Individuals who begin using alcohol prior to 14 years of age are 4 times more likely to progress to addiction than those who do not initiate use until 21 years of age. The nucleus accumbens septi undergoes dramatic developmental transitions during the adolescent period, and dopaminergic activity within this region has been identified as a central neurochemical mediator of drug reward, addiction and dependence. Thus, alcohol-induced neurochemical alterations in dopaminergic activity within this brain region likely mediate the heightened vulnerability to addiction observed in adolescent alcohol users. To investigate this idea, Sprague-Dawley rats were exposed to intraperitoneal injections of either saline or ethanol (0.5, 1.0 or 2.0 g/kg) twice daily over four days beginning on postnatal day 21, 31, 41 or 56. Cannulas were implanted toward the nucleus accumbens septi, subsequent in vivo microdialysis was used to collect samples, and both basal and ethanol-stimulated dopamine overflow was measured using high performance liquid chromatography with electrochemical detection. A developmental transition in basal levels of dopamine in the nucleus accumbens septi was apparent with peak levels at postnatal day 45. An ethanol challenge produced unique responses across ages, with greater peak effects relative to baseline in younger animals (postnatal day 25 and 35). Following repeated exposure to ethanol, a significant increase in basal dopamine was apparent for all ages, and when these animals were challenged with ethanol, peak effects relative to baseline were decreased in younger animals, but unchanged in older animals (postnatal day 45 and 60). Results indicate that there is a key developmental transition in the ability of rats to adapt to the effects of repeated ethanol exposure, which occurs between postnatal day 35 and 45. This alteration may explain the increased addiction vulnerability observed in individuals who initiate alcohol use during early adolescence.

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The data show that the developmental processes of adolescence influence general responsiveness to alcohol. Specifically, late-adolescent animals (PND 45) seem to prefer doses of alcohol that are either not reinforcing (0.5 g/kg) or are aversive (1.0 g/kg) at other ages. These processes need to be examined thoroughly to understand the development of addiction in adolescence. This is especially important given that alcohol abuse in adolescence may interfere with the usual pattern of brain development as it relates to alcohol reinforcement.

The data show that the developmental processes of adolescence influence general responsiveness to alcohol. Specifically, late-adolescent animals (PND 45) seem to prefer doses of alcohol that are either not reinforcing (0.5 g/kg) or are aversive (1.0 g/kg) at other ages. These processes need to be examined thoroughly to understand the development of addiction in adolescence. This is especially important given that alcohol abuse in adolescence may interfere with the usual pattern of brain development as it relates to alcohol reinforcement.

BackgroundMinocycline, a member of the tetracycline family, has a low risk of adverse effects and an ability to improve behavioral performance in humans with cognitive disruption. We performed a single-arm open-label trial in which 25 children diagnosed with Angelman syndrome (AS) were administered minocycline to assess the safety and tolerability of minocycline in this patient population and determine the drug’s effect on the cognitive and behavioral manifestations of the disorder.MethodsParticipants, age 4-12 years old, were randomly selected from a pool of previously screened children for participation in this study. Each child received 3 milligrams of minocycline per kilogram of body weight per day for 8 weeks. Participants were assessed during 3 study visits: baseline, after 8-weeks of minocycline treatment and after an 8-week wash out period. The primary outcome measure was the Bayley Scales of Infant and Toddler Development 3rd Edition (BSID-III). Secondary outcome measures included the Clinical Global Impressions Scale (CGI), Vineland Adaptive Behavior Scales 2nd Edition (VABS-II), Preschool Language Scale 4th Edition (PLS-IV) and EEG scores. Observations were considered statistically significant if p < 0.05 using ANOVA and partial eta squared (η2) was calculated to show effect size. Multiple comparisons testing between time points were carried out using Dunnett’s post hoc testing.ResultsSignificant improvement in the mean raw scores of the BSID-III subdomains communication and fine motor ability as well as the subdomains auditory comprehension and total language ability of the PLS-IV when baseline scores were compared to scores after the washout period. Further, improvements were observed in the receptive communication subdomain of the VABS-II after treatment with minocycline. Finally, mean scores of the BSID-III self-direction subdomain and CGI scale score were significantly improved both after minocycline treatment and after the wash out period.ConclusionThe clinical and neuropsychological measures suggest minocycline was well tolerated and causes improvements in the adaptive behaviors of this sample of children with Angelman syndrome. While the optimal dosage and the effects of long-term use still need to be determined, these findings suggest further investigation into the effect minocycline has on patients with Angelman syndrome is warranted.Trial registrationNCT01531582 – clinicaltrials.gov

