Search

Methylphenidate (MPD) is psychostimulant, similar to cocaine and amphetamine, that is commonly used to treat attention deficit hyperactivity disorder and is increasingly being abused by healthy subjects for its psychoactive effects such as memory retention cognitive enhancement for young, adult and the elderly and recreation. MPD’s action on the brain reward/motive circuit is still under investigation, however it is known that in animals chronic use of MPD leads to behavioral sensitization, an experimental indicator associated with dependence. To investigate this neural circuit’s role in response to acute and chronic MPD, three different lesions (non-specific, dopaminergic specific, and glutaminergic specific lesions) have been conducted at the nucleus accumbens (NAc), the ventral tegmental area (VTA), the caudate nucleus (CN), and the prefrontal cortex (PFC), to assess the structure, dopaminergic signaling, and glutaminergic signaling roles in response to MPD. The three types of lesions show that each one of the above four brain areas participate differently in the acute and chronic effect of MPD and have helped determine which type of signaling is critical for the acute and/or chronic behavioral adaptions to MPD.

Opioid addiction is classified as a Substance Use Disorder (SUD), a complex and chronic health condition with physical, social, and psychological consequences. While there is no cure for it, we present a novel approach towards preventing a hallmark feature of addiction-- the opiate withdrawal syndrome. Opioids exert numerous effects, acutely and chronically, on the nervous system with physical dependence, tolerance, and withdrawal being the most adverse chronic features. The degree of opioid dependence can be quantified by the frequency and/or intensity of the behavioral expression of withdrawal seen after abrupt termination of opioid consumption or after treatment with an opioid antagonist such as naloxone. Although the Central Nervous System (CNS) is the primary area of opioid impact, the involvement of the immune system in modifying CNS phenomena was suggested nearly two centuries ago and proved by several groups within the last few decades. Through a series of studies with immunomodulators alpha interferon, cyclosporine A, and cortisol, preclinical experiments show that administration of these agents prior to chronic morphine exposure prevents the expression of opiate withdrawal a hallmark feature of addiction. This review provides updates on current developments in the management of the opioid epidemic and an overview of studies on preventative immunomodulation prior to repetitive opioid administration as a means of addressing one of the underlying symptomatology driving the epidemic.

The dose-dependent response to variable methylphenidate (MPD) doses on the behavior of male and female adolescent (post-natal day 39) and adult (post-natal day 60) rats of three different genetic strains was studied to examine whether there are sex, age and strain dependent differences in response to MPD. Twenty-four male and twenty-four female groups were used. The 48 groups each had an N=8. The results show that female adolescents and adult rats of Sprague-Dawley (SD) and Spontaneous Hyperactive Rat (SHR) strains were more sensitive to the acute exposure of MPD. Furthermore, female adult rats of the SD, SHR and Wistar-Kyoto (WKY) strains generally responded with greater increase in locomotor activity than the adolescent females of these strains. In the WKY strain, adolescent males tended to experience a greater increase in activity than adult males. Lastly, significant differences in response to MPD also were observed among the three genetic strains. These variable responses to the acute dose of MPD reinforce the need to study the effects of this psychostimulant across the various sexes, ages and strains.

Psychostimulants such as methylphenidate (MPD) and amphetamine (AMP) are often prescribed to young children and adolescents to treat behavioral disorders, or used to improve their intellectual performance in our competitive society. This is concerning as the temporal effects of how MPD exposure at a young age influences the response to MPD and AMP administration later in adulthood remains unclear. The objective of this study was to test whether MPD has the characteristics of substances that elicit behavioral symptoms of dependence and whether those effects are influenced by the initial age of MPD exposure. Three control and nine experimental groups of male rats were used. They were exposed to repetitive (chronic) 0.6, 2.5, or 10.0 mg/kg MPD in adolescence only, adulthood only, or adolescence and adulthood respectively. Then all groups were subsequently re-challenged with a single AMP dose in adulthood to test whether cross-sensitization between MPD and AMP was expressed, potentially as a result of prior MPD consumption. Exposure to 2.5 mg/kg and 10.0 mg/kg MPD in adolescence and adulthood or in adulthood alone led to cross-sensitization with AMP while exposure to 0.6 mg/kg MPD in adolescence and adulthood or in adulthood alone did not lead to cross-sensitization with AMP. Thus, these results indicate that MPD cross-sensitization with AMP is dose dependent.

Opioid addiction is classifi ed as a Substance Use Disorder (SUD), a complex and chronic health condition with physical, social, and psychological consequences. While there is no cure for it, we present a novel approach towards preventing a hallmark feature of addiction-- the opiate withdrawal syndrome. Opioids exert numerous effects, acutely and chronically, on the nervous system with physical dependence, tolerance, and withdrawal being the most adverse chronic features. The degree of opioid dependence can be quantifi ed by the frequency and/or intensity of the behavioral expression of withdrawal seen after abrupt termination of opioid consumption or after treatment with an opioid antagonist such as naloxone. Although the Central Nervous System (CNS) is the primary area of opioid impact, the involvement of the immune system in modifying CNS phenomena was suggested nearly two centuries ago and proved by several groups within the last few decades. Through a series of studies with immunomodulators alpha interferon, cyclosporine A, and cortisol, preclinical experiments show that administration of these agents prior to chronic morphine exposure prevents the expression of opiate withdrawal a hallmark feature of addiction. This review provides updates on current developments in the management of the opioid epidemic and an overview of studies on preventative immunomodulation prior to repetitive opioid administration as a means of addressing one of the underlying symptomatology driving the epidemic.

Methylphenidate (MPD) and amphetamine (AMP) are both psychostimulants that are often used to treat behavioral disorders. More recently, it has also been increasingly used illicitly for recreation as well as to improve intellectual performance. Many factors such as age, gender, genetic background, and environment govern the development of behavioral sensitization to MPD and cross-sensitization with other drugs, which are experimental behavioral markers indicating potential of substance dependence and abuse. This study examines the effects of the environment and age when MPD was exposed in adulthood alone as well as in adolescence into adulthood on cross-sensitization with AMP in female SD rats by randomizing animals to either receive the drug in a home cage or a test cage during adolescence, adulthood, or both. In a 34 day experiment, 16 groups of animals starting in adolescence were treated with saline on experimental day one (ED1), followed by a 6 day (ED2-ED7) treatment with either saline, 0.6 mg/kg AMP, 0.6, 2.5, or 10.0 mg/kg MPD. Experimental groups were then subject to a 3-day washout period (ED8-ED10) and then a retreatment with the respective drug on ED11 in adolescence (P-38 to P-49). Experiments continued in the same animal groups now in adulthood (P-60) with a saline treatment (ED1), followed by the same sequence of treatments in adolescence (ED2-ED11;P-61 to P-69). A rechallenge with the same AMP or MPD dose was performed on ED11 (P-70) followed by a single exposure to 0.6 mg/kg AMP on ED12 (P-71) to assess for cross sensitization between MPD and AMP. Animals treated with MPD in both adolescence and adulthood and in the last experimental day of AMP (ED12) showed higher intensity of cross-sensitivity between MPD and AMP as compared to animals treated with MPD only in adulthood. AMP and MPD treatment in adolescence and into adulthood in the home or test cage resulted in significantly higher responses to the drug as compared to those treated only in adulthood. Overall, we conclude that environmental alteration and adolescent exposure to MPD appeared to increase the risk of cross-sensitization to AMP in female SD rats i.e, using MPD in adolescence may increase the probability of becoming dependent on drugs of abuse. This further indicates that age, sex, and environment all influence the response to MPD and AMP, and further work is needed to elucidate the risks associated with MPD and AMP use.

