Methylphenidate Research Paper

Methylphenidate, commonly known as Ritalin, is a commonly prescribed central nervous system stimulant used to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy. Medical use of methylphenidate began in 1960 and an estimated 2.4 billion doses are prescribed a year. Methylphenidate is thought to act through the inhibition of dopamine and norepinephrine transporters in neurons, especially those of dopaminergic pathways of the brain. The dopaminergic pathways of the brain are composed of neurons that synthesize and transmit the neurotransmitter dopamine, to different regions of the brain. Dopamine signaling from these pathways is associated with several integral cognitive processes including reward-motivated behavior, motor control, attentional control, and planning. Structural changes and mutations in neurons of these pathways play central roles in many disorders including addiction, depression, schizophrenia, and attention deficit disorder (Mayo). The mechanism of action of these pathways involve the release of dopamine from the dopaminergic neurons through exocytosis of vesicles into the synaptic cleft. Release of the vesicles is mainly stimulated by action potentials, but can be stimulated through other mechanisms. In the synaptic cleft, dopamine binds to and activates dopamine binding g-coupled protein receptors. The receptors then modulate intracellular levels of cAMP dependent on the type of receptor is bound. Dopamine is then released from the receptors and are then cleared from the cleft by reabsorption back into the presynaptic cell. The reabsorption is mainly mediated through the dopamine transporter and nopinephrine transporter. Once back in the cell, dopamine is either recycled back into vesicles for release or broken down. The dopamine transporter consists of twelve transmembrane domains and acts as a symporter transporting dopamine and sodium ions from the synaptic cleft into the cell. Models propose that sodium ions bind to the transporter before dopamine, which causes a conformational change once upon binding allowing both sodium and dopamine to unbind on the intracellular side of the membrane. Dopamine transporters are associated and abundant in areas of the brain associated with dopaminergic pathways, specifically the mesocortical, mesolimbic, ventral tegmental, and nigrostriatal regions. Regulation of the transporter is controlled by several kinases like PKA and MAPK, changes in phosphorylation of the transporter can modulate the rate of action as well as cause the internalization of the transporter(NP). The exact mechanism of action for methylphenidate is not completely elucidated and not well understood. However, it is believed that methylphenidate acts as a dopamine and norepinephrine reuptake inhibitor, resulting in a gradual buildup of dopamine in the synaptic cleft, that interacts with the dopamine receptors on the postsynaptic neurons activating the mesolimbic system and thus prolongation of dopamine receptor effects. Methylphenidate may inhibit the dopamine transporter by acting as an antagonist of dopamine for these transporters (Voltz). Treatment …show more content…
Physiologically methylphenidate acts like other central nervous system stimulants and produces several effects including increased alertness and increases in blood pressure, heart rate, respiration, and body temperature. It has also been found to increase regional cerebral blood flow in the midbrain/substantia nigra and thalamus. In small-scale studies in children with ADHD, methylphenidate modulates the activity and connectivity between ] frontal-striatal and frontal-parietal regions of the brain. These modulations suppress the activity in the default mode network, which is involved in mind-wandering. A recent meta-analysis of functional magnetic resonance imaging in patients with ADHD suggests that the long-term use of stimulants, like methylphenidate, may change the size of some brain structures that are typically smaller in children with ADHD …show more content…
When the drug was first introduced it was sold as a racemic mixture of the isomers, but today the drug is also sold as with only d-threo-methylphenidate. Studies have shown there were few differences in binding affinities between the isomers (Markowitz). However, studies using Positron Emission Tomography in the human brain with radioactively-labeled methylphenidate have shown that therapeutic doses block more than 50% of the dopamine transporters, and significantly enhance extracellular dopamine (DA) in the basal ganglia. Recent in-vitro studies have shown d-methylphenidate exhibits significant affinity with the norepinephrine transporter as well as the dopamine transporter when compared to l-methylphenidate (Hannestad). These studies have shown methylphenidate to be potent inhibitor of both the dopamine transporter and norepinephrine transporter with experimentally determined KIs of = 0.06 μM and 0.10 μM respectively. KI is an indicator of inhibitor potency and corresponds to the concentration required to produce half maximum