Pamela B. Yang

The role of age, genotype, sex, and route of acute and chronic administration of methylphenidate : A review of its locomotor effects

Children with attention deficit hyperactivity disorder (ADHD) are treated for extended periods of time with the psychostimulant methylphenidate (MPD). The psychostimulants cocaine, amphetamine, and MPD exhibit similar structural configuration and pharmacological profile. The consequence of the long-term use of psychostimulants such as MPD as treatment for ADHD in the developing brain of children is unknown. Repeated treatment with psychostimulants has been shown to elicit adverse effects in behavior, such as dependence, paranoia, schizophrenia, and behavioral sensitization. Behavioral sensitization and cross-sensitization between two drugs are used as experimental markers to determine the potential of a drug to develop dependence/addiction. Although there are many reviews written about behavioral sensitization involving psychostimulants, scarcely any have focused specifically on MPD-elicited behavioral sensitization and cross-sensitization with other psychostimulants. Moreover, the response to MPD and the expression of ADHD vary among females and males and among different populations due to genetic variability. Since the interpretation and synthesis of the data reported are controversial, this review focuses on the adverse effects of MPD and the role of age, sex, and genetic composition on the acute and chronic effects of MPD, such as MPD-elicited behavioral sensitization and cross-sensitization with amphetamine in animal models. Animal models of drug-induced locomotor stimulation, particularly locomotor sensitization, can be used to understand the mechanisms underlying human drug-induced dependence.

Chronic exposure to MDMA (Ecstasy) elicits behavioral sensitization in rats but fails to induce cross-sensitization to other psychostimulants

BackgroundThe recreational use of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) among adolescents and young adults has become increasingly prevalent in recent years. While evidence suggests that the long-term consequences of MDMA use include neurodegeneration to serotonergic and, possibly, dopaminergic pathways, little is known about susceptibility, such as behavioral sensitization, to MDMA.MethodsThe objectives of this study were to examine the dose-response characteristics of acute and chronic MDMA administration in rats and to determine whether MDMA elicits behavioral sensitization and whether it cross-sensitizes with amphetamine and methylphenidate. Adult male Sprague-Dawley rats were randomly divided into three MDMA dosage groups (2.5 mg/kg, 5.0 mg/kg, and 10.0 mg/kg) and a saline control group (N = 9/group). All three MDMA groups were treated for six consecutive days, followed by a 5-day washout, and subsequently re-challenged with their respective doses of MDMA (day 13). Rats were then given an additional 25-day washout period, and re-challenged (day 38) with similar MDMA doses as before followed by either 0.6 mg/kg amphetamine or 2.5 mg/kg methylphenidate on the next day (day 39). Open-field locomotor activity was recorded using a computerized automated activity monitoring system.ResultsAcute injection of 2.5 mg/kg MDMA showed no significant difference in locomotor activity from rats given saline (control group), while animals receiving acute 5.0 mg/kg or 10.0 mg/kg MDMA showed significant increases in locomotor activity. Rats treated chronically with 5.0 mg/kg and 10.0 mg/kg MDMA doses exhibited an augmented response, i.e., behavioral sensitization, on experimental day 13 in at least one locomotor index. On experimental day 38, all three MDMA groups demonstrated sensitization to MDMA in at least one locomotor index. Amphetamine and methylphenidate administration to MDMA-sensitized animals did not elicit any significant change in locomotor activity compared to control animals.ConclusionMDMA sensitized to its own locomotor activating effects but did not elicit any cross-sensitization with amphetamine or methylphenidate.

Acute and chronic methylphenidate dose-response assessment on three adolescent male rat strains.

Methylphenidate (MPD), commonly known as Ritalin, is the most frequently prescribed drug to treat children and adults with attention deficit hyperactivity disorder (ADHD). Adolescence is a period of development involving numerous neuroplasticities throughout the central nervous system (CNS). Exposure to a psychostimulant such as MPD during this crucial period of neurodevelopment may cause transient or permanent changes in the CNS. Genetic variability may also influence these differences. Thus, the objective of the present study was to determine whether acute and chronic administration of MPD (0.6, 2.5, or 10.0mg/kg, i.p.) elicit effects among adolescent WKY, SHR, and SD rats and to compare whether there were strain differences. An automated, computerized, open-field activity monitoring system was used to study the dose-response characteristics of acute and repeated MPD administration throughout the 11-day experimental protocol. Results showed that all three adolescent rat groups exhibited dose-response characteristics following acute and chronic MPD administration, as well as strain differences. These strain differences depended on the MPD dose and locomotor index. Chronic treatment of MPD in these animals did not elicit behavioral sensitization, a phenomenon described in adult rats that is characterized by the progressive augmentation of the locomotor response to repeated administration of the drug. These results suggest that the animals age at time of drug treatment and strain/genetic variability play a crucial role in the acute and chronic effect of MPD and in the development of behavioral sensitization.

Methylphenidate (Ritalin): behavioral studies in the rat.