Methylphenidate (MPD) is a psychostimulant used for the treatment of ADHD and works by increasing the bioavailability of dopamine (DA) in the brain. As a major source of DA, the ventral tegmental area (VTA) served as the principal target in this study as we aimed to understand its role in modulating the acute and chronic MPD effect. Forty-eight male Sprague-Dawley rats were divided into control, sham, electrical lesion, and 6-OHDA lesion groups. Given the VTA's implication in the locomotive circuit, three locomotor indices-horizontal activity, number of stereotypy, and total distance-were used to measure the animals' behavioral response to the drug. Baseline recording was obtained on experimental day 1 (ED 1) followed by surgery on ED 2. After recovery, the behavioral recordings were resumed on ED 8. All groups received daily intraperitoneal injections of 2.5 mg/kg MPD for six days after which the animals received no treatment for 3 days. On ED 18, 2.5 mg/kg MPD was re-administered to assess for the chronic effect of the psychostimulant. Except for one index, there was an increase in locomotive activity in all experimental groups after surgery (in comparison to baseline activity), acute MPD exposure, induction with six daily doses, and after MPD re-challenge. Furthermore, the increase was greatest in the electrical VTA lesion group and lowest in the 6-OHDA VTA lesion group. In conclusion, the results of this study suggest that the VTA may not be the primary nucleus of MPD action, and the VTA plays an inhibitory role in the locomotive circuit.

There is growing concern that the psychostimulant Methylphenidate (MPD) is being abused for cognitive enhancement and recreation by healthy adults and adolescents seeking to improve their work or academic performance. This study concomitantly recorded the behavioral and prefrontal cortex (PFC) neuronal activity in freely behaving animals exposed to acute and chronic MPD doses (0.6, 2.5, and 10.0 mg/kg MPD) in order to compare MPD effects on adult and adolescent rats. The PFC is one of the primary brain areas affected by MPD and the drug of choice for treating ADHD. Moreover, the PFC is one of the last brain areas to complete development, suggesting that the behavioral and neurophysiological response to MPD may differ in adolescents and adults. In both adult and adolescent animals, it was observed that the same repetitive (chronic) dose of either 0.6, 2.5, or 10.0 mg/kg MPD elicited behavioral sensitization in some animals and tolerance in others, experimental biomarkers indicating drug of abuse symptoms, and the majority of PFC units recorded in animals expressing behavioral sensitization or tolerance to chronic MPD exposure responded by increasing and decreasing their neuronal firing rate, respectively. Further, it was shown that high doses of 10.0 mg/kg MPD significantly modified adolescent behavioral activity but did not impact adults suggesting that adolescents may be more receptive to chronic MPD exposure. These findings raise concerns regarding the use and abuse of MPD in normal, healthy individuals and support the notion that the adolescent PFC is more susceptible than the adult PFC to neuromodulation from chronic MPD use.

The objective of this study is to gain insight into the behavioral and neuronal changes induced by acute and chronic methylphenidate (MPD) administration. Specifically, there is limited knowledge of the effects of MPD on the locus coeruleus (LC), the main site of norepinephrine synthesis in the brain. In this study, LC neuronal firing rate was recorded simultaneously with locomotor activity in freely moving adolescent rats. Adolescent rats were chosen to mimic the age group in humans most affected by MPD exposure. Following acute dose of 0.6, 2.5 or 10 mg/kg MPD, all rats showed an increase in locomotor activity. However, in response to chronic MPD doses, individual rats showed either a further increase or decrease in their locomotor activity as compared to the effect initiated by the acute dose-expressing either behavioral sensitization or tolerance, respectively. The LC neuronal recordings from animals expressing behavioral sensitization showed that the majority of units responded to chronic MPD exposure by further increasing firing rates as compared to the initial response to the acute MPD exposure. For the LC neuronal units recorded from animals expressing behavioral tolerance, however, the majority of the units responded to chronic exposure by attenuating or no significant effect on their firing rate as compared to the acute MPD exposure. This observation indicates a correlation between the LC neuronal responses and behavioral activity to chronic MPD exposure. The study shows that LC participates in the effect of MPD and the behavioral expression of sensitization and tolerance to chronic exposure of MPD.

The use of methylphenidate (MPD), a commonly prescribed drug to treat attention-deficit hyperactivity disorder (ADHD), has steadily increased over the past 25 years. This trend has been accompanied by more MPD abuse by ordinary individuals for its cognitive enhancing effects. Therefore, understanding the effects of MPD on the prefrontal cortex (PFC), a brain area involved in higher cortical processing such as executive function, language, planning, and attention regulation, is of particular importance. The goal of this study is to investigate the effects of acute and chronic dose-response characteristics following MPD exposure on both the PFC neuronal population and behavioral activity in freely behaving animals implanted previously with permanent electrodes within the PFC. Four groups of animals were used: saline (control), 0.6, 2.5, and 10.0mg/kg MPD. It was observed that the same dose of either 0.6, 2.5, or 10.0mg/kg repetitive (chronic) MPD exposure elicited behavioral sensitization in some animals and behavioral tolerance in others, and that the majority of PFC units recorded from animals expressing behavioral sensitization to chronic MPD exposure responded to MPD by increasing their neuronal firing rate, whereas the majority of PFC neurons recorded from animals expressing behavioral tolerance in response to chronic MPD responded by decreasing their neuronal firing rate. This data suggests that in animals that display behavioral sensitization, chronic MPD exposure causes an increase in the number of post-synaptic D1 dopamine receptors leading to an increase in behavioral and neuronal firing rate, while in animals that display behavioral tolerance, chronic MPD exposure causes an increase in the number of post-synaptic D2 dopamine receptors leading to a decrease in behavioral and neuronal firing rate. This dichotomy needs to be further investigated.

Methylphenidate (MPD) is commonly used to treat attention-deficit hyperactivity disorder (ADHD). Recently, it is being abused for cognitive enhancement and recreation leading to concerns regarding its addictive potential. The prefrontal cortex (PFC) and caudate nucleus (CN) are two of the brain structures involved in the motive/reward circuit most affected by MPD and are also thought to be responsible for ADHD phenomena. This study is unique in that it investigated acute and chronic, dose-response MPD exposure on animals’ behavior activity concomitantly with PFC and CN neuronal circuitry in freely behaving adult animals without the interference of anesthesia. Further, it compared acute and chronic MPD action on over 1,000 subcortical and cortical neurons simultaneously, allowing for a more accurate interpretation of drug action on corticostriatal neuronal circuitry. For this experiment, four groups of animals were used: saline (control), 0.6, 2.5, and 10.0 mg/kg MPD following acute and repetitive exposure. The data shows that the same MPD dose elicits behavioral sensitization in some animals and tolerance in others and that the PFC and CN neuronal activity correlates with the animals' behavioral responses to MPD. The expression of sensitization and tolerance are experimental biomarkers indicating that a drug has addictive potential. In general, a greater percentage of CN units responded to both acute and chronic MPD exposure as compared to PFC units. Dose response differences between the PFC and the CN units were observed. The dichotomy that some PFC and CN units responded to the same MPD dose by excitation and other units by attenuation in neuronal firing rate is discussed. In conclusion, to understand the mechanism of action of the drug, it is essential to study, simultaneously, on more than one brain site, the electrophysiological and behavioral effects of acute and chronic drug exposure, as sensitization and tolerance are experimental biomarkers indicating that a drug has addictive potential. The behavioral and neuronal data obtained from this study indicates that chronic MPD exposure results in behavioral and biochemical changes consistent with a substance abuse disorder.

