The acute side effects of d-amphetamine and methamphetamine on simulated driving performance, cognitive functioning, brain activity, and the standardised field sobriety tests

Recently there has been an increase in awareness of the role of drugs other than alcohol in the causation of road accidents and deaths, with the most recent report indicating that 33% of all Victorian (Australia) road fatalities are drug (other than alcohol) related (TAC, 2006). Currently in Victoria, one of the classes of drugs reported to be of most concern is the amphetamines. The epidemiological driving literature highlights a possible association between amphetamine use and road crashes. However, since the cognitive research generally indicates cognitive enhancing properties following amphetamine consumption, it remains unclear how amphetamines may be related to adverse driving. The present thesis was designed to explore this issue. In response to the increasing number of drug-related road fatalities, the Standardised Field Sobriety Tests (SFSTs), designed and validated for the detection and assessment of impairment associated with alcohol intoxication, are currently being employed by the Victoria Police (Australia) for the identification of driving impairment associated with drugs other than alcohol. The present thesis was designed to evaluate whether the SFSTs are a sensitive measure for identifying impairment associated with a single acute therapeutic amphetamine dose. Furthermore, the accuracy of using the SFSTs to detect driving impairment associated with these amphetamine doses was also evaluated. The present thesis examined the effects of a single acute therapeutic dose of various amphetamine preparations, on simulated driving performance, driving-related cognitive processes (assessed using standard cognitive tasks and the electroencephalogram [EEG]), and performance on the SFSTs, in healthy, stimulant-using, non-fatigued adults. The present thesis consisted of five separate experiments. The first three experiments examined the effects of d-amphetamine, d,l-methamphetamine, and d-methamphetamine, on simulated driving performance, driving-related cognitive processes, and performance on the SFSTs. Experiment 4 and Experiment 5 assessed the effects of d-amphetamine and dmethamphetamine on visual and auditory cognitive processes using the EEG. These forms of amphetamines were selected as they are commonly used recreationally by young adult drivers, and occupationally by truck drivers. Experiment 1, Experiment 2, and Experiment 3 employed a repeated-measures, counterbalanced, double blind, placebo-controlled design. In each experiment, twenty different (i.e. 60 participants in total) healthy volunteers (10 males and 10 females) completed two treatment conditions i) placebo and ii) 0.42mg/kg amphetamine (~30mg). Driving performance was assessed using a driving simulator task, which consisted of four driving tasks; 'freeway traffic driving' and 'city traffic driving' in both day and night conditions. Cognitive performance was assessed using a range of computer and pen and paper tasks designed to assess attention, psychomotor performance, and perceptual speed. Specifically, the tasks were: the Digit Span Test; a Digit Vigilance task; a Movement Estimation Task; the Digit Symbol Substitution Test; a Tracking Task; the Trail-Making Test; and the Inspection Time task. SFSTs performance was assessed using the Horizontal Gaze Nystagmus (HGN) test, the Walk and Turn (WAT) test, and the One Leg Stand (OLS) test. Three blood and saliva samples were obtained throughout all experimental sessions (120, 170, and 240 minutes after drug administration). The results indicated that 0.42mg/kg d-amphetamine significantly impaired simulated driving performance, in recreational stimulant users, 2-3 hours post-drug administration, when mean blood amphetamine concentrations were approximately 90ng/mL. No significant driving decrements were observed following d,l-methamphetamine or dmethamphetamine, when methamphetamine blood concentrations were 90ng/mL and 70ng/mL, respectively. There were only few driving behaviours that were found to be significantly reduced with d-amphetamine, such as reductions in signalling adherence and driving too fast for the traffic conditions. However, during all three amphetamine conditions, drivers travelled at a slower speed on the freeway at the time that an emergency situation occurred, relative to the placebo condition. It was argued that either this may result from more cautious driving, or that the reduction in speed acted as a compensatory mechanism to permit drivers to attend to other aspects of driving. Overall, the present results indicate that a therapeutic dose of amphetamine does not produce considerable impairment to driving, as only minimal amphetamine effects were observed on driving performance. In terms of cognitive performance, the results indicated that a therapeutic dose of various amphetamines has minimal effect on driving-related cognitive functioning, with some significant improvements noted in aspects of attention, psychomotor functioning and perceptual speed. This is consistent with the failure to identify significant driving impairments, described above, following a similar dose. However, the ability to perceive and predict motion and estimate 'time to contact', assessed using a movement estimation task, was affected following d-amphetamine and d-methamphetamine consumption. In terms of performance on the SFSTs, the present thesis demonstrated that following the administration of low-level d-amphetamine, d,l-methamphetamine, and dmethamphetamine, performance on the SFSTs was not impaired. Using the SFSTs, impairment associated with low dose d-amphetamine was identified in only 5% of cases, dmethamphetamine in 5% of cases, and d,l-methamphetamine in 0% of cases. These findings indicate that the degree of impairment produced with the low amphetamine dosing conditions was below the threshold of sensitivity of the SFSTs. However, as significant impairments in driving were not observed with amphetamines, the present SFSTs findings highlight that these tests are unlikely to produce false positive results during police drug evaluation procedures for amphetamine-related impairments. Experiment 4 and Experiment 5 similarly employed a repeated-measures, counterbalanced, double blind, placebo-controlled design. In each experiment, twenty healthy volunteers (10 males and 10 females) completed two treatment conditions i) placebo and ii) 0.42mg/kg amphetamine (~30mg). Tasks designed to assess visual and auditory cognitive functions relevant to driving were administered. Specifically, these processes were: divergent visual system pathways (magnocellular and parvocellular pathways); aspects of visual field processing (central and peripheral visual fields); mismatch negativity (MMN); prepulse inhibition (PPI); selective attention; resource allocation; and speed of processing. Two blood and saliva samples were obtained throughout all experimental session (120 and 200 minutes after drug administration). d-amphetamine and d-methamphetamine generally improved cognitive functioning, as assessed with visual and auditory ERP indices. Specifically, the results demonstrated that a low-level acute dose of d-amphetamine and d-methamphetamine improved early processing of visual information (indexed by improvements to the P100 component for the magnocellular and parvocellular visual pathways). In addition, d-methamphetamine improved the speed at which visual information was evaluated and processed (indexed by decreases in P300 latency), which was consistent with d-methamphetamine-related improvements in reaction time. There was a trend for d-amphetamine to improve the speed that changes in auditory stimulation were automatically detected (indexed by decreases in MMN latency). In addition, d-methamphetamine improved the ability to automatically 'screen out' irrelevant and intrusive auditory information (indexed by increases in PPI of the startle response). d-amphetamine was found to improve the speed at which auditory information was evaluated and processed (indexed by decreases in P300 latency), which was substantiated with corresponding improvements in reaction time and accuracy. Although amphetamines were generally shown to enhance ERP indices, a trend was found for d-amphetamine to differentially affect different regions of the visual field, in terms of selective attention. Specifically, there was a trend-level indication that d-amphetamine improved indices of selective attention (denoted by increases in N200 amplitude) for information presented centrally, but impaired indices of selective attention (denoted by decreases in N200 amplitude) for information presented in the periphery. Although impairments to the peripheral visual field were not similarly observed with dmethamphetamine, decrements to indices of selective attention (denoted by decreases in N200 amplitude) were also found with d-methamphetamine during the auditory oddball task. In terms of driving, these results suggest that drivers dosed with low-level amphetamine may not selectively attend to and discriminate changes within the traffic environment, although further research is required to confirm this. In conclusion, the present thesis has demonstrated that a single acute therapeutic dose of amphetamine produces minimal and inconsistent effects to driving. However, some (inconsistent) evidence was found that suggests that there may be mild impairments such as decreased ability to perceive and predict motion, tunnel vision effects, and decrements to selective attention. In addition, the present thesis highlights that at therapeutic doses, amphetamines do not impair SFSTs performance, which is in accordance with the failure to identify substantive amphetamine-related decrements to driving and cognitive functioning observed in the present thesis

