The effects of para-chlorophenylalanine (PCPA) and 3,4 methylenedioxy-methamphetamine (MDMA, 'ecstasy') were investigated in relation to development, behavior and physiology in larval Drosophila. PCPA blocks the synthesis of serotonin (5-HT) and MDMA is known to deplete 5-HT in mammalian neurons; thus these studies were conducted primarily to target the serotonergic system. Treatment with PCPA and MDMA delayed time to pupation and eclosion. The developmental rate was investigated with a survival analysis statistical approach that is unique for Drosophila studies. Locomotion and eating were reduced in animals exposed to MDMA or PCPA. Sensitivity to exogenously applied 5-HT on an evoked sensory-central nervous system (CNS)-motor circuit showed that the CNS is sensitive to 5-HT but that when depleted of 5-HT by PCPA a decreased sensitivity occurred. A diet with MDMA produced an enhanced response to exogenous 5-HT on the central circuit. Larvae eating MDMA from the first to third instar did not show a reduction in 5-HT within the CNS; however, eating PCPA reduced 5-HT as well as dopamine content as measured by high performance liquid chromatography from larval brains. As the heart serves as a good bioindex of 5-HT exposure, it was used in larvae fed PCPA and MDMA but no significant effects occurred with exogenous 5-HT. In summary, the action of these pharmacological compounds altered larval behaviors and development. PCPA treatment changed the sensitivity in the CNS to 5-HT, suggesting that 5-HT receptor regulation is modulated by neural activity of the serotonergic neurons. The actions of acute MDMA exposure suggest a 5-HT agonist action or possible dumping of 5-HT from neurons.

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The mechanism of action of psychostimulant drugs in the treatment of Attention Deficit Hyperactivity Disorder is still largely unknown, although recent evidence suggests one possibility is that the drugs affect the superior colliculus (SC). We have previously demonstrated that systemically administered d-amphetamine attenuates/abolishes visual responses to whole field light flashes in the superficial layers of the SC in anaesthetised rats, and the present study sought to extend this work to methylphenidate (MPH). Anaesthetised rats were administered MPH at a range of doses (or saline) and subjected to monocular whole field light flashes at two intensities, juxta-threshold and super-threshold. In contrast to d-amphetamine, systemic MPH produced an enhancement of visual activity at both intensities. Methylphenidate was also found to produce activation of the cortical EEG in anaesthetised rats. Furthermore, cortical activation induced by electrical stimulation of the pons was found enhance visual responses in superficial layers of the SC, and when MPH was paired with pontine-induced cortical activation, the response-enhancing effects of MPH were substantially attenuated. Taken together, the results suggest that the enhancement of visual responses in the superficial layers of the SC by MPH in the anaesthetised rat is an artefact of the drug's interaction with cortical arousal.

Distractibility can be defined as an attention deficit where orientation toward irrelevant targets cannot be inhibited. There is now mounting evidence that the superior colliculus is a key neural correlate of distractibility, with increased collicular-activity resulting in heightened distractibility. Heightened distractibility is reduced by amphetamine, which acutely suppresses collicular responsiveness. However, when amphetamine is used to treat distractibility, it is given chronically, yet no data exist on whether chronic amphetamine treatment affects the colliculus. Here, the effect of chronic amphetamine treatment was assessed in healthy hooded lister rats on two collicular dependent behaviours following a twenty-eight day treatment period: i) orienting to visual stimuli, and ii) height-dependent modulation of air-righting. We found no significant impact of amphetamine treatment on visual orienting despite showing dose-dependent decreases in orienting to repeated stimuli. However, we did find that treatment with amphetamine significantly reduced the ability to modulate righting according to the height the animal is dropped from - a function known to be dependent on the colliculus. We suggest that the results are in line with previous research showing acute amphetamine suppresses collicular activity and we speculate that the psychostimulant may increase receptive field size, altering time-to-impact calculations carried out by the colliculus during air-righting.

Background: The phenomenon of locomotor sensitization to injected amphetamine is well-characterised. The increased locomotor activity found acutely is enhanced with repeated intermittent treatment. This effect arises due to hypersensitization of the dopaminergic system and is linked to drug addiction. A clinical population exposed to chronic repeated intermittent amphetamine treatment, such as is found for attention deficit hyperactivity disorder (ADHD), may be expected to be more at risk of addiction following this treatment. However, evidence suggests the opposite may be true. This suggests the route of administration may determine the direction of effects. Aims and methods: We aimed to establish how an oral amphetamine treatment regimen, similar to that used in ADHD, impacts on locomotor activity, specifically whether tolerance or sensitization would arise. Healthy hooded Lister rats were given amphetamine (2 mg/kg, 5 mg/kg and 10 mg/kg) or a vehicle solution once daily for 4 weeks with a 5 day on, 2 day off schedule. Locomotor activity was measured on the first day of treatment to establish the acute effects and on the final day of treatment to examine the chronic effects. Results: As expected, acute doses of amphetamine increased locomotor activity, although this only reached statistical significance for the 5 mg/kg and 10 mg/kg doses. By contrast, after chronic treatment, animals administered these doses showed reduced activity indicating drug tolerance rather than sensitization had occurred. Conclusion: We suggest that the route of administration used in ADHD, which results in more stable and longer duration drug levels in the blood, results in tolerance rather than sensitization and that this effect could explain the reduced likelihood of substance addiction in those treated with psychostimulants for ADHD.