The psychostimulant, methylphenidate (MPD), is the first line treatment as a pharmacotherapy to treat behavioral disorders such as attention deficit hyperactivity disorder (ADHD). MPD is commonly misused in non-ADHD (normal) youth and young adults both as a recreational drug and for cognitive enhancing effects to improve their grades. MPD is known to act on the reward circuit; including the caudate nucleus (CN). The CN is comprised of medium spiny neurons containing largely dopamine (DA) D1 and D2 receptors. It has been widely shown that the DA system plays an important role in the response to MPD exposure. We investigated the role of both D1 and D2 DA receptors in the CN response to chronic MPD administration using specific D1 and D2 DA antagonist. Four groups of young adult, male SD rats were used: a saline (control) and three MPD dose groups (0.6, 2.5, and 10.0 mg/kg). The experiment lasted 11 consecutive days. Each MPD dose group was randomly divided into two subgroups to receive either a 0.4 mg/kg SCH-23390 selective D1 DA antagonist or a 0.3 mg/kg raclopride selective D2 DA antagonist prior to their final (repetitive) MPD rechallenge administration. It was observed that selective D1 DA antagonist (SCH-23390) given 30 min prior to the last MPD exposure at ED11 partially reduced or prevented the effect induced by MPD exposure in CN neuronal firing rates across all MPD doses. Selective D2 DA antagonist (raclopride) resulted in less obvious trends; some CN neuronal firing rates exhibited a slight increase in all MPD doses.

Chronic use of psychostimulants such as methylphenidate (MPD) and amphetamine (Amph) leads to abuse and dependence. Cross-sensitization occurs when exposure to a drug causes a significant intensified response to a different drug as compared to the effect of the drug in subjects with no previous exposure. Cross-sensitization is used as an experimental correlate for a drug's potential to elicit dependence. The present study uses male and female adolescent rats to examine whether cross-sensitization occurs with MPD, a drug not traditionally considered to elicit dependence, and Amph, a drug considered to elicit dependence. The results showed that there is cross-sensitization with MPD to Amph in adolescent rats and that there is a significant difference in male and female responses. Cross-sensitization between MPD and Amph was observed in a linear dose dependent manner in males and in an inverted U-shape pattern in females. Males treated with the highest dose of 10.0 mg/kg MPD and females treated with the mid-dose of 2.5 mg/kg MPD showed the most robust cross-sensitization. Overall, adolescent female rodents had a greater intensity of response to MPD, Amph, and cross-sensitization between MPD and Amph. This study shows that there are significant sex differences in psychostimulant cross-sensitization in adolescence, indicating the maturity of the gonadal system is not the predominant reason for differences between male and female responses to psychostimulant drugs.

Attention Deficit Hyperactivity Disorder (ADHD) is a developmental, behavioral disorder that is characterized by patterns of impulsivity and limited attention. Stimulants, such as methylphenidate (MPD) and amphetamine (Amph), are utilized as first-line agents in the treatment of ADHD. While Amph is known to elicit dependence, MPD is not. Interdependence between MPD and Amph is a growing concern. Therefore, it is important to explore this interaction in animal models to gain insight on its mechanisms. In experimental studies, drugs that elicit behavioral sensitization and cross-sensitization in animals are considered to have the potential to elicit dependence. This study evaluated whether chronic repetitive MPD exposure in adolescence and/or adulthood in various genetic strains of female rats elicits behavioral sensitization as well as cross-sensitization with Amph. We used three strains: SHR (ADHD model), WKY, and SD rats. The three rat strains were exposed to chronic MPD in their adolescence and adulthood or exposed to chronic MPD only in adulthood. When the female rats were treated with MPD only in adulthood, the SHR strain exhibited cross-sensitization to Amph but the WKY and SD strains did not. Whereas, when the female rats were pretreated with MPD in adolescence and adulthood, the SHR and WKY strains exhibited cross-sensitization response to Amph, but the SD strain did not. This study showed that the genetic strain and age of exposure to MPD plays a crucial role in cross-sensitization to Amph in female rodents. Furthermore, we showed that genetics associated with ADHD pre-dispose animals to dependence between drugs even if the exposure starts in adulthood compared to control strains that did not show dependence with adult only MPD exposures. Genetic variability, age of initial drug exposure, and sex of the subject are key variables that should be accounted in studies that explore effects of psychostimulants .

The psychostimulant methylphenidate (MPD) is the most common medication used in treating ADHD in children. Studies have shown an increasing prevalence among adolescents without ADHD to take MPD as a cognitive booster and recreational drug, even though it is a Schedule II drug and has a high potential for abuse. The objective of this study is to explore if there is an association between the animals' behavioral and neurophysiological responses to acute and/or chronic methylphenidate exposure within the ventral tegmental area and the nucleus accumbens, and to compare how these two brain structures fire in response to methylphenidate. Freely moving adolescent rats implanted with semimicroelectrodes within the VTA and NAc were divided into three MPD dosing groups: 0.6, 2.5, and 10 mg/kg i.p., as well as a saline control group. The animals were divided into two groups based on their behavioral responses to chronic MPD, behavioral sensitization and tolerance, and the neuronal responses of the two groups were compared for each MPD dosing. Significant differences in the proportion of neuronal units in the VTA and NAc responding to MPD were observed at the 0.6 and 10.0 mg/kg MPD dosing groups. Moreover, the same doses of 0.6, 2.5, and 10.0 mg/kg MPD elicited behavioral sensitization in some animals and behavioral tolerance in others. This specific study shows that the VTA and NAc neurons respond differently to the same doses of MPD. MPD has different neuronal and behavioral effects depending on the individual, the dosage of MPD, and the brain structure studied.

Methylphenidate (MPD) is the most commonly prescribed psychostimulant for the treatment of attention-deficit hyperactivity disorder (ADHD). MPD acts on brain structures of the reward/motivation system, including the caudate nucleus (CN). The objective of this study was to investigate the acute and chronic dose response effects of MPD on CN neurons in freely behaving adolescent rats. Semi-microelectrodes were implanted into the CN of one hundred and sixty-three adolescent male Sprague-Dawley rats. On experimental day one (ED1), each rat was injected with 0.8 ml saline followed by an injection of MPD (0.6, 2.5, or 10.0 mg/kg). Behavioral and neuronal recordings of 60 min followed each injection. Throughout ED2-6, each rat remained in its home cage and received daily injections of a specific dose of MPD. ED7-9 consisted of a three-day washout period during which no injections were given. On the last day (ED10), each rat was returned to the testing chamber in its home cage and an identical protocol was performed as on ED1. The same repetitive (i.e. chronic) dose of MPD elicited behavioral sensitization in some animals and behavioral tolerance in others. After chronic MPD exposure, CN units recorded from rats expressing behavioral sensitization responded mainly with increased neuronal firing rates. Conversely, rats expressing behavioral tolerance responded mainly with decreased neuronal firing rates. These findings suggest a direct correlation between the behavioral and CN neurophysiological response to chronic MPD in adolescent animals.

The prefrontal cortex (PFC) is involved in complex planning, learning, memory, attention and integrates sensory information. It was reported that the PFC was dysfunctional in attention deficit hyperactivity disorder (ADHD). Methylphenidate (MPD), a drug often prescribed for the treatment of ADHD, has potential for abuse and misuse. Most MPD studies were completed in adult subjects; however, most users were adolescents. The objective of this study was to investigate the acute and chronic dose response characteristics of MPD on PFC neuronal activity recorded in freely behaving adolescent rats. Four groups of animals were used: saline (control), 0.6, 2.5, and 10 mg/kg MPD. Acute MPD elicited a dose response increase in animals’ locomotor activity. Rechallenge with MPD at experimental day (ED10) when compared to the effect of MPD at ED1 showed no significant differences. When the animals were divided into two groups based on their individual responses to chronic MPD exposure, some animals expressed behavioral tolerance and some expressed behavioral sensitization. Electrophysiologically, a dose response characteristic for acute and chronic MPD exposure was observed. With increasing MPD doses, more PFC units responded by changing their firing rate. Moreover, the neuronal responses to chronic MPD recorded from animals expressing behavioral tolerance were significantly different compared to the neuronal population responses recorded from animals expressing behavioral sensitization. The majority of the PFC units recorded from animals expressing behavioral tolerance responded to MPD predominately by decreasing their firing rates, whereas PFC units recorded from behaviorally sensitized animals mainly showed an increase in their firing rates.

