INIA PI Reads

Neuropsychopharmacology. 2017 May 2. doi: 10.1038/npp.2017.96. [Epub ahead of print]
PDE4 Inhibition Restores the Balance Between Excitation and Inhibition in VTA Dopamine Neurons Disrupted by Repeated In Vivo Cocaine Exposure.
Liu X1, Zhong P1, Vickstrom C1, Li Y1, Liu QS1.

Abstract

Phosphodiesterase type 4 (PDE4) is a family of enzymes that selectively degrade intracellular cAMP. PDE4 inhibitors have been shown to regulate the rewarding and reinforcing effects of cocaine, but the underlying mechanisms remain poorly understood. Here we show that pretreatments with the PDE4 inhibitor rolipram attenuated cocaine-induced locomotor sensitization in mice. Repeated cocaine exposure in vivo caused a decrease in inhibitory postsynaptic currents (IPSCs) and an increase in the AMPAR/NMDAR ratio in ventral tegmental area (VTA) dopamine neurons in midbrain slices ex vivo. Cocaine exposure disrupted the balance between excitation and inhibition as shown by an increase in the excitation to inhibition (E/I) ratio. Rolipram pretreatments in vivo prevented cocaine-induced reductions in GABAergic inhibition but did not further increase cocaine-induced potentiation of excitation, leading to the restoration of a balance between excitation and inhibition and normalization of the E/I ratio. In support of this idea, we found that repeated cocaine exposure led to an increase in the single-unit action potential firing rate in vivo in VTA dopamine neurons, which was blocked by rolipram pretreatments. These results suggest that repeated cocaine exposure in vivo disrupts the balance between excitation and inhibition in VTA dopamine neurons, while PDE4 inhibition reestablishes the balance between excitation and inhibition through distinct mechanisms.Neuropsychopharmacology advance online publication, 14 June 2017; doi:10.1038/npp.2017.96.

***************************

PLoS Comput Biol. 2016 Apr 26;12(4):e1004885. doi: 10.1371/journal.pcbi.1004885. eCollection 2016.
Constraints on Biological Mechanism from Disease Comorbidity Using Electronic Medical Records and Database of Genetic Variants
Bagley SC, Sirota M, Chen R, Butte A, Altman RB.

Abstract

Patterns of disease co-occurrence that deviate from statistical independence may represent important constraints on biological mechanism, which sometimes can be explained by shared genetics. In this work we study the relationship between disease co-occurrence and commonly shared genetic architecture of disease. Records of pairs of diseases were combined from two different electronic medical systems (Columbia, Stanford), and compared to a large database of published disease-associated genetic variants (VARIMED); data on 35 disorders were available across all three sources, which include medical records for over 1.2 million patients and variants from over 17,000 publications. Based on the sources in which they appeared, disease pairs were categorized as having predominant clinical, genetic, or both kinds of manifestations. Confounding effects of age on disease incidence were controlled for by only comparing diseases when they fall in the same cluster of similarly shaped incidence patterns. We find that disease pairs that are overrepresented in both electronic medical record systems and in VARIMED come from two main disease classes, autoimmune and neuropsychiatric. We furthermore identify specific genes that are shared within these disease groups.
PMID:27115429 PMCID:PMC4846031 DOI:10.1371/journal.pcbi.1004885

***************************

Nat Rev Drug Discov. 2017 Jan;16(1):19-34. doi: 10.1038/nrd.2016.230. Epub 2016 Dec 2. PMID:27910877
A comprehensive map of molecular drug targets.
Rita Santos, Oleg Ursu, Anna Gaulton, A. Patrícia Bento, Ramesh S. Donadi, Cristian G. Bologa, Anneli Karlsson, Bissan Al-Lazikani, Anne Hersey, Tudor I. Oprea, & John P. Overington

Abstract

The success of mechanism-based drug discovery depends on the definition of the drug target. This definition becomes even more important as we try to link drug response to genetic variation, understand stratified clinical efficacy and safety, rationalize the differences between drugs in the same therapeutic class and predict drug utility in patient subgroups. However, drug targets are often poorly defined in the literature, both for launched drugs and for potential therapeutic agents in discovery and development. Here, we present an updated comprehensive map of molecular targets of approved drugs. We curate a total of 893 human and pathogen-derived biomolecules through which 1,578 US FDA-approved drugs act. These biomolecules include 667 human-genome-derived proteins targeted by drugs for human disease. Analysis of these drug targets indicates the continued dominance of privileged target families across disease areas, but also the growth of novel first-in-class mechanisms, particularly in oncology. We explore the relationships between bioactivity class and clinical success, as well as the presence of orthologues between human and animal models and between pathogen and human genomes. Through the collaboration of three independent teams, we highlight some of the ongoing challenges in accurately defining the targets of molecular therapeutics and present conventions for deconvoluting the complexities of molecular pharmacology and drug efficacy.

****************************
Neural Plast. 2016;2016:5942980. doi: 10.1155/2016/5942980. Epub 2016 Dec 29. PMID:28119786 PMCID:PMC5227175
Transcriptomic Modification in the Cerebral Cortex following Noninvasive Brain Stimulation: RNA-Sequencing Approach.
Ben Holmes, Seung Ho Jung, Jing Lu, Jessica A. Wagner, Liudmilla Rubbi, Matteo Pellegrini, and Ryan Jankord.

Abstract

Transcranial direct current stimulation (tDCS) has been shown to modulate neuroplasticity. Beneficial effects are observed in patients with psychiatric disorders and enhancement of brain performance in healthy individuals has been observed following tDCS. However, few studies have attempted to elucidate the underlying molecular mechanisms of tDCS in the brain. This study was conducted to assess the impact of tDCS on gene expression within the rat cerebral cortex. Anodal tDCS was applied at 3 different intensities followed by RNA-sequencing and analysis. In each current intensity, approximately 1,000 genes demonstrated statistically significant differences compared to the sham group. A variety of functional pathways, biological processes, and molecular categories were found to be modified by tDCS. The impact of tDCS on gene expression was dependent on current intensity. Results show that inflammatory pathways, antidepressant-related pathways (GTP signaling, calcium ion binding, and transmembrane/signal peptide pathways), and receptor signaling pathways (serotonergic, adrenergic, GABAergic, dopaminergic, and glutamate) were most affected. Of the gene expression profiles induced by tDCS, some changes were observed across multiple current intensities while other changes were unique to a single stimulation intensity. This study demonstrates that tDCS can modify the expression profile of various genes in the cerebral cortex and that these tDCS-induced alterations are dependent on the current intensity applied.