Environmental enrichment has no effect on the development of dopaminergic and GABAergic fibers during methylphenidate treatment of early traumatized gerbils

It is widely believed, that environmental factors play a crucial role in the etiology and outcome of psychiatric diseases such as Attention-Deficit/Hyperactivity Disorder (ADHD). A former study from our laboratory has shown that both methylphenidate (MP) and handling have a positive effect on the dopaminergic fiber density in the prefrontal cortex (PFC) of early traumatized gerbils (Meriones unguiculatus). The current study was performed to investigate if enriched environment during MP application has an additional influence on the dopaminergic and GABAergic fiber densities in the PFC and amygdala in this animal model

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

Grund T, Teuchert-Noodt G, Busche A, et al. Administration of oral methylphenidate during adolescence prevents suppressive development of dopamine projections into prefrontal cortex and amygdala after an early pharmacological challenge in gerbils. BRAIN RESEARCH. 2007;1176:124-132.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 H2O 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. (C) 2007 Elsevier B.V. All rights reserved

αCaMKII Autophosphorylation Controls the Establishment of Alcohol Drinking Behavior

The α-Ca(2+)/calmodulin-dependent protein kinase II (αCaMKII) is a crucial enzyme controlling plasticity in the brain. The autophosphorylation of αCaMKII works as a ‘molecular memory' for a transient calcium activation, thereby accelerating learning. We investigated the role of αCaMKII autophosphorylation in the establishment of alcohol drinking as an addiction-related behavior in mice. We found that alcohol drinking was initially diminished in αCaMKII autophosphorylation-deficient αCaMKII(T286A) mice, but could be established at wild-type level after repeated withdrawals. The locomotor activating effects of a low-dose alcohol (2 g/kg) were absent in αCaMKII(T286A) mice, whereas the sedating effects of high-dose (3.5 g/kg) were preserved after acute and subchronic administration. The in vivo microdialysis revealed that αCaMKII(T286A) mice showed no dopamine (DA) response in the nucleus accumbens to acute or subchronic alcohol administration, but enhanced serotonin (5-HT) responses in the prefrontal cortex. The attenuated DA response in αCaMKII(T286A) mice was in line with altered c-Fos activation in the ventral tegmental area after acute and subchronic alcohol administration. In order to compare findings in mice with the human condition, we tested 23 single-nucleotide polymorphisms (SNPs) in the CAMK2A gene for their association with alcohol dependence in a population of 1333 male patients with severe alcohol dependence and 939 controls. We found seven significant associations between CAMK2A SNPs and alcohol dependence, one of which in an autophosphorylation-related area of the gene. Together, our data suggest αCaMKII autophosphorylation as a facilitating mechanism in the establishment of alcohol drinking behavior with changing the DA–5-HT balance as a putative mechanism