Methylphenidate is one of the most common pharmaceutical treatments for Attention Deficit Hyperactive Disorder (ADHD). It is also gaining popularity as a cognitive enhancement and recreational substance. The current study assesses the long-term effects of methylphenidate (MPD) on the circadian rhythm activity pattern of adolescent and adult male Sprague-Dawley (SD) rats. The experiment lasted for 11 days of non-stop recording, the evaluation was divided into 4 phases: acute, induction, washout, and expression phases. Circadian rhythm changes in each phase were compared between the adolescent and adult rats using the following parameters MESOR (midline estimating statistic of rhythm) or average activity, amplitude (distance from MESOR to the peak activity), and acrophase (time at which peak amplitude occurs). Overall, more significant changes in circadian rhythm pattern among adult rats were observed as compared to adolescent rats. As the circadian rhythm governs the diurnal locomotor activity pattern, changes in the locomotor pattern induced by chronic treatment MPD indicate that the drug exerts a long-term effect on the circadian rhythm.

Methylphenidate (MPD) is one of the choices to treat attention-deficit / hyperactivity disorder (ADHD), and its mechanism of action is not clear. Concomitant behavioral and locus coeruleus (LC) neuronal activity were recorded following acute and chronic (0.6, 2.5 and 10 mg/kg) MPD in freely moving rats. The experiment last for 10 days. (1) The behavioral recording showed that acute MPD increases in locomotor activity in a dose dependent manner. (2) The same dose of chronic MPD administration elicits in some animals behavioral sensitization and in others behavioral tolerance. (3) The majority of the LC unit responded to acute MPD exposure by increase their firing rate. (4) The baseline activity on experimental day 10 (ED 10) after six daily repetitive MPD exposure was modulated in most of the LC units. (5) More than 90% of the LC unit respond to chronic MPD exposure and the majority of them by decrease their firing rate compared to the initial MPD effect. (6) The neuronal response to acute and chronic MPD recorded from animals expressing behavioral sensitization was significant difference from the LC units recorded from animals that expressed behavioral tolerance. Results indicated that the LC neuronal activities may contribute to the expression of behavioral sensitization and tolerance induced by chronic MPD administration and suggested that it is essential to record the animal’s behavioral responses concomitantly with the LC neuronal activity events.

The nucleus accumbens (NAc) has been shown to play a key role in the brain's response to methylphenidate (MPD). The present study focuses on neuronal recording from this structure. The study postulates that repetitive exposure to the same dose of MPD will elicit in some rats behavioral sensitization and in others tolerance. Furthermore, the study postulates that NAc neuronal activity recorded from animals expressing behavioral tolerance after repetitive MPD exposure will be significantly different from NAc neuronal activity recorded from animals expressing behavioral sensitization after repetitive MPD exposure at doses of 0.6, 2.5, 5.0, and 10.0 mg/kg. To test this, behavioral and neuronal activity was recorded concomitantly from the NAc of freely behaving adolescent rats (postnatal day 40) before and after acute and repetitive administration of four different MPD doses. Comparing the acute MPD effect to the repetitive MPD effect revealed that the acute response to MPD exhibited dose-response characteristics: an increase in behavioral activity correlated with increasing MPD doses. On the other hand, following repetitive MPD exposure, some animals exhibited attenuated behavior (tolerance), while others exhibited further increases in the recorded behavior (sensitization). Moreover, the neuronal activity following repetitive MPD exposure recorded in animals exhibiting behavioral sensitization was significantly different from neuronal activity recorded in animals exhibiting behavioral tolerance. This implies that when studying the effects of repetitive MPD administration on adolescent rats, it is advisable to simultaneously record both neuronal and behavioral activity and to evaluate all data based on the animals' behavioral response to the repetitive MPD exposure.

Psychostimulants such as methylphenidate (MPD) have long been the treatment of choice in behavioral disorders such as attention deficit/hyperactivity disorder (ADHD) and narcolepsy in both children and adults. However, its abuse by healthy children and adults for academic enhancement or recreation is on the rise. This raises concern for brain chemistry alteration leading to dependence during a period of neuroplasticity and brain development. Psychostimulants such as MPD are indirect dopamine antagonists and are known to act on the dopaminergic system of the brain to produce their effects. The ventral tegmental area (VTA) is one of the primary sources of dopamine in the CNS and is a part of the reward circuits affected by MPD. In order to elucidate the role of the VTA in MPD exposure, five groups of rats were used: VTA intact control, sham VTA surgery, nonspecific electrolytic VTA lesion, glutamatergic specific VTA chemical lesion, and dopaminergic specific VTA chemical lesion. Baseline locomotor activity was established, then the surgeries were performed followed by several days of recovery and establishment of post-surgical baseline. Following the recovery period, the rats were challenged with 6 days of MPD exposure, followed by 3 washout days, then a re-challenge of MPD to assess chronic MPD exposure on animals behavior. Locomotive activity was recorded for 120 min after each injection by a computerized animal activity monitor system. The results indicate that glutamatergic synapses in the ventral tegmental area are critical for acute and chronic MPD response, while dopaminergic synapses contribute to tonic inhibition of the ventral tegmental area on rat locomotor excitation.

Acute and chronic methylphenidate (MPD) exposure was recorded simultaneously for the rat's locomotor activity and the nucleus accumbens (NAc) neuronal activity. The evaluation of the neuronal events was based on the animal's behavior response to chronic MPD administration: 1) Animals exhibiting behavioral sensitization, 2) Animals exhibiting behavioral tolerance. The experiment lasted for 10days with four groups of animals; saline, 0.6, 2.5, and 10.0mg/kg MPD. For the main behavioral findings, about half of the animals exhibited behavioral sensitization or behavioral tolerance to 0.6, 2.5, and/or 10mg/kg MPD respectively. Three hundred and forty one NAc neuronal units were evaluated. Approximately 80% of NAc units responded to 0.6, 2.5, and 10.0mg/kg MPD. When the neuronal activity was analyzed based on the animals' behavioral response to chronic MPD exposure, significant differences were seen between the neuronal population responses recorded from animals that expressed behavioral sensitization when compared to the NAc neuronal responses recorded from animals exhibiting behavioral tolerance. Three types of neurophysiological sensitization and neurophysiological tolerance can be recognized following chronic MPD administration to the neuronal populations. Collectively, these findings show that the same dose of chronic MPD can elicit either behavioral tolerance or behavioral sensitization. Differential statistical analyses were used to verify our hypothesis that the neuronal activity recorded from animals exhibiting behavioral sensitization will respond differently to MPD compared to those animals exhibiting behavioral tolerance, thus, suggesting that it is essential to record the animal's behavior concomitantly with neuronal recordings.

