DrugsNutrition and Drugs

The Effects of Ritalin on Mouse and Rat Behaviors

By April 20, 2020 No Comments

Ritalin has been prescribed for decades to treat Attention Deficit Hyperactivity Disorder (ADHD). More recently, its popularity has surged among healthy people who use it off-label as a cognitive enhancer or “smart drug.” In 2013, more than 2.4 billion doses of methylphenidate were consumed worldwide, and the United States is responsible for nearly 85% of production and consumption.

In a related article, we focused on the effects of Adderall on rodent behavior. Here, in this article, we will explore what Ritalin is and see what the studies say about its wide-ranging behavioral effects, with a focus on studies in rodents.

What is Ritalin?

Ritalin is a brand name for methylphenidate, one of the most widely prescribed psychostimulants for children with ADHD. Although methylphenidate is sold under many different brand names with slightly different formulations, Ritalin was the first and is still the most common.

Methylphenidate is classified by the Drug Enforcement Administration as a Schedule II controlled substance, meaning the drug has medical uses but carries the possibility of severe psychological or physical dependence.

Ritalin’s Chemical Composition

Methylphenidate is a stimulant of the phenethylamine and piperidine classes. This means it shares part of its structure with catecholamines, the monoamine neurotransmitters such as dopamine and serotonin.

The methylphenidate molecule contains two chiral centers, giving four possible enantiomers: erythro-threo and dextro-levo. Initially, Ritalin was marketed as a mixture of the threo-erythro racemates, specifically, 80% (±)-erythro and 20% (±)-threo.

However, studies soon demonstrated that the efficacy of methylphenidate resides solely in the threo racemate. Current preparations contain a racemic mixture of only d,l-threo-methylphenidate, with the d-threo isomer primarily responsible for its pharmacological activity.[1]

A Brief History of Ritalin

Methylphenidate was first synthesized in 1944 by Italian chemist Leandro Panizzon while working at Ciba (now Novartis), a Swiss pharmaceutical company. He named the drug Ritalin, after the nickname of his wife Rita.[2]

A decade or so later, Ritalin’s stimulant properties were fully uncovered and it was approved for medical use by the Food and Drug Administration (FDA) in 1955. Initially, it was indicated for treating chronic fatigue, lethargic and depressed states, narcolepsy, and as an analeptic to reverse barbiturate-induced comas.

Following the studies of Charles Bradley, who utilized pharmacotherapy for behaviorally-challenged children, Ritalin started being used to treat hyperactivity in “maladjusted” children.[2] By the 1990s, the number of Ritalin prescriptions soared with the growing recognition of ADHD in the medical and mental health communities. Today, Methylphenidate is the 47th most prescribed drug, amounting to almost 16.5 million prescriptions.

Ritalin’s Therapeutic Uses

Methylphenidate is approved by the FDA for the treatment of ADHD and also narcolepsy. One systematic review of over 130 trials concluded that in children and adolescents, methylphenidate is the preferred first-choice medication for the short-term treatment of ADHD. In children, therapeutic doses for ADHD range from 0.3–1.0 mg/kg.[3]

Methylphenidate may also be prescribed off-label for managing treatment-resistant major depressive disorder and bipolar disorder. In addition, a large body of literature suggests methylphenidate can help treat depressive symptoms in medically ill geriatric patients, stroke patients, cancer patients, and traumatic brain injury patients. In some cases, methylphenidate may be prescribed for treating hyperactivity in neuropsychiatric conditions such as autism.[4]

Ritalin is available as tablets of 5 mg, 10 mg, or 20 mg for oral administration. When taken orally, methylphenidate has a bioavailability of about 30%, ranging from 11 to 52% depending on the individual. After ingestion, peak brain levels of methylphenidate occur approximately 1-2 hours after dosing. The effects last for about six hours. However, slow-release formulations are also available, such as Ritalin SR, which may last up to twice as long.[5]

Regardless of its medical uses, methylphenidate is generally considered safe in therapeutic doses but it comes with a fair share of side effects. This long list includes increased blood pressure, palpitations, appetite suppression, tremor, and sleep disturbances. Overdoses can lead to nervous system overstimulation, ultimately causing vomiting, agitation, muscle twitching, confusion, hallucinations, delirium, hyperthermia, headache, and cardiac arrhythmias. Ritalin should not be used in patients with a history of psychosis or underlying heart conditions since it can further exacerbate those conditions.[5]

Ritalin’s Mechanism of Action

Ritalin is a norepinephrine-dopamine reuptake inhibitor (NDRI), meaning it prevents the reuptake of norepinephrine and dopamine. Ritalin works by binding to dopamine and norepinephrine transporters and blocking the reuptake of dopamine and norepinephrine.

