Embase and the Cochrane Database were used to search for relevant articles. Changes in the ADHD Rating Scale (ADHD-RS) scores and the Conners’ Parent Rating Scale-Revised (CPRS) scores were used as outcomes for efficacy. Withdrawals due to all-cause, adverse effects and lack of efficacy were defined as primary outcomes evaluating the safety of such medications. Both pair-wise and network meta-analyses were performed. Efficacy and safety of atomoxetine (ATX), bupropion (BUP), clonidine hydrochloride (CLON), guanfacine extended release (GXR), lisdexamfetamine dimesylate (LDX), and methylphenidate (MPH) were evaluated. LDX has the highest efficacy and a relatively lower rate of adverse effects compared to BUP, CLON and GXR. MPH has the lowest incidence rate of adverse effects and takes second place concerning ADHD-RS scores and third place concerning CPRS scores. ATX has the lowest incidence rate of all-cause withdrawals. The efficacy of ATX seems, however, to be lower than CLON, GXR, LDX and MPH. Adversely, BUP has the highest incidence rate of withdrawals and the second highest probability of causing adverse effects as well as lack of efficacy; therefore it should not be recommended as a treatment for ADHD.     

The use of actigraphy in the monitoring of methylphenidate versus placebo in ADHD: a meta-analysis

Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder of childhood. There is an increasing need to find objective measures and markers of the disorder in order to assess the efficacy of the therapy and to improve follow-up strategies. Actigraphy is an objective method for recording motor activity and sleep parameters using small, computerized, watch-like devices worn on the body, and it has been used in many clinical trials to assess methylphenidate efficacy and adverse effects in ADHD. Our article aim is to systematically review and perform a meta-analysis of the current evidence on the role of actigraphy in both the detection of changes in activity and in sleep patterns in randomized clinical trials that compared methylphenidate against placebo in the treatment of ADHD. A comprehensive literature search of PubMed/MEDLINE, Scopus, Embase, Cochrane Library, CINHAL and PsycINFO databases was carried out to find randomized clinical trials comparing methylphenidate versus placebo in children with ADHD, using actigraphic measures as an outcome. No start date limit was used and the search was updated until June 2013. The primary outcome measures were ‘total sleep time’ and daytime ‘activity mean’. As secondary outcomes, we analyzed ‘sleep onset latency’, ‘sleep efficiency’ and ‘wake after sleep onset’. Eight articles comprising 393 patients were included in the analysis. Children with ADHD using MPH compared to placebo have a significant difference of a large effect with a diminishing value in the activity mean. For the total sleep time, we found a significant and large effect in the decrease in sleep in MPH group. This study shows that MPH may effectively reduce mean activity in ADHD children, but it may negatively affect total sleep time.     

Methylphenidate is not clastogenic in cultured human lymphocytes and in the mouse bone-marrow micronucleus test

Methylphenidate (MPH) is one of the most frequently prescribed drugs for the treatment of attention deficit hyperactivity disorder (ADHD). A report on cytogenetic effects observed in peripheral lymphocytes from children treated for 3 months with MPH raised questions about the genetic toxicity of this compound. A critical review of this data concluded that the cytogenetic effects in treated children remain unexplained. A literature review showed that MPH was found negative in most genetox studies performed, but no in vitro chromosome aberration data in human lymphocytes have been published. Therefore, we conducted a chromosomal aberration study in cultured human peripheral lymphocytes. The results of this investigation showed that d,l-methylphenidate (MPH, Ritalin) in concentrations up to 10 mM did neither induce structural nor numerical chromosome abnormalities. An oral mouse bone-marrow micronucleus test in B6C3F(1) mice, with doses up to 250 mg/kg bw, was negative too. The data of these studies confirm the absence of clastogenic activity of MPH in non-clinical studies.     

A prospective look at substance use and criminal behavior in urban ADHD youth: what is the role of maltreatment history on outcome?

Children with attention-deficit/hyperactivity disorder (ADHD) are at heightened risk of antisocial behavior during adolescence/early adulthood. Here, we characterize the antisocial outcomes of a sample of urban, lower-socioeconomic-status, ethnically diverse ADHD youth and investigate the impact of maltreatment history on criminal and substance use disorder (SUD) outcomes. Ninety-eight participants diagnosed with ADHD in childhood were re-assessed 10 years later and compared with controls. Regression analyses investigated the effect of maltreatment on antisocial outcomes among four groups based on ADHD and maltreatment status. ADHD subjects and controls did not differ in rates of arrest, conviction, incarceration, or recidivism. ADHD youth were younger at their first arrest with higher rates of SUDs when compared to controls. Controls and ADHD subjects with maltreatment had significantly higher rates of SUDs compared to the no-ADHD/no-maltreatment group. Only ADHD youth with maltreatment had significantly higher rates of arrest than the reference group. In contrast to prior studies, ADHD youth did not differ from controls on most measures of antisocial behavior. Maltreatment increased the rate of arrest only among ADHD youth, though increased the rate of SUD for ADHD youth and controls. This suggests that ADHD youth, in the absence of maltreatment, are at no greater risk of SUDs or arrest than controls without maltreatment.     

Adolescent oxytocin exposure causes persistent reductions in anxiety and alcohol consumption and enhances sociability in rats

Previous studies have suggested that administration of oxytocin (OT) can have modulatory effects on social and anxiety-like behavior in mammals that may endure beyond the time of acute OT administration. The current study examined whether repeated administration of OT to male Wistar rats (n = 48) during a key developmental epoch (early adolescence) altered their physiology and behavior in later-life. Group housed rats were given intraperitoneal injections of either 1 mg/kg OT or vehicle during early adolescence (post natal-days [PND] 33–42). OT treatment caused a transient inhibition of body weight gain that recovered quickly after the cessation of treatment. At PND 50, the rats pre-treated with OT displayed less anxiety-like behavior on the emergence test, while at PND 55 they showed greater levels of social interaction. A subgroup of OT pre-treated rats examined at PND 63 showed a strong trend towards increased plasma OT levels, and also displayed significantly increased OT receptor mRNA in the hypothalamus. Rats pre-treated with OT and their controls showed similar induction of beer intake in daily 70 min test sessions (PND 63 onwards) in which the alcohol concentration of beer was gradually increased across days from 0.44% to 4.44%. However, when given ad libitum access to beer in their home cages from PND 72 onwards (early adulthood), consumption of beer but not water was significantly less in the OT pre-treated rats. A “booster” shot of OT (1 mg/kg) given after 25 days of ad libitum access to beer had a strong acute inhibitory effect on beer intake without affecting water intake. Overall these results suggest that exogenous OT administered during adolescence can have subtle yet enduring effects on anxiety, sociability and the motivation to consume alcohol. Such effects may reflect the inherent neuroplasticity of brain OT systems and a feed-forward effect whereby exogenous OT upregulates endogenous OT systems.