Acute Psychostimulant Administration Research Articles

P67. Chronic Exposure to Psychostimulants in Pediatric ADHD Moderates Striatal Resting-State Functional Connectivity and Symptom Severity Over Two Years

Acute administration of psychostimulants, the most common medication for Attention-Deficit/Hyperactivity Disorder (ADHD), attenuates symptoms via upregulation of striatal dopamine activity. Less is known about the effects of long-term psychostimulant exposure. We explored exposure-dependent changes in striatal resting-state functional connectivity (rs-FC) and their relation to symptom outcome across two years in the Adolescent Brain Cognitive Development dataset.

Evaluation of NDEL1 oligopeptidase activity in blood and brain in an animal model of schizophrenia: effects of psychostimulants and antipsychotics

Nuclear distribution element-like 1 (NDEL1) enzyme activity is important for neuritogenesis, neuronal migration, and neurodevelopment. We reported previously lower NDEL1 enzyme activity in blood of treated first episode psychosis and chronic schizophrenia (SCZ) compared to healthy control subjects, with even lower activity in treatment resistant chronic SCZ patients, implicating NDEL1 activity in SCZ. Herein, higher NDEL1 activity was observed in the blood and several brain regions of a validated animal model for SCZ at baseline. In addition, long-term treatment with typical or atypical antipsychotics, under conditions in which SCZ-like phenotypes were reported to be reversed in this animal model for SCZ, showed a significant NDEL1 activity reduction in blood and brain regions which is in line with clinical data. Importantly, these results support measuring NDEL1 enzyme activity in the peripheral blood to predict changes in NDEL1 activity in the CNS. Also, acute administration of psychostimulants, at levels reported to induce SCZ-like phenotype in normal rat strains, increased NDEL1 enzyme activity in blood. Therefore, alterations in NDEL1 activity after treatment with antipsychotics or psychostimulants may suggest a possible modulation of NDEL1 activity secondary to neurotransmission homeostasis and provide new insights into the role of NDEL1 in SCZ pathophysiology.

Statistical uncertainty and sensitivity analysis of intracellular signaling models - through approximate Bayesian computation and variance based global sensitivity analysis

Statistical uncertainty and sensitivity analysis of intracellular signaling models - through approximate Bayesian computation and variance based global sensitivity analysis

Segregation and crosstalk of D1 receptor-mediated activation of ERK in striatal medium spiny neurons upon acute administration of psychostimulants.

The convergence of corticostriatal glutamate and dopamine from the midbrain in the striatal medium spiny neurons (MSN) triggers synaptic plasticity that underlies reinforcement learning and pathological conditions such as psychostimulant addiction. The increase in striatal dopamine produced by the acute administration of psychostimulants has been found to activate not only effectors of the AC5/cAMP/PKA signaling cascade such as GluR1, but also effectors of the NMDAR/Ca2+/RAS cascade such as ERK. The dopamine-triggered effects on both these cascades are mediated by D1R coupled to Golf but while the phosphorylation of GluR1 is affected by reductions in the available amount of Golf but not of D1R, the activation of ERK follows the opposite pattern. This segregation is puzzling considering that D1R-induced Golf activation monotonically increases with DA and that there is crosstalk from the AC5/cAMP/PKA cascade to the NMDAR/Ca2+/RAS cascade via a STEP (a tyrosine phosphatase). In this work, we developed a signaling model which accounts for this segregation based on the assumption that a common pool of D1R and Golf is distributed in two D1R/Golf signaling compartments. This model integrates a relatively large amount of experimental data for neurons in vivo and in vitro. We used it to explore the crosstalk topologies under which the sensitivities of the AC5/cAMP/PKA signaling cascade to reductions in D1R or Golf are transferred or not to the activation of ERK. We found that the sequestration of STEP by its substrate ERK together with the insensitivity of STEP activity on targets upstream of ERK (i.e. Fyn and NR2B) to PKA phosphorylation are able to explain the experimentally observed segregation. This model provides a quantitative framework for simulation based experiments to study signaling required for long term potentiation in MSNs.

What about me…? The PVT: a role for the paraventricular thalamus (PVT) in drug-seeking behavior

GENERAL COMMENTARY article Front. Behav. Neurosci., 06 March 2013Sec. Motivation and Reward Volume 7 - 2013 | https://doi.org/10.3389/fnbeh.2013.00018

Acute atomoxetine effects on the EEG of children with Attention-Deficit/Hyperactivity Disorder

Although stimulant medications are the most commonly-used treatments for Attention-Deficit/Hyperactivity Disorder (AD/HD), as many as 20% of treated children do not respond clinically to stimulants. This study investigated the effects of an acute dose of atomoxetine, a selective noradrenaline reuptake inhibitor (SNRI), on the electroencephalogram (EEG) and performance of children with AD/HD. An initial pre-medication EEG was recorded during an eyes-closed resting condition. Within two weeks, a second EEG was recorded 1 h after ingestion of 20 mg of atomoxetine. Data were Fourier transformed to provide absolute and relative power estimates for the delta, theta, alpha, beta and gamma bands. Compared to controls, the unmedicated AD/HD children had significantly elevated global absolute and relative delta, with reduced global relative alpha, and absolute and relative gamma, and many topographic differences. Atomoxetine produced significant global increases in absolute and relative beta, with several topographic changes in other bands, and a significant reduction in omission errors on a Continuous Performance Task. These results indicate that SNRIs can produce substantial normalisation of the AD/HD EEG profile, together with behavioural performance improvements. Although EEG changes induced by acute administration of psychostimulants (methylphenidate/dexamphetamine) and atomoxetine are not identical, both classes of AD/HD drugs produce similar EEG band changes. Further analysis of EEG responses to SNRIs and psychostimulants could reveal common neurophysiological processes closely linked to clinical improvement of AD/HD symptoms in response to pharmacotherapy, providing translational markers for clinical efficacy studies and potential translational biomarkers for AD/HD drug discovery.

Genomic organization of the murine G protein beta subunit genes and related processed pseudogenes.

The functional significance of heterotrimeric guanine nucleotide binding protein (G protein) for the many physiological processes including the molecular mechanisms of drug addiction have been described. In investigating the changes of mRNA expression after acute psychostimulant administration, we previously identified a cDNA encoding a G protein beta1 subunit (Gbeta1) that was increased up to four-fold in certain brain regions after administration of psychostimulants. The mouse Gbeta1 gene (the mouse genetic symbol, GNB1) was mapped to chromosome 4, but little was known of its genetic features. To characterize the GNB1 gene further, we have cloned and analyzed the genomic structures of the mouse GNBI gene and its homologous sequences. The GNBI gene spans at least 50 kb, and consists of 12 exons and 11 introns. The exon/intron boundaries were determined and found to follow the GT/AG rule. Exons 3-11 encode the Gbeta1 protein, and the exon 2 is an alternative, resulting in putative two splicing variants. Although intron 11 is additional for GNBI compared with GNB2 and GNB3, the intron positions within the protein coding region of GNB1, GNB2 and GNB3 are identical, suggesting that GNB1 should have diverged from the ancestral gene family earlier than the genes for GNB2 and GNB3. We also found the 5'-truncated processed pseudogenes with 71-89% similarities to GNBI mRNA sequence, suggesting that the truncated cDNA copies, which have been reverse-transcribed from a processed mRNA for GNB1, might have been integrated into several new locations in the mouse genome.