These transporters are the main mechanism for the removal of these neurotransmitters, so blocking their action leads to increased neurotransmitter levels at the synapse level.[6] The increase in extracellular levels of dopamine and norepinephrine is responsible for the stimulating effects that Ritalin induces. This includes its general arousal-promoting properties, such as boosting attention, increasing alertness, and combatting fatigue. However, as we’ll explore in more detail soon, methylphenidate has a paradoxical “calming” response in individuals with ADHD.

Ritalin’s stimulant properties are primarily dopaminergic in origin and are attributable to the d-isomer of threo-methylphenidate. Indeed, at therapeutic doses (0.3-0.6 mg/kg), methylphenidate is estimated to occupy more than half of the brain’s dopamine transporters.[7]

According to PET scan studies, the highest area of methylphenidate uptake is in the striatum in humans. However rat studies have shown that methylphenidate inhibits dopamine reuptake not only in the striatum, but also in the nucleus accumbens, olfactory tubercle, and prefrontal cortex.

In low doses, methylphenidate primarily targets neurons in the prefrontal cortex, which explains its ability to enhance executive functioning.[8] At higher doses, the potential for significant abuse arises because Ritalin dose-dependently increases the extracellular dopamine levels in the mesocortical dopamine reward pathway. This pathway connects the Ventral Tegmental Area (VTA) in the midbrain to the ventral striatum of the basal ganglia in the forebrain.[7] Higher dopamine in this region is associated with dependence disorders.

In the upcoming sections, we will overview how Ritalin impacts ADHD symptoms, behavior in early development, memory, and circadian rhythmicity in rodents.

Ritalin’s Effects on ADHD Symptoms

ADHD is a widely prevalent disorder primarily characterized by inappropriate or impairing levels of inattention, impulsivity, and hyperactivity. Currently, it is estimated to affect approximately 6.1 million children in the United States alone.

ADHD is tightly linked to dysfunctions in dopamine and norepinephrine signaling, particularly within the prefrontal cortex, an area that is responsible for executive functions like planning, problem solving, organization, and inhibition control.

There is a growing body of research that indicates that ADHD represents a hypodopaminergic state in the brain, due in part from having increased dopamine transporters compared to normal people.[9] Having high concentrations of dopamine transporters but unchanged dopamine levels is the basic premise of the hypodopaminergic state hypothesis of ADHD.  Thus, methylphenidate’s therapeutic effects may result from restoring normal levels of neurotransmission.

In this section, we will overview how methylphenidate impacts the core behavioral criteria of ADHD in rodents (hyperactivity and impulsivity), as well as their behavioral correlates in humans.

The Effects of Ritalin on ADHD Hyperactivity

Similar to the effects of Adderall, Ritalin is known to produce a paradoxical calming effect on hyperactivity for individuals with ADHD. Many human and rodent studies in the literature show that methylphenidate reduces hyperactive behavior. In this section, we will overview three murine models of ADHD and how methylphenidate impacts hyperactivity in these models.

A Single Oral Dose of Methylphenidate Reduces Locomotor Activity in Prenatal Nicotine-exposed Mice

One model that produces ADHD-like behavior in mice is the prenatal nicotine exposure model. Prenatal nicotine-exposed mice have behavioral characteristics that closely resemble ADHD in humans. This model produces hyperactivity, reductions in cingulate cortical volume, and decreased turnover of dopamine in the frontal cortex.[10]

In 2012, Zhu and colleagues found that a single oral dose of methylphenidate at 0.75 mg/kg transiently decreased spontaneous locomotor activity in this model. These effects lasted for approximately ten hours as measured by activity levels in the testing cages with photo beam motion sensors. Interestingly, they found that intraperitoneal injections of the same dose (0.75 mg/kg) did not affect locomotor activity. This suggests that the route of administration plays a role in determining the extent of Ritalin’s effects on ADHD-related hyperactivity.