Attention Deficit Hyperactivity Disorder (ADHD) is a neuropsychiatric syndrome with an onset in childhood characterized by an inability to remain focused or to concentrate for prolonged periods of time. Children suffering from this disease are many times described as either inattentive or as hyperactive-impulsive depending on what form of the disease they manifest. Methylphenidate is the preferred treatment for this behavioral disorder and is used for long term disease management. Much still remains unknown concerning this stimulant and its effects on behavior and future abuse potential are pertinent questions. Since animal models are used to study the mechanism of drug action and rats are used often in drug studies, the objective of this review is to summarize the research reports that mainly have used rats as the model to investigate the action of methylphenidate. Topics discussed in this review include: (1) What effect does a single dose of methylphenidate have on locomotion activity; (2) Does repeated administration of methylphenidate result in tolerance or sensitization; and (3) Does methylphenidate have rewarding properties as measured by the self-administration and condition placed preference paradigms.

Prolonged methylphenidate treatment alters the behavioral diurnal activity pattern of adult male Sprague-Dawley rats.

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 (p<0.05, p=0.001, p<0.001) respectively, and the 10.0 mg/kg MPD group exhibited changes during the washout and re-challenge periods (p<0.01, p<0.001), respectively. In conclusion, prolonged administration of MPD modulated the diurnal HA pattern in a dose-dependent manner.

Chronic administration of methylphenidate produces neurophysiological and behavioral sensitization

The electrophysiological properties of acute and chronic methylphenidate (MPD) on neurons of the prefrontal cortex (PFC) and caudate nucleus (CN) have not been studied in awake, freely behaving animals. The present study was designed to investigate the dose-response effects of MPD on sensory evoked potentials recorded from the PFC and CN in freely behaving rats previously implanted with permanent electrodes, as well as their behavioral (locomotor) activities. On experimental day 1, locomotor behavior of rats was recorded for 2 h post-saline injection, and sensory evoked field potentials were recorded before and after saline and 0.6, 2.5, and 10 mg/kg, i.p., MPD administration. Animals were injected for the next five days with daily 2.5 mg/kg MPD to elicit behavioral sensitization. Locomotor recording was resumed on experimental days 2 and 6 after the MPD maintenance dose followed by 3 days of washout. On experimental day 10, rats were connected again to the electrophysiological recording system and rechallenged with saline and the identical MPD doses as on experimental day 1. On experimental day 11, rats locomotor recording was resumed before and after 2.5 mg/kg MPD administration. Behavioral results showed that repeated administration of MPD induced behavioral sensitization. Challenge doses (0.6, 2.5, and 10.0 mg/kg) of MPD on experimental day 1 elicited dose-response attenuation in the response amplitude of the average sensory evoked field potential components recorded from the PFC and CN. Chronic MPD administration resulted in attenuation of the PFCs baseline recorded on experimental day 10, while the same treatment did not modulate the baseline recorded from the CN. Treatment of MPD on experimental day 10 resulted in further decrease of the average sensory evoked response compared to that obtained on experimental day 1. This observation of further decrease in the electrophysiological responses after chronic administration of MPD suggests that the sensory evoked responses on experimental day 10 represent neurophysiological sensitization. Moreover, two different response patterns were obtained from PFC and CN following chronic methylphenidate administration. In PFC, the baseline and effect of methylphenidate expressed electrophysiological sensitization on experimental day 10, while recording from CN did not exhibit any electrophysiological sensitization.

Chronic methylphenidate modulates locomotor activity and sensory evoked responses in the VTA and NAc of freely behaving rats

Repeated exposure to psychostimulants leads to behavioral sensitization. The mode of action of brain circuitry responsible for behavioral sensitization is not well understood. There is some evidence that psychostimulants, such as amphetamine and cocaine, activate the ventral tegmental area (VTA) and nucleus accumbens (NAc). However, little is known about the effect of methylphenidate (MPD) on the electrophysiological properties of VTA and NAc neurons. The study was designed to investigate the chronic effects of MPD administration on sensory evoked field potentials of VTA and NAc in freely behaving rats previously implanted with permanent electrodes. On experimental day 1, locomotor behavior was recorded for 2 h post-saline injection followed by sensory evoked field potential recordings after saline and three different escalating (0.6, 2.5, and 10.0 mg/kg) MPD doses. After completion of the last recording, the rat was returned to its home cage. To induce behavioral sensitization, animals were injected for five days with 2.5 mg/kg MPD. Following a rechallenge with saline and identical MPD doses as those given on experimental day 1, locomotor recording of the rat was also performed on experimental days 2, 6 and 11. Results showed that repeated administration of MPD increased locomotion in dose-response manner and elicited behavioral sensitization, while the amplitude of the sensory evoked field responses of the VTA and NAc exhibited dose-response attenuation on both recording days (days 1 and 10). In addition, repeated administration of MPD resulted in attenuating the baseline amplitudes of sensory input on experimental day 10, while MPD administration on experimental day 10 elicited further attenuation of the VTA and NAc sensory evoked responses. Such further attenuation can be interpreted as electrophysiological sensitization.

