Therapeutic effects of Delta9-THC and modafinil in a marmoset Parkinson model.

Current therapies for Parkinson's disease (PD) like l-dopa and dopamine (DA) agonists have declined efficacy after long term use. Therefore, research towards supplementary or alternative medication is needed. The implementation in PD can be expedited by application of compounds already used in the clinic. In this study the therapeutic effects of the psychoactive compounds Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and modafinil were tested in the 1-methyl-1,2,3,6-tetrahydropyridine (MPTP)-marmoset model for PD. The anti-parkinson effects of Delta(9)-THC (4 mg/kg) and modafinil (100 mg/kg) in parkinsonian marmosets were assessed with two behavioral rating scales covering parkinsonian symptoms and involuntary movements and two test systems assessing the locomotor activity and hand-eye coordination. Delta(9)-THC improved activity and hand-eye coordination, but induced compound-related side-effects. Modafinil improved activity and observed parkinsonian symptoms but not hand-eye coordination. It can be concluded that both compounds have therapeutic values and could supplement existing therapies for PD.

Efficacy of caffeine and modafinil in counteracting sleep deprivation in the marmoset monkey.

BACKGROUND AND PURPOSE: The effects of sleep deprivation are a burden in our 24-h society. The use of wake-promoting compounds could improve the performance in situations where sleep cannot be allowed. In this study, the efficacy of the wake-promoting compounds, modafinil and caffeine, in counteracting the effects of 24-h sleep deprivation in the marmoset monkey were tested. As caffeine is habitually used, the efficacy of both compounds after short- and long-term use was investigated. MATERIALS AND METHODS: After a normal active day, the animals were kept awake and received wake-promoting compounds during the whole night. Three times during the sleep-deprived night, putative fatigue was assessed with an activity test and the vigilance and ability to execute a task was assessed with a hand-eye coordination (HEC) task. RESULTS: Both compounds were able to counteract to some extent the decline in performance. Modafinil was able to keep the activity at baseline performance, but performance on the HEC task was not improved. Caffeine was able to keep performance in the HEC task at a level just below daytime level but was not able to keep activity at daytime levels during the last part of the night. Caffeine and modafinil administration for 2 weeks showed a comparable effect on activity as acute use. The performance on the HEC task was similar after chronic caffeine and improved after chronic modafinil. CONCLUSION: It is therefore concluded that modafinil and caffeine were both able to postpone or prevent the decline in vigilance and psychomotor performance and increase in fatigue induced by sleep deprivation.

Neuroprotective effects of modafinil in a marmoset Parkinson model: behavioral and neurochemical aspects.

The vigilance-enhancing agent modafinil has neuroprotective properties: it prevents striatal ischemic injury, nigrostriatal pathway deterioration after partial transsection and intoxication with 1-methyl-1,2,3,6-tetrahydropyridine. The present study determines the protective effects of modafinil in the marmoset 1-methyl-1,2,3,6-tetrahydropyridine Parkinson model on behavior and on monoamine levels. Twelve marmoset monkeys were treated with a total dose of 6 mg/kg 1-methyl-1,2,3,6-tetrahydropyridine. Simultaneously, six animals received a daily oral dose of modafinil (100 mg/kg) and six animals received vehicle for 27 days. Behavior was observed daily and the locomotor activity, hand-eye coordination, small fast movements, anxiety-related behavior and startle response of the animals were tested twice a week for 3 weeks. Modafinil largely prevented the 1-methyl-1,2,3,6-tetrahydropyridine-induced change in observed behavior, locomotor activity, hand-eye coordination and small fast movements, whereas the vehicle could not prevent the devastating effects of 1-methyl-1,2,3,6-tetrahydropyridine. Dopamine levels in the striatum of the vehicle+1-methyl-1,2,3,6-tetrahydropyridine-treated animals were reduced to 5% of control levels, whereas the dopamine levels of the modafinil+1-methyl-1,2,3,6-tetrahydropyridine-treated animals were reduced to 41% of control levels. The present data suggest that modafinil prevents decrease of movement-related behavior and dopamine levels after 1-methyl-1,2,3,6-tetrahydropyridine intoxication and can be an efficaceous pharmacological intervention in the treatment of Parkinson's disease.

Behavioral effects of modafinil in marmoset monkeys.

RATIONALE: Modafinil is increasingly used in sleep disturbances in general and in neurodegenerative diseases and is recently being used in healthy people for attention control. However, the application of modafinil is possibly not only restricted to alertness enhancing effects. More insight in this compound may lead to new applications. Not all behavioral aspects have been studied sufficiently; therefore, more detailed investigations on modafinil's positive and aversive behavioral effects are addressed in this paper. OBJECTIVES: Determination of effects of modafinil in marmoset monkeys with observational methods and with behavioral tests measuring locomotor activity, hand-eye coordination, response to a threat situation and startle response. MATERIALS AND METHODS: Two hours after oral administration of modafinil in doses of 50, 100, 150, and 225 mg/kg, animals were observed and tested in the behavioral test systems. RESULTS: Locomotor activity was increased after 100 mg/kg modafinil in the Bungalow test and after 100, 150, and 225 mg/kg, as found in the movement parameters of the human threat test. Moreover, modafinil showed anxiolytic-like effects in the human threat test. No other side effects were observed, nor were the hand-eye coordination and startle response affected. CONCLUSIONS: Besides psychostimulation, modafinil has no aversive effects in the doses used in the domains measured. The potential anxiolytic-like effects of modafinil may create new possibilities for the therapeutic use of modafinil.