Cannabis and its effects on driving skills.

Traffic policies show growing concerns about driving under the influence of cannabis, since cannabinoids are one of the most frequently encountered psychoactive substances in the blood of drivers who are drug-impaired and/or involved in accidents, and in the context of a legalization of medical marijuana and of recreational use. The neurobiological mechanisms underlying the effects of cannabis on safe driving remain poorly understood. In order to better understand its acute and long-term effects on psychomotor functions involved in the short term ability and long-term fitness to drive, experimental research has been conducted based on laboratory, simulator or on-road studies, as well as on structural and functional brain imaging. Results presented in this review show a cannabis-induced impairment of actual driving performance by increasing lane weaving and mean distance headway to the preceding vehicle. Acute and long-term dose-dependent impairments of specific cognitive functions and psychomotor abilities were also noted, extending beyond a few weeks after the cessation of use. Some discrepancies found between these studies could be explained by factors such as history of cannabis use, routes of administration, dose ranges, or study designs (e.g. treatment blinding). Moreover, use of both alcohol and cannabis has been shown to lead to greater odds of making an error than use of either alcohol or cannabis alone. Although the correlation between blood or oral fluid concentrations and psychoactive effects of THC needs a better understanding, blood sampling has been shown to be the most effective way to evaluate the level of impairment of drivers under the influence of cannabis. The blood tests have also shown to be useful to highlight a chronic use of cannabis that suggests an addiction and therefore a long-term unfitness to drive. Besides blood, hair and repeated urine analyses are useful to confirm abstinence.

Electrode location and clinical outcome in hippocampal electrical stimulation for mesial temporal lobe epilepsy.

PURPOSE: To study the clinical outcome in hippocampal deep brain stimulation (DBS) for the treatment of patients with refractory mesial temporal lobe epilepsy (MTLE) according to the electrode location. METHODS: Eight MTLE patients implanted in the hippocampus and stimulated with high-frequency DBS were included in this study. Five underwent invasive recordings with depth electrodes to localize ictal onset zone prior to chronic DBS. Position of the active contacts of the electrode was calculated on postoperative imaging. The distances to the ictal onset zone were measured as well as atlas-based hippocampus structures impacted by stimulation were identified. Both were correlated with seizure frequency reduction. RESULTS: The distances between active electrode location and estimated ictal onset zone were 11±4.3 or 9.1±2.3mm for patients with a >50% or <50% reduction in seizure frequency. In patients (N=6) showing a >50% seizure frequency reduction, 100% had the active contacts located <3mm from the subiculum (p<0.05). The 2 non-responders patients were stimulated on contacts located >3mm to the subiculum. CONCLUSION: Decrease of epileptogenic activity induced by hippocampal DBS in refractory MTLE: (1) seems not directly associated with the vicinity of active electrode to the ictal focus determined by invasive recordings; (2) might be obtained through the neuromodulation of the subiculum.

Rnd1 regulates axon extension by enhancing the microtubule destabilizing activity of SCG10.

The GTPase Rnd1 affects actin dynamics antagonistically to Rho and has been implicated in the regulation of neurite outgrowth, dendrite development, and axon guidance. Here we show that Rnd1 interacts with the microtubule regulator SCG10. This interaction requires a central domain of SCG10 comprising about 40 amino acids located within the N-terminal-half of a putative alpha-helical domain and is independent of phosphorylation at the four identified phosphorylation sites that regulate SCG10 activity. Rnd1 enhances the microtubule destabilizing activity of SCG10 and both proteins colocalize in neurons. Knockdown of Rnd1 or SCG10 by RNAi suppressed axon extension, indicating a critical role for both proteins during neuronal differentiation. Overexpression of Rnd1 in neurons induces the formation of multiple axons. The effect of Rnd1 on axon extension depends on SCG10. These results indicate that SCG10 acts as an effector downstream of Rnd1 to regulate axon extensions by modulating microtubule organization.

The control of microtubule stability in vitro and in transfected cells by MAP1B and SCG10.

In neurons, the regulation of microtubules plays an important role for neurite outgrowth, axonal elongation, and growth cone steering. SCG10 family proteins are the only known neuronal proteins that have a strong destabilizing effect, are highly enriched in growth cones and are thought to play an important role during axonal elongation. MAP1B, a microtubule-stabilizing protein, is found in growth cones as well, therefore it was important to test their effect on microtubules in the presence of both proteins. We used recombinant proteins in microtubule assembly assays and in transfected COS-7 cells to analyze their combined effects in vitro and in living cells, respectively. Individually, both proteins showed their expected activities in microtubule stabilization and destruction respectively. In MAP1B/SCG10 double-transfected cells, MAP1B could not protect microtubules from SCG10-induced disassembly in most cells, in particular not in cells that contained high levels of SCG10. This suggests that SCG10 is more potent to destabilize microtubules than MAP1B to rescue them. In microtubule assembly assays, MAP1B promoted microtubule formation at a ratio of 1 MAP1B per 70 tubulin dimers while a ratio of 1 SCG10 per two tubulin dimers was needed to destroy microtubules. In addition to its known binding to tubulin dimers, SCG10 binds also to purified microtubules in growth cones of dorsal root ganglion neurons in culture. In conclusion, neuronal microtubules are regulated by antagonistic effects of MAP1B and SCG10 and a fine tuning of the balance of these proteins may be critical for the regulation of microtubule dynamics in growth cones.

Role of the microtubule destabilizing proteins SCG10 and stathmin in neuronal growth.

The related proteins SCG10 and stathmin are highly expressed in the developing nervous system. Recently it was discovered that they are potent microtubule destabilizing factors. While stathmin is expressed in a variety of cell types and shows a cytosolic distribution, SCG10 is neuron-specific and membrane-associated. It contains an N-terminal targeting sequence that mediates its transport to the growing tips of axons and dendrites. SCG10 accumulates in the central domain of the growth cone, a region that also contains highly dynamic microtubules. These dynamic microtubules are known to be important for growth cone advance and responses to guidance cues. Because overexpression of SCG10 strongly enhances neurite outgrowth, SCG10 appears to be an important factor for the dynamic assembly and disassembly of growth cone microtubules during axonal elongation. Phosphorylation negatively regulates the microtubule destabilizing activity of SCG10 and stathmin, suggesting that these proteins may link extracellular signals to the rearrangement of the neuronal cytoskeleton. A role for these proteins in axonal elongation is also supported by their growth-associated expression pattern in nervous system development as well as during neuronal regeneration.