Additionally, the researchers found the same dose of methylphenidate increased dopamine turnover in the frontal cortex, suggesting that methylphenidate’s therapeutic effects may be a result of the drug normalizing the hypodopaminergic state observed in the frontal cortex.[10]

Methylphenidate Decreases Hyperactivity in the 6-OHDA Murine Model

The 6-hydroxydopamine-lesioned (6-OHDA) murine model is a widely used animal model of ADHD. This model involves the neonatal lesioning of nigrostriatal dopaminergic pathways, producing dopamine-deficient mice that exhibit typical ADHD symptoms such as impulsivity, behavioral disinhibition, and hyperactivity.[11]

A study by Avele et al. assessed the behavioral phenotype of this model and the behavioral effects of 10 mg/kg methylphenidate administered intraperitoneally in 6-OHDA-lesioned mice. Before administering methylphenidate, the researchers found that this murine model recapitulates many of the core symptoms of ADHD. The 6-OHDA mice showed enhanced locomotor activity in the open field arena, specifically, a two-fold increase in horizontal activity compared to control mice. In addition, these mice demonstrated marked behavioral disinhibition as evidenced by more time spent in the central area of the open field and more time spent in the open arms of the elevated plus maze compared to controls.[11]

After methylphenidate administration, the control mice significantly increased their locomotor activity in response to methylphenidate. On the other hand, the 6-OHDA-lesioned mice demonstrated paradoxical hypolocomotion, seen as significantly reduced horizontal activity scores.

In sum, the neonatal lesioning of central dopaminergic pathways severely diminishes dopamine in the striatum of 6-OHDA mice, producing a dopamine deficiency in the midbrain and ADHD-like behavior such as hyperactivity and poor inhibition control. The paradoxical hyperlocomotor response to methylphenidate in this ADHD model parallels the paradoxical behavioral effects of psychostimulants on behavior in ADHD humans.[11]

Methylphenidate Reduces Exploratory Behavior in the Spontaneously Hypertensive Rat Model

The spontaneously hypertensive rat is another popular rat model of ADHD that does not require any surgical or neurotoxic interventions. These rats show reduced dopamine release and express high levels of inattention, impulsivity, and hyperactivity.[12]  Furthermore, the spontaneously hypertensive rat is a model of ADHD because of several physiological indicators of altered dopaminergic function. MRI studies have shown that spontaneously hypertensive rats have differences in their brain compared to normal rats, like smaller vermis cerebelli and caudate-putamen. They also express lower levels of dopamine D4 receptor gene expression and protein synthesis in the prefrontal cortex.[13]

A study by Wultz et al. investigated the behavioral effects of 1-24 mg/kg of methylphenidate in spontaneously hypertensive rats.  The researchers assessed exploratory activity, a commonly used behavioral indicator of hyperactivity (quantified as the numbers of crossings and rearings), in a modified two-compartment free-exploration open field.[12] The researchers chose the two-compartment free-exploration open field because it evokes less fear than the classic open field apparatus, allowing the rat to access the field from a familiar place (its home cage).

At baseline, the researchers noted that the spontaneously hypertensive rats showed pronounced hyperactivity. They spent most of the time in the open field, showing more crossings (horizontal activity) and rearings (vertical activity). On the other hand, the control rats spent most of the time reserved within the cage, avoiding the field.[12]

At low to medium doses (1-6 mg/kg) of methylphenidate, the spontaneously hypertensive rats increased their already high activity in the open field, although to a lesser extent than the control rats.[12] However, with increasing doses of methylphenidate (starting at medium doses above 9 mg/kg), locomotor activity in the field decreased for the spontaneously hypertensive rats compared to control rats. In addition, methylphenidate elicited stereotyped head nodding in both groups, increasing in a dose-dependent fashion. While stereotypy was produced in controls at 6 mg/kg, a dose of 9mg/kg elicited head nodding stereotypy in the ADHD rats. The researchers concluded that the exploratory behavior of this rat model is less impacted by methylphenidate than the exploratory behavior of controls, however, there was not a significant “paradoxical” effect of the drug on hyperactivity.[12]

