Gestational Nicotine Exposure Modifies Myelin Gene Expression in the Brains of Adolescent Rats With Sex Differences.

Gestational nicotine exposure modifies myelin gene expression in the brains of adolescent rats with sex differences.

Transl Psychiatry. 2013; 3: e247
Cao J, Wang J, Dwyer JB, Gautier NM, Wang S, Leslie FM, Li MD

Myelination defects in the central nervous system (CNS) are associated with various psychiatric disorders, including drug addiction. As these disorders are often observed in individuals prenatally exposed to cigarette smoking, we tested the hypothesis that such exposure impairs central myelination in adolescence, an important period of brain development and the peak age of onset of psychiatric disorders. Pregnant Sprague Dawley rats were treated with nicotine (3?mg?kg(-1) per day; gestational nicotine (GN)) or gestational saline via osmotic mini pumps from gestational days 4-18. Both male and female offsprings were killed on postnatal day 35 or 36, and three limbic brain regions, the prefrontal cortex (PFC), caudate putamen and nucleus accumbens, were removed for measurement of gene expression and determination of morphological changes using quantitative real-time PCR (qRT-PCR) array, western blotting and immunohistochemical staining. GN altered myelin gene expression at both the mRNA and protein levels, with striking sex differences. Aberrant expression of myelin-related transcription and trophic factors was seen in GN animals, which correlated highly with the alterations in the myelin gene expression. These correlations suggest that these factors contribute to GN-induced alterations in myelin gene expression and also indicate abnormal function of oligodendrocytes (OLGs), the myelin-producing cells in the CNS. It is unlikely that these changes are attributable solely to an alteration in the number of OLGs, as the cell number was changed only in the PFC of GN males. Together, our findings suggest that abnormal brain myelination underlies various psychiatric disorders and drug abuse associated with prenatal exposure to cigarette smoke. HubMed – addiction

The evolving landscape of therapeutic drug development for hepatocellular carcinoma.

Contemp Clin Trials. 2013 Apr 13;
Qingqing DC, Tan IB, Su-Pin C, Toh HC

Currently, only one drug, sorafenib, is FDA approved for the treatment of advanced hepatocellular carcinoma (HCC), achieving modest objective response rates whilst still conferring an overall survival benefit. Unlike other solid tumours, no oncogenic addiction loops have been validated as clinically actionable targets in HCC. Outcomes of HCC could potentially be improved if critical molecular subclasses with distinct therapeutic vulnerabilities can be identified, biomarkers that predict recurrence or progression early can be determined and key epigenetic, genetic or microenvironment drivers that determine best response to a specific targeting treatment can be uncovered. Our Group and others have examined the molecular heterogeneity of hepatocellular carcinoma. We have developed a panel of patient dervied xenograft models to enable focused pre-clinical drug development of rationally designed therapies in specific molecular subgroups. We observed unique patterns, including synergies, of drug activity across our molecularly diverse HCC xenografts, pointing to specific therapeutic vulnerabilities for individual tumours. These efforts inform clinical trial designs and catalyze therapeutic development. It also argues for efficient strategic allocation of patients into appropriate enriched clinical trials. Here, we will discuss some of the recent important therapeutic studies in advanced HCC and also some of the potential strategies to optimize clinical therapeutic development moving forward. HubMed – addiction

Corticotropin-releasing factor (CRF) and ? 2 adrenergic receptors mediate heroin withdrawal-potentiated startle in rats.

Int J Neuropsychopharmacol. 2013 Apr 16; 1-9
Park PE, Vendruscolo LF, Schlosburg JE, Edwards S, Schulteis G, Koob GF

Anxiety is one of the early symptoms of opioid withdrawal and contributes to continued drug use and relapse. The acoustic startle response (ASR) is a component of anxiety that has been shown to increase during opioid withdrawal in both humans and animals. We investigated the role of corticotropin-releasing factor (CRF) and norepinephrine (NE), two key mediators of the brain stress system, on acute heroin withdrawal-potentiated ASR. Rats injected with heroin (2 mg/kg s.c.) displayed an increased ASR when tested 4 h after heroin treatment. A similar increase in ASR was found in rats 10-20 h into withdrawal from extended access (12 h) to i.v. heroin self-administration, a model that captures several aspects of heroin addiction in humans. Both the ? 2 adrenergic receptor agonist clonidine (10 ?g/kg s.c.) and CRF1 receptor antagonist N,N-bis(2-methoxyethyl)-3-(4-methoxy-2-methylphenyl)-2,5-dimethyl-pyrazolo[1,5-a] pyrimidin-7-amine (MPZP; 20 mg/kg s.c.) blocked heroin withdrawal-potentiated startle. To investigate the relationship between CRF1 and ? 2 adrenergic receptors in the potentiation of the ASR, we tested the effect of MPZP on yohimbine (1.25 mg/kg s.c.)-potentiated startle and clonidine on CRF (2 ?g i.c.v.)-potentiated startle. Clonidine blocked CRF-potentiated startle, whereas MPZP partially attenuated but did not reverse yohimbine-potentiated startle, suggesting that CRF may drive NE release to potentiate startle. These results suggest that CRF1 and ? 2 receptors play an important role in the heightened anxiety-like behaviour observed during acute withdrawal from heroin, possibly via CRF inducing the release of NE in stress-related brain regions. HubMed – addiction

Fluorinated Tropanes.

Curr Top Med Chem. 2013 Apr 16;
Stehouwer JS

The development of tropane-derivatives as cocaine-addiction therapeutics identified numerous compounds with affinities for the dopamine, serotonin, and norepinephrine transporters. Many of these compounds were then adapted for use as imaging radiotracers. Incorporation of fluorine into the molecule often improved the physiochemical properties of the compound and also provided a position for radiolabeling with fluorine-18. This review provides an overview of the efforts devoted to developing fluorine-18 radiolabeled tropanes for imaging use with positron emission tomography. HubMed – addiction

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