Age and genetic strain differences in response to chronic methylphenidate administration

Methylphenidate hydrochloride (MPD) is a psychostimulant used in the treatment of attention deficit hyperactive disorder (ADHD) in adolescents and adults alike. Adolescence involves a period of neural development that is highly susceptible to environmental and pharmacological influence. Exposure to a psychostimulant like MPD during this crucial time period may cause permanent changes in neuronal function and formation. Another factor that may influence changes in neuronal function and formation is genetic variability. It has been reported that genetic variability affects both the initial behavioral response to drugs in general and psychostimulants in particular, and subsequently whether tolerance or sensitization is induced. The objective of the present study is to investigate the dose-response effects of repeated MPD administration (0.6, 2.5, or 10.0mg/kg, i.p.) using an open field assay to investigate if there are differences between adolescent and adult Wistar-Kyoto (WKY), Spontaneously Hyperactive rat (SHR), and Sprague-Dawley (SD) rats, respectively, and if the genetic variability between the strains influences the degree of change in locomotion. The acute and chronic administration of MPD resulted in unique differences in the level of increasing intensity in locomotor activity in each rat strain, with adult rats for the most part having a more intense increase in locomotor activity when compared to their adolescent counterparts. In conclusion, significant response differences among rat strains and age to acute and chronic MPD administration were observed only following the 2.5 and 10.0mg/kg i.p. doses and not following the lower MPD dose (0.6 mg//kg i.p.). In addition the variability in activity among the rat strain and age suggests that MPD may affect the same neuronal circuit differently in each strain and age. The unique differences among the individual locomotor indices suggest also that each locomotor index is regulated by different neuronal circuits, and each affected differently by MPD.

Sensory-evoked potentials recordings from the ventral tegmental area, nucleus accumbens, prefrontal cortex, and caudate nucleus and locomotor activity are modulated in dose-response characteristics by methylphenidate

Most of the studies investigating the effects of methylphenidate (MPD) are using behavioral and biochemical approaches. There are some electrophysiological studies about the effects of MPD on spontaneous electrical activity; however, there is none about the effects of MPD on sensory inputs. The objectives of the present study were to investigate the MPD dose-response characteristics on locomotor activity and sensory inputs using acoustic stimuli. Freely behaving rats previously implanted with semi-microelectrodes were used to record from four brain areas known to be sites of psychostimulant action. For locomotor behavior assessment, rats received saline on experimental day 1 and an acute administration of MPD (0.6, 2.5, or 10.0 mg/kg, i.p.) on experimental day 2. Using an automated, computerized activity-monitoring system, locomotor behavior was recorded for 2-h postinjection on both days. For the electrophysiological experiments, animals were implanted with permanent electrodes in the ventral tegmental area (VTA), nucleus accumbens (NAc), prefrontal cortex (PFC), and caudate nucleus (CN) under general anesthesia. Five to seven days after electrode implantation, they were used to study the effects of three different MPD doses on the response to sensory inputs. The lowest dose of MPD (0.6 mg/kg, i.p.) failed to alter locomotor activity, while the two higher MPD doses (2.5 and 10.0 mg/kg) elicited increase in locomotion, with the 10.0 mg/kg dose increased at least twice as much as the 2.5 mg/kg dose. However, the same three MPD doses elicited significant attenuation of sensory inputs in dose-response characteristics, i.e., as MPD dose increased, evoked sensory inputs decreased. These opposite effects (motor activation and sensory input suppression) were further discussed.

Does repetitive Ritalin injection produce long-term effects on SD female adolescent rats?

Methylphenidate (MPD), or Ritalin, is a psychostimulant that is prescribed for an extended period of time to children and adolescents with attention deficit hyperactivity disorder. Adolescence is a time of critical brain maturation and development, and the drug exposure during this time could lead to lasting changes in the brain that endure into the adulthood. Circadian rhythms are 24 h rhythms of physiological processes that are synchronized by the master-clock, the suprachiasmatic nucleus, to keep the body stable in a changing environment. The aim of present study is to observe the effect of repeated MPD exposure on the locomotor diurnal rhythm activity patterns of female adolescent Sprague-Dawley (SD) rats using the open field assay. 31 female adolescent SD rats were divided into four groups: control, 0.6 mg/kg, 2.5 mg/kg, and 10 mg/kg MPD group. On experimental day 1, all groups were given an injection of saline. On experimental days 2-7, animals were injected once a day with either saline, 0.6 mg/kg, 2.5 mg/kg, or 10 mg/kg MPD, and experimental days 8-10 were the washout period. A re-challenge injection was given to each animal on experimental day 11 with the similar dose as the experimental days 2-7. The locomotor movements were counted by the computerized animal activity monitoring system. The data were analyzed statistically to find out whether the diurnal rhythm activity patterns were altered. The obtained data showed that repeated administrations of 2.5 mg/kg and 10 mg/kg MPD were able to change the locomotor diurnal rhythm patterns, which suggests that these MPD doses exerts long-term effects.