Methylphenidate (MPD) is a widely prescribed psychostimulant for the treatment of attention deficit hyperactivity disorder, and is growing in use as a recreational drug and academic enhancer. MPD acts on the reward/motive and motor circuits of the CNS to produce its effects on behavior. The caudate nucleus (CN) is known to be a part of these circuits, so a lesion study was designed to elucidate the role of the CN in response to acute and chronic MPD exposure. Five groups of n = 8 rats were used: control, sham CN lesions, non-specific electrolytic CN lesions, dopaminergic-specific (6-OHDA toxin) CN lesion, and glutaminergic-specific (ibotenic acid toxin) CN lesions. On experimental day (ED) 1, all groups received saline injections. On ED 2, surgeries took place, followed by a 5-day recovery period (ED 3–7). Groups then received six daily MPD 2.5 mg/kg injections (ED 9–14), then three days of washout with no injection (ED 15–17), followed by a re-challenge with the previous 2.5 mg/kg MPD dose (ED 18). Locomotive activity was recorded for 60 min after each injection by a computerized animal activity monitor. The electrolytic CN lesion group responded to the MPD acute and chronic exposures similarly to the control and sham groups, showing an increase in locomotive activity, i.e. sensitization. The dopaminergic-specific CN lesion group failed to respond to MPD exposure both acute and chronically. The glutaminergic-specific CN lesion group responded to MPD exposure acutely but failed to manifest chronic effects. This confirms the CN's dopaminergic system is necessary for MPD to manifest its acute and chronic effects on behavior, and demonstrates that the CN's glutaminergic system is necessary for the chronic effects of MPD such as sensitization. Thus, the dopaminergic and glutaminergic components of the CN play a significant role in differentially modulating the acute and chronic effects of MPD respectively.

Methylphenidate (MPD), known as Ritalin, is a common drug prescribed for those diagnosed with Attention Deficit Hyperactivity Disorder (ADHD).There are reports that many MPD users consume alcohol, resulting in toxic effects and hospitalization. The goal of this study was to investigate the effects of ethanol in rats concomitant with acute and repetitive MPD exposure. Rats were divided into four groups, control (saline), 0.6 mg/kg MPD, 2.5 mg/kg MPD, and 10.0 mg/kg MPD groups and lasted for 12 consecutive days. Ethanol was given after repeated MPD administration as follows. On experimental day 1 (ED 1), all animals were treated with saline to establish baseline, on ED 2 through ED 7 either saline or MPD (0.6, 2.5, or 10.0 mg/kg) was given. On ED 11, after three days without treatment (ED 8 - 10), rats were treated as they were on ED 2 - 7. At ED 12, 1 g/kg ethanol was administered, and one hour of locomotor activity was recorded after alcohol administration, using the open field assay. The data show a dose response characteristic of increased locomotor activity with increasing doses of MPD. Ethanol administration alone depresses locomotor activity. The depressive effect of alcohol was significantly attenuated in animals treated with MPD, in a dose dependent manner. The higher dose of MPD previously administered resulted in a larger attenuation of the ethanol’s suppressive effect. These trends demonstrate that chronic MPD exposure directly influences the effects of alcohol in rats. Under these circumstances, it is reasonable to assume that a subject will need to consume an increased amount of ethanol in order to attain the ethanol effect desired. This discrepancy between effects and exposure may be a liability for ethanol toxicity.

There are no reports on the effect of amphetamine on female WKY circadian activity pattern. The objective of this study is to investigate whether repeated daily exposure to the psychostimulant amphetamine alters the locomotor circadian rhythm activity patterns of female adult Wistar-Kyoto (WKY) rats. Twenty-four rats were divided into two groups, control (N = 12) and experimental (N = 12), and kept in a 12:12 h light/dark cycle in an open field cage. After 5 to 7 days of acclimation, 11 days of consecutive non-stop recordings began. On experimental day 1, all groups were given an injection of saline. On experimental days 2 to 7, the experimental group was injected with 0.6 mg/kg amphetamine and the control group with saline followed by a washout phase from experimental day 8 to 10, and amphetamine re-challenge or saline on experimental day 11 similar to experimental day 2. Locomotor movements were determined using a computerized animal activity monitoring system, and cosine statistical analysis was used to fit a24-hour curve to the activity pattern. The horizontal activity (HA), total distance (TD), number of stereotypy (NOS), and stereotypical movements (SM) were analyzed for alterations in the circadian rhythm activity patterns. The data demonstrated that chronic amphetamine administration alters the mesor parameter of the circadian rhythm activity patterns, indicating that chronic amphetamine treatment exerts long term effects on these rats.

The effects of chronic cocaine administration on the locomotor rhythmic patterns of adult female Sprague-Dawley (SD) rats were recorded using an open-field testing assay. The animals were divided into four groups, control (saline), 3.0 mg/kg, 7.5 mg/kg, and 15.0 mg/kg i.p. cocaine group respectively. On experimental day (ED 1), all animals were treated with saline. On ED 2 to ED 7, either saline or cocaine (3.0, 7.5, or 15.0 mg/kg i.p.) was given followed by three days of no treatment (ED 8 to ED 10). On ED 11, rats were treated as they were on ED 2 to ED 7, i.e. either saline, 3.0, 7.5, or 15.0 mg/kg i.p. cocaine. The locomotor activities of rats were recorded for 23 hours daily, allowing one hour for the animal handling and injections, using open field cages with 16 infrared beams of motion detectors. Any breakages of these beams due to the movement of the animals were recorded and compiled by a computer and analyzed. It was observed that all three doses of repeated cocaine administration (3.0 mg/kg, 7.5 mg/kg, and 15.0 mg/kg i.p. cocaine) significantly alter the locomotor rhythmic activity patterns of the adult female SD rats, which suggest that repeated cocaine exposure modulates body homeostasis.

Methylphenidate (MPD) is considered as the first-line pharmacotherapy to treat ADHD. More recently, MPD has also been used as a cognitive enhancement recreationally. Its therapeutic effects are not fully understood, nor are the long term effects of the drug on brain development. The ventral tegmental area (VTA) neuronal activity was recorded from freely behaving adolescent rats using a wireless recording system. Five groups were used: saline, 0.6, 2.5, 5.0 and 10.0 mg/kg MPD. The experiment lasted for 10 days. This study demonstrated that VTA neurons respond to MPD in a dose response characteristic and the same dose of MPD can cause both behavioral sensitization and behavioral tolerance. The neuronal unit activity was evaluated based on the animals’ behavioral activity following chronic MPD administration. The study showed that the animals’ behavioral response to different acute MPD of 0.6, 2.5 and 10.0 mg/kg doses responded in a dose response characteristics. Moreover, the same chronic dose of 0.6, 2.5, and 10.0 mg/kg MPD elicits in some animals’ behavioral sensitization and in some others behavioral tolerance. Therefore, the neuronal activity recorded from animals expressing behavioral sensitization was analyzed separately from the neuronal activity recorded from of behaviorally tolerant animals and it was found that the VTA units of the behaviorally sensitization animals responded significantly different to the drug than those VTA units recorded from animals expressing behavioral tolerance.

Methylphenidate (MPD) is one of the most prescribed pharmacological agents and also used as cognitive enhancement and for recreational purposes. The objective of this study was to investigate the repetitive dose-response effects of MPD on rhythm locomotor activity pattern of female WKY rats and compare to prior study done on male. The hypothesis is that change in the circadian activity pattern indicates a long-lasting effect of the drug. Four animal groups (saline control, 0.6, 2.5, and 10.0 mg/kg MPD dose groups) were housed in a sound-controlled room at 12:12 light/dark cycle. All received saline injections on experimental day 1 (ED 1). On EDs 2-7, the control group received saline injection; the other groups received 0.6, 2.5, or 10.0 mg/kg MPD, respectively. On ED 8-10, injections were withheld. On ED 11, each group received the same dose as EDs 2-7. Hourly histograms and cosine statistical analyses calculating the acrophase (ϕ), amplitude (A), and MESOR (M) were applied to assess the 24-hour circadian activity pattern. The 0.6 and 2.5 mg/kg MPD groups exhibited significant (p

