Attention-Deficit Hyperactivity Disorder, also known as ADHD, is a common condition that has many underlying causes. The common ADHD treatment is methylphenidate, which is a stimulant drug that affects the brain’s levels dopamine. This neurotransmitter is involved in reward systems and has been misused. However, methylphenidate’s therapeutic effects are not well understood.
Researchers from the Okinawa Institute of Science and Technology Graduate University in Japan (OIST) and scientists from the University of Otago and New Zealand’s University of Auckland conducted experiments to examine methylphenidate’s interactions with dopamine systems in rats. They discovered a feedback loop that regulates dopamine levels in rats’ brains when the drug is administered to them using dopamine cell recordings, electrochemical monitoring, and computer modeling. This regulatory process may shed some light on methylphenidate’s therapeutic properties in ADHD. The findings of the researchers are published in Neurobiology is moving forward.
“We know a lot more about how methylphenidate acts at the molecular and greater neural levels, but we don’t know much about its effects on larger systems. Professor Jeff Wickens from OIST’s Neurobiology Research Unit said that it’s still not clear how this drug improves ADHD symptoms. “This mystery has led us to investigate how different parts the brain interact to produce therapeutic effect.”
Discover the secrets to dopamine
The international team administered methylphenidate in a concentration of 5.0 mg/kg, to an adult male group of rats. A control group was not given any drugs. The researchers surgically implanted electrodes into the rats’ brains. They then used an electrochemical technique called “voltammetry” to monitor changes in the cellular dopamine concentrations in brain regions affected by ADHD. The researchers also measured the brain slices of live rats’ forebrains, and midbrains.
OIST scientists, including Kavinda Liliyanagama, developed a computer program to simulate the effects of methylphenidate in dopamine systems.
Dopamine is released by neurons in different ways. Phasic release is characterised by high-intensity spikes in neurotransmitter activity, often in response o sugary treats or drugs. Tonic release is a slower, more frequent firing of dopamine neurons and is involved with muscle and joint movements.
Wickens and his colleagues initially believed that methylphenidate would increase the phasic dose of dopamine, as it blocks dopamine reuptake by brain receptors. After analyzing their data, however, they discovered the opposite. Methylphenidate did no increase phasic doses of dopamine. Wickens believes this is because the brain has a powerful feedback mechanism to maintain brain dopamine levels under control, even when methyphenidate blocks it.
Wickens stated that methylphenidate can be used in intact brains to counteract the direct effects. “Methylphenidate could have indirect effects on this feedback loop.
Computer modeling suggests that methylphenidate has a predominant effect on the tonic dopamine signal. ADHD may be treated by a shift in the tonic dopamine signaling.
Wickens admits that the study was performed in healthy rats. The next step for the group is to examine this feedback loop using animal models of ADHD.
Wickens believes ADHD is a complex disorder that requires combination therapies. Wickens hopes to study the mechanisms of other treatments as well.