Previous to this study, Myers et al. reported that d-amphetamine at low and moderate doses had a paradoxical effect in spontaneously hypertensive rats, decreasing activity in the field but increasing it in control Wistar rats.[12] However, this study demonstrates that spontaneously hypertensive rats do not demonstrate a “full” paradoxical behavioral response to methylphenidate. However, they do appear to be less susceptible to its stimulating effects compared to control rats, especially at low dosages. Overall, this study highlighted the difficulties involved in studying Ritalin’s effects on ADHD behaviors. Researchers must consider multiple variables and behaviors (from exploration to stereotypy) in order to fully understand how Ritalin affects behavior.

Effects of Ritalin on ADHD Impulsivity

Impulsivity is another one of the core behavioral criteria for ADHD, defined as acting without foresight, planning, or rational thinking. In individuals with ADHD, methylphenidate reliably decreases impulsive choices on delayed-to-reinforcement procedures and reduces delay discounting. Delay discounting refers to the preference for small, immediate rewards over larger, but delayed, rewards. In other words, ADHD individuals are predisposed to favor instant gratification.[14]

Neurobiologically, dopamine is the major neuromodulator that signals rewarding stimuli and regulates behavior under conditions of delayed reward. Therefore, dopaminergic dysfunction  (having lower than normal levels of tonic dopamine) may produce delay aversion and impulsivity in ADHD patients. Methylphenidate helps to restore normal levels of dopaminergic neurotransmission in frontostriatal circuits and mesolimbic reward pathways.[14] Methylphenidate may act therapeutically on impulsivity by increasing the perceived value of delayed rewards, or by modifying the cost of the delay.

Let’s take a look at how several studies assessed the effects of methylphenidate on impulsivity in rodents.

The Effects of Ritalin on Normal Rodents

Methylphenidate Reduces Premature Responding in the 5-choice Serial Reaction Time Test

Impulsive action and vigilance can be reliably assessed in rodents with the 5-choice serial reaction time test (5CSRTT), a task that is based on the continuous performance test used in humans. In the 5CSRTT, animals learn to nose poke into one of five apertures after a brief visual stimulus is presented in a given aperture. Impulsivity is defined by an increase in the number of premature responses, that is, nose pokes that occur before the presentation of the visual stimulus.

Using this test, Puumala et al. found that methylphenidate (0.1 mg/kg) slightly improved sustained attention performance and reduced the probability of premature responses in poorly performing rats. At higher doses (1 mg/kg), methylphenidate increased the impulsivity of both poorly performing and normal rats.[15] These results were similar to the findings presented in a 2008 study by Navarra and colleagues who found that methylphenidate at 2.5 mg/kg improved overall attention in performing rats. However, administration at a higher dose of 5.0 mg/kg significantly increased impulsivity by increasing premature responding.[16]

Methylphenidate Increases Preference for Delayed Rewards in Delay-discounting Procedures

Methylphenidate reliably reduces impulsive choice in delay-discounting procedures. In a study by Bizot et al., rats were trained using a T-maze to choose between an immediate reward or a larger reward that was delayed by 30 seconds. The researchers found that methylphenidate administered at a dose of 3 mg/kg increased the number of choices of the larger, delayed reward.[17] 

Similar results have been found in humans. In a study by Pietras et al., participants were presented with repeated choices between a small amount of money given after a short delay and a larger amount of money delivered after a longer delay which adjusted as a function of previous choices. Methylphenidate treatment decreased impulsivity in over half of the participants, seen as an increased number of self-control choices.[18]

Overall, methylphenidate may be an effective pharmacological treatment for impulsivity, a behavioral hallmark of ADHD. Animal and human studies support its ability to reduce impulsive choice and impulsive action as measured in delay discounting and 5-choice serial reaction time tests. Methylphenidate may increase the value of delayed rewards by altering reward processing through its dopamine-enhancing effects in the midbrain.

In the next section, we will explore how Ritalin affects early developmental behavior in juvenile rodents.