Methylphenidate (MPD), also known as Ritalin, is a psychostimulant used to treat attention deficit hyperactivity disorder. However, it is increasingly being misused by normal adolescents for recreation and academic advantage. Therefore, it is important to elucidate the behavioral and neurophysiological effects of MPD in normal subjects. MPD inhibits the reuptake of catecholamines, mainly found in the ventral tegmental area (VTA) and locus coeruleus (LC). The VTA and LC normally mediate attention, motivation, and drug reward behaviors. Selective neuronal connections between the VTA and LC have been identified implicating regular interaction between the structures. The objective of this study was to compare the neuronal responses of the VTA and LC to MPD in normal adolescent rats. Animals were implanted with permanent electrodes in the VTA and LC, and neuronal units were recorded following acute and repetitive (chronic) saline or 0.6, 2.5, or 10.0 mg/kg MPD exposure. Animals displayed either behavioral sensitization or tolerance to all three doses of MPD. Acute MPD exposure elicited excitation in the majority of all VTA and LC units. Chronic MPD exposure elicited a further increase in VTA and LC neuronal activity in animals exhibiting behavioral sensitization and an attenuation in VTA and LC neuronal activity in animals exhibiting behavioral tolerance, demonstrating neurophysiological sensitization and tolerance, respectively. The similar pattern in VTA and LC unit activity suggests that the two structures are linked in their response to MPD. These results may help determine the exact mechanism of action of MPD, resulting in optimized treatment of patients. NEW & NOTEWORTHY The same dose of 0.6, 2.5, and 10 mg/kg methylphenidate (MPD) elicits either behavioral sensitization or tolerance in adolescent rats. There is a direct correlation between the ventral tegmental area (VTA) and locus coeruleus (LC) neuronal response to chronic MPD exposure. Both the VTA and LC are involved in the behavioral and neurophysiological effects of chronic MPD.

Cocaine is one of well-known drugs of abuse, and many children experience early exposure to cocaine. Because of an immature neuronal system in adolescents, they may react differently to repeated cocaine administration compared to adults. Most of the published papers report the effect of cocaine on adult male rats and this paper focused on the effects of cocaine on the 24 h locomotor activity rhythm patterns activity of adolescent Sprague Dawley (SD) female rats. Changes in the locomotor activity rhythm patterns could indicate that cocaine elicits long-term changes in the clock genes of the body that regulate different physiological processes. The objective of this study was to investigate whether cocaine in adolescent female rats modulated their daily activity pattern. Animals were divided into control (saline), 3.0, 7.5, 15.0 mg/kg cocaine groups. On experimental day 1 (ED 1), all groups were given saline injection. From ED 2 to ED 7, either saline or cocaine (3.0, 7.5, or 15.0 mg/kg) was given daily. ED 8 to ED 10 were the washout days, where no injection was given. On ED 11, the animals were injected with saline or with the same dose of cocaine as they were treated on ED 2 to ED 7. Each animal’s locomotor activities was recorded nonstop following saline or cocaine injection for 11 consecutive days using the open field assay. In conclusion, it was observed that all three groups receiving repeated cocaine administration (3.0, 7.5, and 15.0 mg/kg) displayed significantly altered locomotor activity rhythm patterns.

Methylphenidate (MPD) is a widely prescribed psychostimulants used for the treatment of attention deficit hyperactive disorder (ADHD). Unlike the psychostimulants cocaine and amphetamine, MPD does not exhibit direct actions on the serotonin transporter, however there is evidence suggesting that the therapeutic effects of MPD may be mediated in part by alterations in serotonin transmission. This study aimed to investigate the role of the dorsal raphe (DR) nucleus, one of the major sources of serotonergic innervation in the mammalian brain, in the response to MPD exposure. Freely behaving adolescent rats previously implanted bilaterally with permanent electrodes were used. An open field assay and a wireless neuronal recording system were used to concomitantly record behavioral and DR electrophysiological activity following acute and chronic MPD exposure. Four groups were used: one control (saline) and three experimental groups treated with 0.6, 2.5, and 10.0 mg/kg MPD respectively. Animals received daily MPD or saline injections on experimental days 1–6, followed by 3 washout days and MPD rechallenge dose on experimental day (ED)10. The same chronic dose of MPD resulted in either behavioral sensitization or tolerance, and we found that neuronal activity recorded from the DR neuronal units of rats expressing behavioral sensitization to chronic MPD exposure responded significantly differently to MPD rechallenge on ED10 compared to the DR unit activity recorded from animals that expressed behavioral tolerance. This correlation between behavioral response and DR neuronal activity following chronic MPD exposure provides evidence that the DR is involved in the acute effects as well as the chronic effects of MPD in adolescent rats.

Catherine M Claussen, Lindsey J Witte, Nachum Dafny Department of Neurobiology and Anatomy, The University of Texas Health Science Center Medical School at Houston, Houston, TX, USA Abstract: Methylphenidate (MPD) is a readily prescribed drug for the treatment of attention deficit hyperactivity disorder (ADHD) and moreover is used illicitly by youths for its cognitive-enhancing effects and recreation. MPD exposure in rodents elicits increased locomotor activity. Repetitive MPD exposure leads to further augmentation of their locomotor activity. This behavioral response is referred to as behavioral sensitization. Behavioral sensitization is used as an experimental marker for a drug’s ability to elicit dependence. There is evidence that dopamine (DA) is a key player in the acute and chronic MPD effect; however, the role of DA in the effects elicited by MPD is still debated. The objective of this study was to investigate the role of D1 and/or D2 DA receptors in the acute and chronic effect of MPD on locomotor activity. The study lasted for 12 consecutive days. Seven groups of male Sprague Dawley® rats were used. A single D1 or D2 antagonist was given before and after acute and chronic MPD administration. Single injection of D1 DA antagonist was able to significantly attenuate the locomotor activity when given prior to the initial MPD exposure and after repetitive MPD exposure, while the D2 DA antagonist partially attenuated the locomotor activity only when given before the second MPD exposure. The results show the role, at least in part, of the D1 DA receptor in the mechanism of behavioral sensitization, whereas the D2 DA receptor only partially modulates the response to acute and chronic MPD. Keywords: behavior, Ritalin, dopamine anatagonist, behavioral sensitization&nbsp

The electrophysiological properties of the locus coeruleus (LC) neurons in response to acute and chronic administration of methylphenidate (MPD) were investigated. The extracellular LC neuronal activities were recorded from non-anesthetized, freely behaving rats previously implanted bilaterally with permanent semi microelectrodes. The main findings were: (1) On experimental day 1 (ED1), 87% (94/108) of LC units significantly changed their firing rate after initial (acute) MPD (2.5 mg/kg, i.p.) administration. The majority of the responsive units (80%, 75/94) increased their firing rate; (2) Daily MPD (2.5 mg/kg) injection was given on ED2 through ED6 followed by 3 washout days (ED7 to 9). On ED10, all LC units exhibited a significant change of their baseline activity compared to their baseline activity on ED1; (3) MPD rechallenge on ED10 elicits 94% (101/108) of LC units significantly changed their firing rate; the majority of them (78%, 79/101) increased their firing rate; (4) The effect of rechallenge MPD administration on ED10 were compared to the effect of initial MPD on ED1, 98% of the LC units exhibited a significant change in their firing rate. 41% (43/106) of them exhibited a significant increase in their firing rate while 59% (63/106) units significantly decreased their firing rate which can be interpreted as electrophysiological sensitization or tolerance respectively. In conclusion, the majority of LC neurons significantly increased their firing rate after acute and chronic MPD administration. This data demonstrated that enhanced LC neuronal activities play important role in the effect of MPD.

