Administration of oral methylphenidate during adolescence prevents suppressive development of dopamine projections into prefrontal cortex and amygdala after an early pharmacological challenge in gerbils.

The enduring effects of postweaning subchronic methylphenidate (MP) treatment and/or previous early preweaning methamphetamine (MA) application on dopamine (DA) fiber density were investigated in multiple cortical and subcortical areas of the gerbil brain. The study aimed to explore three questions: (1) is the development of DA fiber innervation in control animals sensitive to a clinically relevant subchronic treatment with MP? (2) Is the development of DA fiber innervation in the forebrain altered by a single early MA challenge? (3) If so, might the subsequent institution of a therapeutically relevant MP application scheme interfere with such early induced alternative developmental trajectories for DA fiber innervation? For this purpose, gerbils pretreated both with saline and MA (50 mg/kg, i.p.) on day 14 received either H(2)O or MP (5 mg/kg) orally on days 30 to 60. On day 90, DA fibers were immunohistochemically detected and quantified. As a result, MP on its own did not have any significant influence on the postnatal development of the DA fiber systems, whereas it prevented a previously MA triggered suppressive development of DA fiber innervation in the prefrontal cortex and amygdala complex (30% less fiber innervation in both areas). Thus, MP prevented previously initiated miswiring of DA fibers from actually being implemented in the gerbil forebrain. During earlier studies, rather complex miswiring has been documented in response to an early preweaning MA challenge. This miswiring was associated with functional deficits resembling some of the symptoms of patients with ADHD. Therefore, morphogenetic properties of MP need further attention.

Hemisphere-specific effects on serotonin but not dopamine innervation in the nucleus accumbens of gerbils caused by isolated rearing and a single early methamphetamine challenge.

The aim of this study was twofold: We examined whether serotonin (5-HT) and dopamine (DA) innervations of the nucleus accumbens are lateralised and whether the environment or the combination with an early pharmacological impact might interfere with the postnatal maturation of the monoaminergic innervation. Male gerbils were assigned to either enriched rearing (ER) or isolated rearing (IR). Animals from both rearing conditions additionally received a single dose of either methamphetamine [MA (50 mg/kg ip)] or saline on postnatal day 14. DA and 5-HT fibres of the adult animals (postnatal day 90-110) were immunocytochemically stained and fibre densities were quantified in nucleus accumbens core and shell of both the left and right hemisphere. Our data demonstrate that the DA and 5-HT innervation is not lateralised in saline-treated animals of both rearing conditions. IR increases the DA fibre density in both hemispheres of saline controls, whereas an additional MA treatment reverses this effect. In both ER and IR groups, MA provokes an excessive 5-HT fibre in growth of only the right hemisphere. The combination of IR with MA induces right-side asymmetries of the 5-HT fibre density in both the core and shell. From the data obtained, we conclude that the maturation of the monoaminergic innervation of the nucleus accumbens is vulnerable to postnatal stimuli. The subtle "innervation imbalance" observed in our studies is consistent with previously reported effects in other brain regions of this animal model and may be causative for behavioural disturbances.

Postnatal maturation of cortical serotonin lateral asymmetry in gerbils is vulnerable to both environmental and pharmacological epigenetic challenges.

Long-term effects of postnatal differential rearing conditions and/or early methamphetamine (MA) application on serotonin (5-HT) fibre density were investigated in several cortical areas of both hemispheres of gerbils. The aim of this study was twofold: (1) Is the 5-HT fibre innervation of the cerebral cortex lateralised, and (2) if so, do postnatal environmental conditions and/or an early drug challenge interfere with development of 5-HT cerebral asymmetries? For that purpose, male gerbils were reared either under semi-natural or restricted environmental and social conditions, under both conditions once (on postnatal day 14) being treated with either a single dose of MA (50 mg/kg, i.p.) or saline. On postnatal day 110, 5-HT fibres were immunohistochemically stained and innervation densities quantified in prefrontal cortex, insular cortex, frontal cortex, parietal cortex, and entorhinal cortex. It was found that (1) 5-HT innervation in the cerebral cortex was clearly lateralised; (2) direction and extent of this asymmetry were not uniformly distributed over the different areas investigated; (3) both early methamphetamine challenge and rearing condition differentially interfered with adult 5-HT cerebral asymmetry; (4) combining MA challenge with subsequent restricted rearing tended to reverse the effects of MA on 5-HT cerebral asymmetry in some of the cortical areas investigated; and (5) significant responses in 5-HT cerebral asymmetry only occurred in prefrontal and entorhinal association cortices. The present findings suggest that the ontogenesis of cortical laterality is influenced by epigenetic factors and that disturbances of the postnatal maturation of lateralised functions may be associated with certain psychopathological behaviours.