Cooperativity of imprinted genes inactivated by acquired chromosome 20q deletions

Large regions of recurrent genomic loss are common in cancers; however, with a few well-characterized exceptions, how they contribute to tumor pathogenesis remains largely obscure. Here we identified primate-restricted imprinting of a gene cluster on chromosome 20 in the region commonly deleted in chronic myeloid malignancies. We showed that a single heterozygous 20q deletion consistently resulted in the complete loss of expression of the imprinted genes L3MBTL1 and SGK2, indicative of a pathogenetic role for loss of the active paternally inherited locus. Concomitant loss of both L3MBTL1 and SGK2 dysregulated erythropoiesis and megakaryopoiesis, 2 lineages commonly affected in chronic myeloid malignancies, with distinct consequences in each lineage. We demonstrated that L3MBTL1 and SGK2 collaborated in the transcriptional regulation of MYC by influencing different aspects of chromatin structure. L3MBTL1 is known to regulate nucleosomal compaction, and we here showed that SGK2 inactivated BRG1, a key ATP-dependent helicase within the SWI/SNF complex that regulates nucleosomal positioning. These results demonstrate a link between an imprinted gene cluster and malignancy, reveal a new pathogenetic mechanism associated with acquired regions of genomic loss, and underline the complex molecular and cellular consequences of “simple” cancer-associated chromosome deletions