In mammals, there is an underlying mechanism that dictates the organism's biological functions and daily activity schedule, known as circadian rhythms, which play a major role in maintaining steady metabolism, homeostasis, and immunity. Limited research has been done investigating the effects of continuous opiate administration on the circadian rhythm activity pattern. A change in circadian activity pattern is suggested as an experimental model to demonstrate long-term effect of the drug. The objective of this study was to investigate the effects of morphine treatment on the long term activity (24 h) of the animal as well as the activity after abrupt removal, since prescribed medication containing morphine is widely used and abused and its long term effects are not known. Male Sprague–Dawley rats were contained in stable conditions with a standard light/dark cycle recordings taken before, during and after morphine pellet implantation. Cosinor analysis was used to fit a 24-hour curve to the activity pattern. Results indicate that morphine pellet administration alters the mesor, amplitude, the day-time and night-time activity levels, and demonstrates a remarkable change in the maximal circadian rhythm timing during the withdrawal period. The question whether morphine changes the circadian rhythm or a change in circadian rhythm results in tolerance and withdrawal is discussed.

The psychostimulant methylphenidate (MPD) is currently the most prescribed drug therapy for attention deficit hyperactivity disorder (ADHD) and is used by students as a cognitive enhancer. The caudate nucleus (CN) is a structure within the motive circuit where MPD exerts its effects, it is known to contain high levels of dopaminergic cells and directly influence motor activity. The objective of this study was to understand the role of CN in response to acute and chronic administration of MPD. Specific and non-specific bilateral ablations were created in the CN using electrolytic lesion and 6-Hydoxydopamine (6-OHDA). Four groups of rats were used: control (n = 4), sham (n = 4), CN electrolytic lesion group (n = 8) and CN 6-OHDA injected group (n = 8). On experimental day one (ED 1) all rats received a saline injection and baseline locomotive activity was recorded. On ED 2 and ED 3 CN sham, electrolytic lesion and/or 6-OHDA injected groups were made followed by four to five days recovery (ED 3–7), followed by six daily 2.5 mg/kg MPD injections (ED 9–14), three days of washout (ED 15–17) and an MPD re-challenge of drug proceeding the washout days (ED 18). Locomotor activity was obtained at ED 1, 8, 9, and 18 using an open field assay. The results show that the CN electrolytic lesion group responded to the acute and chronic MPD administration similar to the control and sham group, while the CN 6-OHDA injected group prevented the acute and the chronic effects of MPD administration. One possible interpretation why nonspecific electroyltic lesioning of the CN failed to prevent acute and chronic effects of MPD administration is due to destruction of both the direct and the indirect CN pathways which act as an inhibitory/excitatory balance, electroylticelectroyltic. The selective dopaminergic lesioning prevented the effects of MPD administration suggesting that dopaminergic pathways in CN play a significant role in the effects of MPD.

Today's students around the world are striking deals to buy and sell the drug methylphenidate (MPD) for cognitive enhancement. Our knowledge on the effects of MPD on the brain is very limited. The present study was designed to investigate the acute and chronic effect of MPD on the prefrontal cortex (PFC) neurons. On experimental day 1 (ED1) recordings were obtained following saline injections and after 2.5 mg/kg MPD. On ED2 through ED6, daily single 2.5 mg/kg MPD was given followed by 3 washout days (ED7 to 9). On ED10, neuronal recordings were resumed from the same animal after saline and MPD injection similar to that obtained at ED1. Ninety PFC units were recorded, all responded to the initial MPD injection, 66 units (73%) increased their activity at ED10. Recordings were resumed for the 66 units that increased their firing rate at ED1, and following MPD injection 54 units (82%) exhibited significant increases in their baseline firing rates compared to ED1 baseline. When these 54 units were rechallenged (chronic effect) with MPD, 39/54 (72%) exhibited reduction in their firing rate which can be interpreted as tolerance. From the 24 (27%) units that responded to MPD at ED1 by decreasing their activity, 14 units (58%) exhibited a decrease in their baseline firing rates at ED10 compared to ED1 baseline. However, following MPD rechallenge of these 14 units, 11 units (79%) exhibited an increase in their firing rate which is interpreted as sensitization. In conclusion, all PFC units modified their neural baseline activity.

Methylphenidate (MPD) is a psychostimulant that enhances dopaminergic neurotransmission in the central nervous system by using mechanisms similar to cocaine and amphetamine. The mode of action of brain circuitry responsible for an animal’s neuronal response to MPD is not fully understood. The nucleus accumbens (NAc) has been implicated in regulating the rewarding effects of psychostimulants. The present study used permanently implanted microelectrodes to investigate the acute and chronic effects of MPD on the firing rates of NAc neuronal units in freely behaving rats. On experimental day 1 (ED1), following a saline injection (control), a 30 minute baseline neuronal recording was obtained immediately followed by a 2.5 mg/kg i.p. MPD injection and subsequent 60 min neuronal recording. Daily 2.5 mg/kg MPD injections were given on ED2 through ED6 followed by 3 washout days (ED7 to 9). On ED10, neuronal recordings were resumed from the same animal after a saline and MPD (rechallenge) injection exactly as obtained on ED1. Sixty-seven NAc neuronal units exhibited similar wave shape, form and amplitude on ED1 and ED10 and their firing rates were used for analysis. MPD administration on ED1 elicited firing rate increases and decreases in 54% of NAc units when compared to their baselines. Six consecutive MPD administrations altered the neuronal baseline firing rates of 85% of NAc units. MPD rechallenge on ED10 elicited significant changes in 63% of NAc units. These alterations in firing rates are hypothesized to be through mechanisms that include D1 and D2-like DA receptor induced cellular adaptation and homeostatic adaptations/deregulation caused by acute and chronic MPD administration.

Methylphenidate (MPD) is the most widely used drug in the treatment of attention-deficit hyperactivity disorder (ADHD). ADHD has a high incidence in children and can persist in adolescence and adulthood. The relation between sex and the effects of acute and chronic MPD treatment was examined using adolescent male and female rats from three genetically different strains: spontaneously hyperactive rat (SHR), Wistar-Kyoto (WKY) and Sprague-Dawley (SD). Rats from each strain and sex were randomly divided into a control group that received saline injections and three MPD groups that received either 0.6 or 2.5 or 10 mg/kg MPD injections. All rats received saline on experimental day 1 (ED1). On ED2 to ED7 and ED11, the rats were injected either with saline or MPD and received no treatment on ED8 to ED10. The open field assay was used to assess the dose response of acute and chronic MPD administration. Significant sex differences were found. Female SHR and SD rats were significantly more active after MPD injections than their male counterparts, while the female WKY rats were less active than the male WKY rats. Dose dependent behavioral sensitization or tolerance to MPD treatment was not observed for SHR or SD rats, but tolerance to MPD was found in WKY rats for the 10 mg/kg MPD dose. The use of dose response protocol and evaluating different locomotor indices provides the means to indentify differences between the sexes and the genetic strain in adolescent rats. In addition these differences suggest that the differences to MPD treatment between the sexes are not due to the reproductive hormones.

Circadian pattern of activity regulates many aspects of mammalian physiology and behavior to particular times of the day by entraining the circadian clocks to external environmental signals. Since circadian rhythms are sensitive to many pharmacological agents, it is important to understand if the repetitive use of psychostimulants such as amphetamine will alter the circadian rhythm behavioral activity pattern. The present study uses male Sprague–Dawley rats to study the long-term effects of amphetamine on the locomotor circadian rhythm activity pattern. Rats were randomly assigned to a testing cage that recorded their locomotor activity nonstop for eleven days using the open field assay, as follows: one day of baseline activity was recorded and then the experimental group was injected with amphetamine (0.6 mg/kg) for 6 days, no treatment for 3 days (i.e., washout days) and then re-challenged with amphetamine for one more day while the control group was treated similarly with saline. The Cosine Curve Statistical Analysis (CCSA) test was used to fit a 24-hour curve to activity pattern. Results indicate that repetitive daily amphetamine injections cause behavioral sensitization and a significant change of circadian rhythm of locomotor activity pattern, and elicit behavioral expectation to receive the drug or expression of withdrawal during the washout days. The results suggest that either changes in circadian rhythm caused sensitization and withdrawal or sensitization and withdrawal caused the change in circadian rhythm activity.

