Experiments are being conducted to assess the direct effects of abused drugs, or drugs proposed as treatments for drug abuse, on on-going behavior, on brain neurochemistry, as discriminative stimuli and on physiological function. Currently, studies are focusing on cannabinoids, nicotine, the constituents of psychoactive bath salts products (cathinones), cocaine and methamphetamine. Methamphetamine is a highly addictive psychostimulant that causes profound damage to the brain and other body organs. Post mortem studies of human tissues have linked the use of this drug to diseases associated with aging, such as coronary atherosclerosis, but the molecular mechanism underlying these findings remains unknown. We have now found that methamphetamine accelerates cellular senescence and activates transcription of genes involved in cell-cycle control and inflammation by stimulating production of the sphingolipid messenger ceramide. This pathogenic cascade is triggered by reactive oxygen species, likely generated through methamphetamine metabolism via cytochrome P450, which recruit nuclear factors to induce expression of enzymes in the de novo pathway of ceramide biosynthesis. Inhibitors of ceramide formation prevent methamphetamine-induced senescence and attenuate systemic inflammation and health deterioration in rats self-administering the drug. The results suggest new therapeutic strategies to reduce the adverse consequences of methamphetamine abuse and improve effectiveness of abstinence treatments. Products containing synthetic cannabinoids have seen increased use recently. These drugs produce subjective effects similar to THC. However, because of their unique chemical structures and high potency, we sought to compare the physiological effects of these drugs with those of THC. Separate groups of male rats were implanted with telemetry transmitters for either the measurement of body temperature or blood pressure (BP). In addition to THC (0.3-1.0 mg/kg), we tested: CP55940 (0.01-0.3 mg/kg), JWH018 (0.1-3.0 mg/kg), AM2201 (0.03-0.3 mg/kg), XLR11 (0.3-3.0 mg/kg) and UR144 (0.3-3.0 mg/kg). Rats were injected s.c. prior to being placed in an isolation cubicle on top of the telemetry receiver. Rats were monitored for 3 hours. All of the cannabinoids produced clear decreases in body temperature of up to 3oC during the last 2 hours of the session. The order of potency was CP55940 > AM2201 = JWH018 > THC = XLR11 = UR144. The hypothermic effects were reversed by pretreatment with the CB1 antagonist/inverse agonist rimonabant. None of the drugs had a significant effect on heart rate. Rats injected with the synthetic cannabinoids, except UR144, showed elevated BP in the first hour following the injection when compared to vehicle. The order of potency was CP55940 > AM2201 > JWH018 = XLR11. Neither the inverse agonist rimonabant, the neutral CB1 antagonist AM4113 nor the CB2 antagonist AM630 altered the BP effect of CP55940, suggesting this effect is not mediated by cannabinoid receptors. On body temperature the synthetic cannabinoids mimicked the effects of THC. Rats treated with the synthetic cannabinoids were more likely to show higher BP following treatment, an effect not seen with THC. Although the hypertensive effect was modest, our results illustrate that there may differences from THC in the effects of the synthetic cannabinoids.
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