Ritalin’s Effects on Early Developmental Behavior

The use and misuse of methylphenidate are increasingly prevalent to public health. Yet, the long-term neuronal and behavioral consequences of its chronic use, which may persist into adulthood, are mostly unknown. Since Ritalin is prescribed to children and young adults, the long-term consequences of this practice have yet to be established. To this end, many rodent studies of methylphenidate have examined the effects of chronic administration on rodent behavior during their developmental period.

High Dose Methylphenidate Treatment Increases Exploratory Behavior and Decreases Anxiety-like Behavior in Juvenile Mice

Carrey and colleagues examined the effects of subchronic methylphenidate administration on the behavioral and cognitive development of prepubertal mice. The researchers treated male CD-1 mice with 40 mg/kg of methylphenidate or saline daily from postnatal days 26-32. From postnatal day 33-37, the mice were tested for locomotion and exploration in the open field, anxiety behavior in the elevated plus-maze, and spatial memory in the Morris water maze.[19]

Compared to the saline-treated mice, the methylphenidate-treated mice spent more time in the center squares of the open field. Additionally, they spent more time in the open arms and displayed more head dips in the elevated plus-maze. Taken together, methylphenidate caused increased exploratory behavior and decreased anxiety-like behavior at a high dose of 40 mg/kg. Interestingly, the researchers found no significant difference between saline-treated controls and the methylphenidate group on Morris water maze performance.[19] The researchers note, however, that these memory-related results may not generalize to more complex learning paradigms, such as the passive avoidance task, which also require the inhibition of a response.

Methylphenidate Treatment in Juvenile Period Alters Behavioral Responses to Emotional Stimuli during Adulthood

Early exposure to methylphenidate and its effects on behavior have also been investigated in adolescent rats. A 2003 study by Bolanos and colleagues investigated the long-term behavioral consequences of twice-daily injections of 2.0 mg/kg of methylphenidate in rats during their juvenile period (postnatal days 20-35).[20] After methylphenidate treatment, the animals were left undisturbed until adulthood (90+ days old). Then, the researchers assessed their behavioral responses to multiple emotional stimuli.

The researchers found the methylphenidate-treated animals were less responsive to natural rewards such as sucrose, measured in a two-bottle choice paradigm where the rats could choose freely between water and sucrose. The animals were also less responsive to novelty when placed in new environments, as evidenced by less locomotor activity when placed in a novel circular chamber. In addition, methylphenidate treatment reduced both the initiation and performance of sexual behavior compared to control animals.

Next, the researchers noted enhanced responsiveness to aversive situations in the methylphenidate-treated group. Specifically, the rats were more sensitive to stressors, as measured by a shorter time to immobilization in the forced swim test compared to control animals. Interestingly, and in contrast to the aforementioned study, the methylphenidate-treated rats showed more anxiety-like behavior, spending significantly more time self-grooming in the closed arms of the elevated plus maze and less time in the open arms of the maze compared to controls. To quantify the enhanced reactivity to stressful situations in these animals, the researchers noted significantly higher plasma levels of corticosterone in the methylphenidate-treated group during restraint stress.

Since the behavioral effects were examined in healthy rats, the authors note that a similar methylphenidate treatment in animal models for ADHD may lead to different, even contrary results.[20]

Methylphenidate Causes Behavioral Deficits and Hippocampal Abnormalities in Juvenile Rats

A 2016 study by Schmitz et al. examined the biochemical, histochemical, and behavioral effects of chronic methylphenidate within the hippocampus of juvenile rats. Previous research had found that methylphenidate dose-dependently increases norepinephrine levels in the hippocampus of adolescent rodents, suggesting this developing region in adolescence is affected by the drug.[21]

Schmitz and colleagues chronically administered methylphenidate at 2.0 mg/kg from postnatal day 15 to day 45. They found that the methylphenidate-treated group had less cell survival compared to the saline-treated group, measured as more astrocyte and neuron loss in the hippocampus. Additionally, brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) were reduced compared to saline controls. These trophic factors are crucially required for the establishment and survival of synaptic connections during development. Inflammatory mediators like TNF-α, IL-6, and Iba-1 (a microglia marker) were also increased, whose heightened levels correlate to neuroinflammation, inhibited synaptic plasticity, and reduced neurogenesis.[21]

The researchers then sought to determine if the biochemical and immunohistochemical alterations coincided with behavioral impairments. The researchers assessed the methylphenidate-treated rats on the elevated plus maze and open field. The methylphenidate-treated group explored less of the open arms in the elevated plus-maze and showed a reduced curiosity to explore the novel environment in the open field test.

