Neurodevelopmental Disruption of Cortico-Striatal Function Caused by Degeneration of Habenula Neurons

The habenula plays an important role on cognitive and affective functions by regulating monoamines transmission such as the dopamine and serotonin, such that its dysfunction is thought to underlie a number of psychiatric conditions. Given that the monoamine systems are highly vulnerable to neurodevelopmental insults, damages in the habenula during early neurodevelopment may cause devastating effects on the wide-spread brain areas targeted by monoamine innervations.Using a battery of behavioral, anatomical, and biochemical assays, we examined the impacts of neonatal damage in the habenula on neurodevelopmental sequelae of the prefrontal cortex (PFC) and nucleus accumbens (NAcc) and associated behavioral deficits in rodents. Neonatal lesion of the medial and lateral habenula by ibotenic acid produced an assortment of behavioral manifestations consisting of hyper-locomotion, impulsivity, and attention deficit, with hyper-locomotion and impulsivity being observed only in the juvenile period, whereas attention deficit was sustained up until adulthood. Moreover, these behavioral alterations were also improved by amphetamine. Our study further revealed that impulsivity and attention deficit were associated with disruption of PFC volume and dopamine (DA) receptor expression, respectively. In contrast, hyper-locomotion was associated with decreased DA transporter expression in the NAcc. We also found that neonatal administration of nicotine into the habenula of neonatal brains produced selective lesion of the medial habenula. Behavioral deficits with neonatal nicotine administration were similar to those caused by ibotenic acid lesion of both medial and lateral habenula during the juvenile period, whereas they were different in adulthood.Because of similarity between behavioral and brain alterations caused by neonatal insults in the habenula and the symptoms and suggested neuropathology in attention deficit/hyperactivity disorder (ADHD), these results suggest that neurodevelopmental deficits in the habenula and the consequent cortico-striatal dysfunctions may be involved in the pathogenesis and pathophysiology of ADHD

Control of 5-hydroxytryptamine release in the dorsal raphe nucleus by the noradrenergic system in rat brain. Role of alpha-adrenoceptors

The interactions between the brainstem serotonergic (5-hydroxytryptamine, 5-HT) and noradrenergic (NA) systems are important for the pathophysiology and treatment of affective disorders. We examined the influence of -adrenoceptors on 5-HT and NA release in the rat dorsal raphe nucleus (DR) using microdialysis. 5-HT and NA concentrations in DR dialysates were virtually suppressed by TTX and increased by veratridine. The local and systemic administration of the 1-adrenoceptor antagonist prazosin reduced the DR 5-HT output but not that of NA. The maximal 5-HT reduction induced by local prazosin administration (-78% at 100 M) was more marked than by its systemic administration (-43% at 0.3 mg/kg). The local application of NA and desipramine, to increase the tone on DR 1-adrenoceptors, did not enhance 5-HT release. The local (100 M) or systemic (0.1–1 mg/kg s.c.) administration of clonidine reduced 5-HT and NA release (-48 and -79%, respectively, at 1 mg/kg), an effect reversed by RX-821002, which by itself increased both amines when given systemically. DSP-4 pretreatment prevented the effects of clonidine on 5-HT, suggesting the participation of 2-adrenoceptors on NA elements. Moreover, the systemic effect of clonidine on 5-HT (but not NA) was cancelled by lesion of the lateral habenula and by anesthesia, and was slightly enhanced by cortical transection. These data support the view that 1-adrenoceptors in the DR tonically stimulate 5-HT release, possibly at nearly maximal tone. Likewise, the 5-HT release is modulated by 2-adrenoceptors in NA neurons and in forebrain areas involved in the distal control of 5-HT neurons.Peer reviewe

Early determinants of attention and hyperactivity problems in adolescents: the 11-year follow-up of the 1993 Pelotas (Brazil) birth cohort study Determinantes precoces de problemas de atenção e hiperatividade na adolescência: a visita de 11 anos da coorte de nascimentos de Pelotas, Rio Grande do Sul, Brasil, 1993

The aim of this study was to assess early determinants of attention and hyperactivity problems in adolescents. In 1993, all hospital births in the city of Pelotas, Rio Grande do Sul State, Brazil, were monitored and mothers were interviewed (N = 5,249). At 11 years of age, 4,423 mothers answered the Strengths and Difficulties Questionnaire (SDQ) in order to evaluate attention and hyperactivity problems in the adolescents. Crude and adjusted prevalence ratios were calculated using Poisson regression. Prevalence of attention and hyperactivity problems was 19.9%. Factors associated with the outcome in the adjusted analysis were: male gender, low family income, smoking during pregnancy, minor psychiatric disorders in the mother, and history of child's behavioral/emotional problems at four years of age. Early life events impacted attention and hyperactivity problems in adolescence. Risk factors for attention and hyperactivity problems found in this study were similar to those reported in other cultures.<br>O objetivo deste trabalho foi estudar determinantes precoces dos problemas de atenção e hiperatividade em adolescentes. Em 1993, os nascimentos foram recrutados e as mães entrevistadas (n = 5.249). Aos 11 anos, 4.423 mães responderam ao Strengths and Difficulties Questionnaire (SDQ) para avaliar problemas de atenção e hiperatividade nos adolescentes. Variáveis socioeconômicas, demográficas, biológicas e psicológicas foram investigadas como prováveis fatores de risco. Razões de prevalência brutas e ajustadas foram calculadas com regressão de Poisson. A prevalência de problemas de atenção e hiperatividade foi 19,9%. Sexo masculino, baixa renda familiar, tabagismo materno na gestação, transtornos psiquiátricos maternos e problemas de comportamento/emocionais do adolescente aos quatro anos permaneceram associados na análise ajustada. Eventos do início da vida influenciaram os problemas de atenção e hiperatividade na adolescência. Os fatores de risco para problemas de atenção e hiperatividade foram similares aos encontrados em diferentes culturas

Hyperactivity, increased nicotine consumption and impaired performance in the five-choice serial reaction time task in adolescent rats prenatally exposed to nicotine

RATIONALE: Prenatal exposure to nicotine has been linked to accelerated risk for different psychiatric disorders, including conduct disorder, attention deficit hyperactivity disorder (ADHD) and drug abuse. We examine a potential link between prenatal nicotine exposure, hyperactivity, anxiety, nicotine consumption, and cognitive performance in rats. METHODS: Adolescent offspring of females exposed during pregnancy to 0.06 mg/ml nicotine solution as the only source of water and of a group of pair-fed females, used as a control for anorexic effects of nicotine, were evaluated in a battery of tests, including locomotor activity, the elevated plus maze, two-bottle free-choice nicotine solution consumption, the five-choice serial reaction time test (5-CSRTT) and a delay-discounting test. All tests were conducted between postnatal day (PND) 25 and PND 50. RESULTS: Nicotine-exposed animals expressed hyperactivity, increased number of open arms entries in the elevated plus maze and increased numbers of anticipatory responses in the 5-CSRTT. Decreased aversion for nicotine solution in the free-choice test and decreased numbers of omission errors in the 5-CSRTT were observed both in nicotine-exposed and pair-fed offspring. Neither nicotine exposure nor pair-feeding had an effect on impulsive choice in a delay-discounting test. CONCLUSIONS: Our study confirms deleterious effects of prenatal nicotine exposure on important aspects of behaviour and inhibitory control in adolescent rats and supports epidemiological findings that show increased levels of symptoms of ADHD and related disorders among those whose mothers smoked during their pregnancy. It also suggests a link between food restriction during pregnancy and addiction-related behaviours in offspring