Poisoning With Depilatory Agents in Iran.

Poisoning with depilatory agents in Iran.

J Res Med Sci. 2013 Feb; 18(2): 168-9
Mehrpour O, Farzaneh E, Hasanian-Moghaddam H, Abdollahi A, Rayesson MR, Abdollahi M

HubMed – addiction

Addiction is a Reward Deficit and Stress Surfeit Disorder.

Front Psychiatry. 2013; 4: 72
Koob GF

Drug addiction can be defined by a three-stage cycle – binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation – that involves allostatic changes in the brain reward and stress systems. Two primary sources of reinforcement, positive and negative reinforcement, have been hypothesized to play a role in this allostatic process. The negative emotional state that drives negative reinforcement is hypothesized to derive from dysregulation of key neurochemical elements involved in the brain reward and stress systems. Specific neurochemical elements in these structures include not only decreases in reward system function (within-system opponent processes) but also recruitment of the brain stress systems mediated by corticotropin-releasing factor (CRF) and dynorphin-? opioid systems in the ventral striatum, extended amygdala, and frontal cortex (both between-system opponent processes). CRF antagonists block anxiety-like responses associated with withdrawal, block increases in reward thresholds produced by withdrawal from drugs of abuse, and block compulsive-like drug taking during extended access. Excessive drug taking also engages the activation of CRF in the medial prefrontal cortex, paralleled by deficits in executive function that may facilitate the transition to compulsive-like responding. Neuropeptide Y, a powerful anti-stress neurotransmitter, has a profile of action on compulsive-like responding for ethanol similar to a CRF1 antagonist. Blockade of the ? opioid system can also block dysphoric-like effects associated with withdrawal from drugs of abuse and block the development of compulsive-like responding during extended access to drugs of abuse, suggesting another powerful brain stress system that contributes to compulsive drug seeking. The loss of reward function and recruitment of brain systems provide a powerful neurochemical basis that drives the compulsivity of addiction. HubMed – addiction

The role of the glucocorticoids in developing resilience to stress and addiction.

Front Psychiatry. 2013; 4: 68
Srinivasan S, Shariff M, Bartlett SE

There is emerging evidence that individuals have the capacity to learn to be resilient by developing protective mechanisms that prevent them from the maladaptive effects of stress that can contribute to addiction. The emerging field of the neuroscience of resilience is beginning to uncover the circuits and molecules that protect against stress-related neuropsychiatric diseases, such as addiction. Glucocorticoids (GCs) are important regulators of basal and stress-related homeostasis in all higher organisms and influence a wide array of genes in almost every organ and tissue. GCs, therefore, are ideally situated to either promote or prevent adaptation to stress. In this review, we will focus on the role of GCs in the hypothalamic-pituitary adrenocortical axis and extra-hypothalamic regions in regulating basal and chronic stress responses. GCs interact with a large number of neurotransmitter and neuropeptide systems that are associated with the development of addiction. Additionally, the review will focus on the orexinergic and cholinergic pathways and highlight their role in stress and addiction. GCs play a key role in promoting the development of resilience or susceptibility and represent important pharmacotherapeutic targets that can reduce the impact of a maladapted stress system for the treatment of stress-induced addiction. HubMed – addiction

Molecular Determinants for Ligand Binding at Serotonin 5-HT2A and 5-HT2C GPCRs: Experimental Affinity Results Analyzed by Molecular Modeling and Ligand Docking Studies.

Int J Quantum Chem. 2012 Dec 15; 112(24): 3807-3814
Córdova-Sintjago T, Sakhuja R, Kondabolu K, Canal CE, Booth RG

Ligands that activate the serotonin 5-HT2C G protein-coupled receptor (GPCR) may be therapeutic for psychoses, addiction, and other neuropsychiatric disorders. Ligands that are antagonists at the closely related 5-HT2A GPCR also may treat neuropsychiatric disorders; in contrast, 5-HT2A activation may cause hallucinations. 5-HT2C-specific agonist drug design is challenging because 5-HT2 GPCRs share 80% transmembrane (TM) homology, same second messenger signaling, and no crystal structures are reported. To help delineate molecular determinants underlying differential binding and activation of 5-HT2 GPCRs, 5-HT2A, and 5-HT2C homology models were built from the ? 2-adrenergic GPCR crystal structure and equilibrated in a lipid phosphatidyl choline bilayer performing molecular dynamics simulations. Ligand docking studies at the 5-HT2 receptor models were conducted with the (2R, 4S)- and (2S, 4R)-enantiomers of the novel 5-HT2C agonist/5-HT2A/2B antagonist trans-4-phenyl-N,N-dimethyl-2-aminotetralin (PAT) and its 4′-chlorophenyl congners. Results indicate PAT-5-HT2 molecular interactions especially in TM domain V are important for the (2R, 4S) enantiomer, whereas, TM domain VI and VII interactions are more important for the (2S, 4R) enantiomer. HubMed – addiction

Sirtuin and pan-class I/II deacetylase (DAC) inhibition is synergistic in preclinical models and clinical studies of lymphoma.

Blood. 2013 Aug 2;
Amengual JE, Clark-Garvey S, Kalac M, Scotto L, Marchi E, Neylon E, Johannet P, Wei Y, Zain J, O’Connor OA

Understanding the molecular pathogenesis of lymphoma has led to paradigm changing treatment opportunities. One example relates to tailoring specific agents based on the cell of origin in aggressive lymphomas. Germinal center (GC) derived DLBCL is known to be driven by an addiction to Bcl6, while the ABC-subtype is driven by NF-kB. In the GC-subtype there is a critical inverse relationship between Bcl6 and p53, the functional status of which is linked to each transcription factor’s degree of acetylation. Deacetylation of Bcl6 is required for its transcriptional repressor effects allowing for the oncogene to drive lymphomagenesis. Conversely, acetylation of p53 is activating when class III DACs, or sirtuins, are inhibited by niacinamide. Treatment of DLBCL cell lines with pan-DAC inhibitors in combination with niacinamide produces synergistic cytotoxicity in GC- over ABC-subtypes. This correlated with acetylation of both Bcl6 and p53. This combination also produced remissions in a spontaneous aggressive B-cell lymphoma mouse model expressing Bcl6. In a phase I proof-of-principle clinical trial, 24% of patients with relapsed or refractory lymphoma attained a response to vorinostat and niacinamide, while 57% experienced disease stabilization. We report herein on the preclinical and clinical activity of this targeted strategy in aggressive lymphomas. (ClinicalTrials.gov identifier NCT00691210). HubMed – addiction