They also observed long-term memory impairments in the methylphenidate-treated group in an object recognition task. Specifically, the methylphenidate group spent less time exploring both the novel and familiar object and could not distinguish between the two as well as the control group. In conclusion, the researchers suggest that the behavioral effects could be the result of astrocyte and neuron loss seen in the hippocampus. The observed inhibition of cell survival pathways and activation of cell death pathways regulated by cytokines and neurotrophins could play a mechanistic role in this process.[21]

Methylphenidate is widely used during the developmental period in humans, so rodent models offer an important window into the behavioral effects of treatment during this critical period of time. While acute, high doses of methylphenidate appear to decrease anxiety-like behavior in mice, longer-term methylphenidate treatment at clinically relevant doses in the animal juvenile period produces behavioral abnormalities such as heightened anxiety-like behavior and enhanced reactivity to stressful situations in adulthood.

In addition, biochemical and histochemical assays establish that early methylphenidate exposure can have complex effects on CNS development, such as neuron and astrocyte loss in the hippocampus, a critical region of the brain for memory processes. In the next section, we will explore methylphenidate’s putative memory-promoting properties.

Ritalin’s Effects on Memory

Dopamine and norepinephrine, the two main neurotransmitters influenced by Ritalin, are known to affect memory processes. In humans, Ritalin has been found to enhance working memory capacity and verbal memory in healthy individuals as well as increase declarative memory in adults with ADHD.[22-24]

Non-human primate studies have shown methylphenidate dose-dependently modulates activity in the prefrontal cortex, caudate, and hippocampus. Specifically, through a dopamine-mediated mechanism, methylphenidate has been found to increase functional connectivity between the caudate and hippocampus. Given the central role of the hippocampus in memory, this enhanced functional connection may be one mechanism through which methylphenidate influences memory function.[25]

In addition, the proper functioning of the prefrontal cortex, especially with respect to attention and memory processes, depends on the maintenance of a delicate balance between dopamine and norepinephrine signaling. Enhancing norepinephrine and dopaminergic transmission in this region may, therefore, provide a boost in executive functioning and memory-related processes.

Many rodent studies have demonstrated that methylphenidate enhances the retrieval and retention of memories, particularly within spatial memory and fear memory paradigms.

Ritalin’s Mixed Effects on Spatial Memory

A study by Kaczmarcyzk et al. investigated the memory impairments of mice fed a high-fat diet. After one week on this diet, the mice exhibited abnormal dopamine metabolism, triggering anxiety-like behavior and memory impairments prior to the onset of weight gain or pre-diabetes.

The researchers found that 2.5 mg/kg of methylphenidate (intraperitoneal injections) rescued memory impairments in the high-fat diet mice by improving their performance in the novel object recognition task.[26]

In another study, Carmack and colleagues reported that 1 or 10 mg/kg of methylphenidate given to mice in the pre-training phase enhances the retention of spatial memory in the Morris Water Maze. Additionally, the mice given 10 mg/kg of methylphenidate learned the location of the fixed hidden platform faster than mice trained on saline or 1 mg/kg of methylphenidate.[27] Interestingly, these results persisted even when the mice were off the drug.

However, a 2010 study by Scherer and colleagues showed that chronic administration of methylphenidate (2.0 mg/kg for 30 days) induced cognitive impairments on spatial reference and working memory tasks assessed in the Morris Water Maze. The researchers saw concomitant reductions in brain-derived neurotrophic factor in prefrontal cortex.[28] These results suggest that chronic methylphenidate treatment, particularly in the early developmental period, may produce deficits in spatial memory.

