The faster drugs of abuse reach the brain, the more addictive they can be. It is not known why this is. Environmental stimuli associated with drugs can promote the development and persistence of addiction by invigorating and precipitating drug-seeking behaviour. We determined, therefore, whether cues associated with the self-administration of rapidly delivered cocaine (injected intravenously over 5 versus 90 seconds) would acquire greater conditioned rewarding properties, as assessed by the performance of an operant response reinforced solely by the cues. Rats nose-poked for intravenous cocaine infusions delivered either over 5 or 90 seconds. Discrete visual cues accompanied each infusion. The rats could then press a lever to obtain the cues—now a conditioned reward—or an inactive lever. Rats in both the 5- and 90-second groups pressed more on the active versus inactive lever following extensive (24 sessions) but not following limited (3 sessions) self-administration training. There were no group differences in this behaviour. Following withdrawal from cocaine self-administration, lever discrimination progressively abated in both groups and was lost by withdrawal day 30. However, the rewarding properties of the cues were not “forgotten” because on withdrawal days 32–33, amphetamine selectively enhanced active-lever pressing, and did so to a similar extent in both groups. Thus, cues paired with rapid or slower cocaine delivery acquire similar conditioned rewarding properties. We conclude, therefore, that the rapid delivery of cocaine to the brain promotes addiction by mechanisms that might not involve a greater ability of drug cues to control behaviour.
Left ventricular diastolic dysfunction (LVDD) is characterized by the disturbance of ventricle’s performance due to its abnormal relaxation or to its increased stiffness during the diastolic phase. The molecular mechanisms underlying LVDD remain unknown. We aimed to identify normalization genes for accurate gene-expression analysis of LVDD using quantitative real-time PCR (RT-PCR) in a new rabbit model of LVDD. Eighteen rabbits were fed with a normal diet (n = 7) or a 0.5% cholesterol-enriched diet supplemented with vitamin D2 (n = 11) for an average of 14.5 weeks. We validated the presence of LVDD in this model using echocardiography for diastolic function assessment. RT-PCR was performed using cDNA derived from left ventricle samples to measure the stability of 10 genes as candidate reference genes (Gapdh, Hprt1, Ppia, Sdha, Rpl5, Actb, Eef1e1, Ywhaz, Pgk1, and G6pd). Using geNorm analysis, we report that Sdha, Gapdh and Hprt1 genes had the highest stability (M <0.2). By contrast, Hprt1 and Rpl5 genes were found to represent the best combination for normalization when using the Normfinder algorithm (stability value of 0.042). Comparison of both normalization strategies highlighted an increase of natriuretic peptides (Bnp and Anp), monocytes chemotactic protein-1 (Mcp-1) and NADPH oxidase subunit (Nox-2) mRNA expressions in ventricle samples of the hypercholesterolemic rabbits compared to controls (P<0.05). This increase correlates with LVDD echocardiographic parameters and most importantly it molecularly validates the presence of the disease in our model. This is the first study emphasizing the selection of stable reference genes for RT-PCR normalization in a rabbit model of LVDD.
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