Adult rats have been phenotyped as high (HRs) or low (LRs) responders to novelty, the former associated with high-risk behaviors. Data indicating that adolescent rodents exhibit increased novelty-seeking relative to adults are equivocal, and phenotypic variations in adolescent novel stimulus reactivity are unknown. To determine whether novelty-seeking differs between adolescent and adult rats, reflecting phenotypic variations within each age, activities in an inescapable novel environment and novel object exploration were measured. Adolescents moved further, faster, and more continuously than adults, and exhibited a greater variability and range of activity in the novel environment. Both adolescent and adult LRs habituated to the environment by the second trial, but HRs maintained increased activity throughout 8 trials. In the free-choice paradigm, adolescents approached the novel object more frequently and spent more time in proximity to the object than adults. Similar results were obtained using arenas and objects of the same size or scaled to animal size. Results confirm that novelty-seeking by adolescents is greater than by adults, a behavior attributed primarily to the response magnitude exhibited by adolescents with the HR phenotype.

Recent research indicates that alcohol use/abuse is often initiated during the adolescent period and that brain reinforcement pathways (e.g., the mesolimbic dopamine [DA] pathway) are undergoing developmental transition. Our research focuses on the effects of ethanol administration on neural mechanisms associated with addiction in preadolescent (postnatal day [PND] 25), adolescent (PND 35, PND 45), and young adult (PND 60) animals. Using conditioned place preference (CPP) testing, we have shown that adolescent animals are unique in their responses to ethanol. Since CPP has been associated with contextually conditioned incentive motivation, our results suggest that younger animals may be more vulnerable to addiction. The present data reveal that adolescent animals are neurochemically distinct in response to ethanol's effects. Using in vivo microdialysis within the nucleus accumbens septi (NAcc), we have determined the DAergic response across development. Results reveal that basal levels of DA transition during the adolescent period and differ from preadolescent or adult animals. Specifically, PND 45 animals exhibited significantly higher, and PND 25 significantly lower, basal DA levels than all other ages examined. Further, repeated exposure to ethanol elevated basal DA levels significantly regardless of age or dose. Basal 3,4-dihydroxyphenylacetic acid (DOPAC)/DA ratio also differed as a function of age, with PND 35 and PND 60 animals demonstrating the highest ratios, and PND 45 animals producing the lowest baseline levels. Repeated ethanol exposure produced significant changes in basal ratios as a function of age. Interestingly, PND 45 animals exhibited no change in ratios with repeated exposure, while all other ages demonstrated a dose-dependent rise in DOPAC/DA ratios. These data indicate an age-dependent difference in the homeostatic alterations of mesolimbic systems in response to repeated ethanol treatment, an effect that may manifest itself as differences in behavioral responsivity and conditionability to the drug and the drug's effects.

Clinical evidence indicates that the nicotinic receptor agonist varenicline improves axial symptoms in patients with spinocerebellar ataxia type 3, but pharmacological evidence in an animal model of olivocerebellar degeneration has not been demonstrated. This study investigated whether varenicline and nicotine were efficacious for attenuating ataxia in rats induced by chemical destruction of the olivocerebellar pathway. Rats were trained to maintain their balance on a rotating rod and walk across a stationary beam; rod and beam performance, locomotor activity, and gait were assessed prior to and after administration of the neurotoxin 3-acetylpyridine (3-AP). The administration of 3-AP led to an 85% loss of neurons in the inferior olive at one week after administration without evidence of recovery over the following 4 weeks. The lesion was accompanied by a 72% decrease in rotorod activity, a 3.1-fold increase in the time required to traverse a stationary beam, a 19% decrease in velocity and 31% decrease in distance moved in the open field, and alterations in both forepaw and hindpaw gait parameters, with a 19% increase in hindpaw stride width. The daily administration of nicotine (0.33 mg free base/kg) improved rotorod performance by 50%, an effect apparent following the first week of administration, and which did not improve further over time. Nicotine also normalized the increased hindpaw stride width induced by the lesion. The ability of nicotine to alleviate both rotorod and gait deficits induced by 3-AP were prevented by the administration of the nicotinic antagonist mecamylamine (0.8 mg free base/kg) prior to the daily administration of nicotine. The effects of varenicline were dose-related and doses of 1.0 and 3.0 mg free base/kg daily improved rotorod performance by approximately 50% following the first week of administration. Further, varenicline did not alter the time required for animals to traverse the stationary beam, but did improve the ability of rats to maintain their balance on the beam by increasing lateral tail movements following 3 weeks of administration at doses of 0.3 and 1.0 mg free base/kg daily. Further, doses of nicotine and varenicline that improved the impaired balance and gait did not affect any measure of locomotor activity in the open field. Results provide evidence that nicotinic agonists are of benefit for alleviating some of the behavioral deficits in olivocerebellar ataxia and warrant further studies to elucidate the specific mechanism(s) involved.