Ritalin’s Effects on Fear Memory

In the aforementioned study, Carmack and colleagues found that 10 mg/kg of methylphenidate administered chronically before Pavlovian fear conditioning dramatically impaired the formation of long-term fear memories.[27] Previous work by Cormack et al. a year earlier found that low, clinically relevant doses (i.e. 1 mg/kg) enhanced fear memory, but at high doses (10 mg/kg) impaired fear memory in a Pavlovian fear learning paradigm.[29]

In another study, Abraham and colleagues investigated methylphenidate’s effects on fear extinction and found that 2.5-10 mg/kg of methylphenidate enhances the extinction of contextual fear by reducing the time of freezing during the fear extinction phase of the task.[30]

In conclusion, methylphenidate in acute, clinically relevant doses may broadly enhance memory by increasing dopamine and norepinephrine release in prefrontal cortex and striatal regions. Its effects on fear memory may make it a clinically-relevant adjuvant alongside behavioral treatments for fear disorders in humans. In addition, psychostimulants like methylphenidate in acute doses could reliably be the standard that novel memory-enhancing nootropics could be compared against.[27]

Ritalin’s Effects on Circadian Rhythm

Many individuals with ADHD experience sleep problems that are exacerbated by psychostimulant pharmacotherapy. In children, methylphenidate treatment has been found to negatively impact multiple measures of sleep quality, including longer sleep onset latency, reduced sleep efficiency, decreased total sleep time, and phase-delayed daily rhythms. These symptoms may emerge from either a lengthened circadian clock or a phase delay in circadian rhythmicity.[31] The circadian rhythm is the natural biological clock mediated by light/dark cycles that governs many important bodily functions such as activity levels, feeding times, sleep cycles, and hormonal cycles.

Methylphenidate Alters the Properties of the Circadian Clock

With this in mind, a 2012 study by Antle et al. examined whether methylphenidate alters the circadian rhythm of mice. In this study, six and 12-week old mice were given either normal drinking water or drinking water with 0.8 mg/mL of methylphenidate. The mice were then examined in light-dark cycles and constant darkness alongside concurrent electrophysiological recordings in the suprachiasmatic nucleus (SCN).[31] The SCN is a part of the hypothalamus and plays the role of the master circadian clock. It sits on top of the same pathway that is involved with vision, giving it the ability to process information regarding light and dark.

The researchers found that the methylphenidate-treated animals significantly increased their activity in the mid- and late-night compared to controls. While the control animals maintained stable circadian rhythms and activity with respect to the 12 hour on- and 12 hour off-light cycle, the methylphenidate-treated animals exhibited a delay in the onset of activity and sleep relative to these light-dark cycles. That is to say, the methylphenidate-treated animals showed progressively later activity onsets and a delay in the onset of sleep at the beginning of the light period over successive weeks of treatment. The activity levels returned to baseline after treatment ended, but the phase angle of entrainment required at least a week to return back to baseline levels. (The phase angle of entrainment refers to the relationship between the timing of the biological clock and the timing of external cues, i.e. light/dark cues.)[31]

Methylphenidate Increases Behavioral Activity in Constant Darkness

In the portion of the experiment conducted in constant darkness, the animals were transferred from the 12:12 light/dark cycle to seven weeks of darkness. The methylphenidate-treated group showed significantly lengthened free-running periods, as measured by their general locomotor rhythms (via passive infrared sensors) and in wheel running. On the other hand, the control animals showed a progressive shortening of their free-running periods over the successive weeks in constant darkness.[31]

Methylphenidate Changes the Electrical Firing Rate Rhythms of the SCN

The SCN electrical activity rhythms were recorded in 9 of the animals over 5 days, and the researchers noted significant differences between the plain-water controls and methylphenidate-treated animals. Methylphenidate was found to alter the electrical firing rate rhythms in the SCN. This was seen as reductions in rhythm variability, delays in the trough of the rhythm, and increases in the amplitude of the rhythm compared to water controls. Taken as a whole, the changes in SCN activity indicate delays in the circadian rhythm and changes in the properties of the central clock corresponding to heightened behavioral activity. The authors note that the changes in SCN activity could be the result of the activation of neurotransmitter pathways, such as norepinephrine, that could then create enduring changes in the circadian clock properties for as long as treatment persists.[31]