The psychostimulant methylphenidate (MPD, Ritalin) is the prescribed drug of choice for treatment of ADHD. In recent years, the diagnosis rate of ADHD has increased dramatically, as have the number of MPD prescriptions. Repeated exposure to psychostimulants produces behavioral sensitization in rats, an experimental indicator of a drug’s potential liability. In studies on cocaine and amphetamine, this effect has been reported to involve the nucleus accumbens (NAc), one of the nuclei belonging to the motive circuit. The aim of this study was to investigate the role of the NAc on the expression of behavioral sensitization as a response to MPD exposure. In the present study, 20 male Sprague-Dawley rats were divided randomly into three groups: an intact control group, a sham operated group, and a NAc bilateral electrical lesion group. Locomotor activity was assessed for the first two hours following 2.5 mg/kg MPD injection, using open field monitoring systems. Recordings were made during six days of continuous MPD administration, and then upon re-challenge with the same dose following three days of washout. Acute MPD exposure elicited an increase in locomotor activity in all three groups. However, the NAc lesion group exhibited significantly increased locomotor activity in comparison to sham and control groups. Chronic MPD did not elicit sensitization in the NAc lesion group, while both sham and control groups did exhibit behavioral sensitization to repetitive MPD administration. These findings suggest that the NAc plays a significant role in eliciting locomotor activity as an acute effect of MPD, and in the expression of sensitization due to chronic MPD exposure.

Acute and chronic methylphenidate (MPD) were given to adults treated with MPD only in adulthood (adult I) and to adults that had been treated repeatedly during adolescence and adulthood (adult II). Two locomotor activity assays, the open field and the running wheel, were used in a dose response experiment to assess whether methylphenidate (MPD) treatment during adolescence would affect responses to MPD in adulthood. Each experiment lasted 11 days as follows: saline control on experimental day 1 (ED 1), followed by a single daily dose of saline, 0.6, 2.5, or 10 mg/kg MPD for 6 days (ED 2 to ED 7), 3 washout days with no drug administration (ED 8 to ED 10), and saline or MPD challenge on ED 11 at a dose identical to that given on ED 2 to ED 7. Acute MPD elicited characteristic dose response increases in locomotion in both experimental assays of adult I and adult II groups. Adult I and adult II rats tested in the open field assay exhibited sensitization to 2.5 mg/kg MPD and tolerance to 10 mg/kg MPD, while in the wheel-running assay all the three MPD doses elicited sensitization in both adult I and adult II rats. MPD treatment in adolescence did not change the baseline activity when animal reached adulthood. However, the responses to MPD in adult II rat groups were significantly different from the adult I group. Similar observations were noted during washout days. At the low and moderate MPD treatment both experimental assay exhibited similar observations while following the high dose of MPD treatment, the open field assay indicated that tolerance to MPD was expressed, while the wheel-running assay indicated that behavioral sensitization was developed. The distinction between the two assays and adult I and II differences are discussed.

Progressive augmentation of behavioral response following repeated psychostimulant administrations is known as behavioral sensitization, and is an indicator of a drug’s liability for abuse. It is known that methylphenidate (MPD) (also known as Ritalin), a drug used to treat Attention-Deficit Hyperactivity Disorder (ADHD), induces sensitization in animals following repeated injections. It was recently reported that bilateral electric (non-specific) lesion of prefrontal cortex (PFC) prevented MPD elicited behavioral sensitization. Since PFC sends glutamatergic afferents to both ventral tegmental area (VTA) and nucleus accumbens (NAc), sites that are involved in induction and expression of behavioral sensitization respectively and glutamate from PFC is known to modulate dopamine cell activity in VTA and NAc, this study investigated the role of descending glutamate from PFC in MPD elicited behavioral sensitization. Locomotor activity of three groups of rats- control, sham operated and group with specific chemical lesion of glutamate neurons of PFC- was recorded using an open-field assay. On experimental day (ED) 1, the locomotor activity was recorded post a saline injection. The sham and lesion groups underwent respective surgeries on ED 2, and were allowed to recover for five days (from ED 3 to ED 7). The post-surgery baseline was recorded on ED 8 following a saline injection. On ED’s 9 through 14, 2.5 mg/kg MPD was given, followed by a four day washout period (ED 15 –18). All three groups received a rechallenge injection of 2.5 mg/kg on ED 19 and their locomotor activity on various days was analyzed. It was found that ibotenic acid lesion modulated the acute and chronic effects of MPD and hence suggests that PFC glutamatergic afferents are involved in the acute effect of MPD as well as in its chronic effects such as behavioral sensitization to MPD.

Methylphenidate (MPD) is becoming a drug of abuse among adult professionals and students, alike. Yet, few studies have investigated its long-term effects on the adult population. We hypothesized that prolonged administration of MPD leads to changes in the diurnal horizontal activity (HA) pattern, an effect persisting beyond acute drug effects. Four groups of adult male Sprague-Dawley rats (N=32) were divided into a saline/control, 0.6, 2.5, or 10.0 mg/kg MPD group. Each group was treated with saline on experimental day 1, followed by six consecutive days of designated treatment (days 2-7), then, after three consecutive days of washout (days 8-10), each group was re-challenged with its respective treatment (day 11). Activity was monitored continuously throughout the 11 experimental days. There was a dose-dependent increase in HA in the first hour post-injection. The 0.6 mg/kg MPD group exhibited changes in diurnal activity pattern only during the wash-out period. The 2.5 mg/kg MPD group exhibited the most profound changes in HA after 6 days of continuous injection, washout, and MPD re-challenge (p0.05, p=0.001, p0.001) respectively, and the 10.0 mg/kg MPD group exhibited changes during the washout and re-challenge periods (p0.01, p0.001), respectively. In conclusion, prolonged administration of MPD modulated the diurnal HA pattern in a dose-dependent manner.

Eight groups of male adolescent and adult spontaneous hyperactive rats (SHR) were used in a dose response (saline, 0.6, 2.5, and 10 mg/kg) experiment of methylphenidate (MPD). Four different locomotor indices were recorded for 2 hours postinjection using a computerized monitoring system. Acutely, the 0.6 mg/kg dose of MPD did not elicit an increase in locomotor activity in either the adolescent or in the adult male SHR. The 2.5 and the 10.0 mg/kg doses increased activity in the adolescent and the adult rats. Chronically, MPD treatment when comparing adolescent and adult gave the following results: the 0.6 mg/kg dose of MPD failed to cause sensitization in the adolescent group but caused sensitization in the adult group, while the 2.5 and 10 mg/kg both caused sensitization in the adolescent and adult groups.

Methylphenidate (MPD) is a psychostimulant drug therapy mainly prescribed for attention deficient hyperactivity disorder (ADHD). Dopamine imbalances in neuronal circuits such as the mesocorticolimbic system involving the ventral tegmental area (VTA) are responsible for the behaviors observed in ADHD. This chapter explores the current literature on the anatomical, molecular, and electrophysiological changes observed in VTA upon MPD administration in rodents. Specifically, we will discuss the phenomenon that the same dose of MPD can lead to either behavioral and neurophysiological sensitization or tolerance among individual rodents.

The young and adults are treated repeatedly for prolonged periods of time with methylphenidate (MPD) as a pharmacotherapy of choice for attention deficit disorder and attention deficit hyperactivity disorder. The dilemma is whether prolonged use of psychostimulants and drug therapy starting at a young age has any unwanted effects. This chapter will review the pharmacology of MPD, the dose of MPD exposure in animal studies, the route of MPD exposure, gender differences in response to MPD, and the property of repetitive MPD on animal behavior, such as behavioral sensitization and cross-sensitization with other stimulants.