In sum, the authors suggest that methylphenidate may alter the underlying circadian rhythm, in part by rendering the animals less susceptible to homeostatic sleep pressure. As a consequence, the animals were awake more throughout the total 24-hour period and extended their activity period by 1 hour into the light period. All of these effects are consistent with clock alterations that could promote sleep-onset insomnia. However, the researchers note that long-term studies (longer than three weeks) will have to be conducted to better capture the human situation and fully determine how methylphenidate interacts with circadian rhythmicity.[31]

Conclusion

Animal models of ADHD have been enormously helpful in delineating the phenotype of ADHD and offer a valuable window into how certain pharmacotherapeutics like Ritalin impact its behavioral characteristics. The studies reviewed above have shown that Ritalin consistently helps to reduce hyperactive behavior and impulsiveness. The most frequently used models of impulsivity include delay-discounting paradigms and the 5-choice serial reaction time test, reflecting impulsive choice and impulsive action, respectively.

Ritalin has been found in human and animal studies to increase the preference for delayed rewards within delay-discounting paradigms. In rodent studies using the 5-choice serial reaction time test, Ritalin reduces premature responding and enhances attentional performance.

Given that Ritalin is frequently used by young individuals and children over a period of many years, studies investigating the effects on rodent behavior during early development offer important translational insight. In juvenile mice, acute methylphenidate treatment at a high dose increases exploratory behavior and decreases anxiety-like behavior. Lower, chronic doses of methylphenidate in juvenile mice produce the opposite behavioral effects, reducing exploratory activity and increasing anxiety-like behavior. In juvenile rats, low (clinically-relevant) doses administered chronically reduce responsiveness to natural rewards, heighten sensitivity to stressors, and produce more anxiety-like behavior. These studies underscore the importance of titrating methylphenidate dose and treatment length to produce the most beneficial effects on behavior.

There have been mixed findings with respect to Ritalin’s effects on memory. In low, acute doses, studies have shown Ritalin helps to improve spatial memory and the extinction of fear memories. In higher doses, Ritalin has been found to impair the formation of fear memory in fear conditioning paradigms. In developing mice, longer-term (30 days+) Ritalin treatment impairs novel object recognition and leads to neuron and astrocyte loss in the hippocampus. Overall, the findings in this domain also appear to vary depending on factors such as dosing, treatment length, the age of the animal, and the route of administration.

Ritalin’s effects on circadian rhythmicity suggest it may exacerbate sleep problems that are already commonly experienced in individuals with ADHD. Ritalin has been found to alter the underlying circadian rhythm, seen as a heightened locomotor activity during the mid- to late-night period, and increased delays for the main sleep period. Additionally, Ritalin modulates the electrical activity of the SCN in a manner that is consistent with heightened behavioral activity and delays in the circadian clock properties.

Overall, the rodent studies overviewed in this article suggest that methylphenidate can offer therapeutic effects on ADHD-like behavior such as hyperactivity and impulsivity. Moreover, its use may confer memory-enhancing effects. However, methylphenidate treatment comes with important caveats. In light of the behavioral impairments that can arise from its use, particularly during the early developmental period, more studies will have to be conducted to determine its safety and effectiveness, especially with its chronic use.

References

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Author Details
Dylan Beard earned his BSc in Physics from the University of California, Santa Barbara. While earning his degree, he worked on a project investigating predictive coding of sensory information in the primary visual cortex of mice using two-photon calcium imaging as well as an independent thesis project using machine learning algorithms to predict neural responses to visual scenes from public access data out of the Allen Brain Institute. He is currently looking into pursuing a systems neuroscience research role in the Pacific Northwest and enjoys freelance science and medical writing in a variety of fields.
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Dylan Beard earned his BSc in Physics from the University of California, Santa Barbara. While earning his degree, he worked on a project investigating predictive coding of sensory information in the primary visual cortex of mice using two-photon calcium imaging as well as an independent thesis project using machine learning algorithms to predict neural responses to visual scenes from public access data out of the Allen Brain Institute. He is currently looking into pursuing a systems neuroscience research role in the Pacific Northwest and enjoys freelance science and medical writing in a variety of fields.