Catherine M. Claussen

Acute and chronic methylphenidate modulates the neuronal activity of the caudate nucleus recorded from freely behaving rats

Methylphenidate (MPD) is currently one of the most prescribed drug therapies for attention deficit/hyperactivity disorder (ADHD) and moreover is abused for cognitive enhancement and used for recreation by the young and adults. Methylphenidate is used for prolonged periods of time and its mechanism of action on the brain is still unknown. The main action of MPD is known to act on the motive circuit of the brain, and one of these structures is the caudate nucleus (CN). The objective of this study was to investigate the neurophysiological properties of the CN neurons in response to acute and chronic administration of MPD in freely behaving animals, previously implanted with permanent semi microelectrodes. Twenty-six rats were permanently implanted with semi microelectrodes into the CN using general anesthesia. On experimental day one (ED1) the rat was placed into the testing chamber, and neuronal activity was recorded using a wireless (telemetric) headstage device following both a saline and a 2.5 mg/kg MPD injection. From ED2 to ED6 daily injections of 2.5 mg/kg MPD were administered without recordings to induce a chronic effect of the drug, preceded by three days of washout (ED7-ED9) where no injections were given. On ED10 rats were placed back into the testing chamber, the wireless headstage device was attached to skull cap and recordings were resumed for 1 h each following both a saline and re-challenge administration of 2.5 mg/kg MPD. Sixty-seven CN neuronal recorded units from twenty-six animals with identical shape and amplitude at ED1 and ED10 were evaluated. All the 67 CN units responded to MPD administration, 70% (47/67) CN units exhibited an increase in activity following initial 2.5 mg/kg MPD administration and 30% (20/67) exhibited a decrease in neuronal activity. On ED10 all the CN units showed a significant change in their firing rate baseline compared to ED1 baseline, 52% (35/67) exhibiting an increase in their ED10 baseline activity compared to ED1 baseline activity and 48% (32/67) of the CN units at ED10 exhibited decreasing activity. All the CN units responded significantly to MPD rechallenge at ED10, 57% (38/67) of the units exhibited increased neuronal activity while 43% (29/67) exhibited decreasing neuronal activity. The results indicate that the majority of the CN units exhibited neurophysiological sensitization.

Nucleus accumbens neuronal activity in freely behaving rats is modulated following acute and chronic methylphenidate administration

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 animals 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 min 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 ED9). 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.

Acute and chronic methylphenidate alters prefrontal cortex neuronal activity recorded from freely behaving rats

Todays 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.

Selective bilateral lesion to caudate nucleus modulates the acute and chronic methylphenidate effects

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.

Acute administration of methylphenidate alters the prefrontal cortex neuronal activity in a dose–response characteristic

The prefrontal cortex (PFC) is part of the collective structures known as the motive circuit. The PFC acts to enhance higher cognitive functions as well as mediate the effects of psychostimulants. Previous literature shows the importance of PFC neuronal adaptation in response to acute and chronic psychostimulant exposure. The PFC receives input from other motive circuit structures, including the ventral tegmental area, which mediates and facilitates the rewarding effects of psychostimulant exposure. PFC neuronal and locomotor activity from freely behaving rats previously implanted with permanent semimicroelectrodes were recorded concomitantly using a telemetric (wireless) recording system. Methylphenidate (MPD) is used as a leading treatment for behavioral disorders and more recently as a cognitive enhancer. Therefore, the property of MPD dose response on PFC neuronal activity was investigated. The results indicate that MPD modulates PFC neuronal activity and behavioral activity in a dose-dependent manner. PFC neuronal responses to 0.6 mg/kg elicited mainly a decrease in PFC neuronal activity, while higher MPD doses (2.5 and 10.0 mg/kg) elicited mainly increased neuronal activity in response to MPD. The correlation between MPD effects on PFC neuronal activity and animal behavior is discussed.

Caudate neuronal recording in freely behaving animals following acute and chronic dose response methylphenidate exposure.

The misuse and abuse of the psychostimulant, methylphenidate (MPD) the drug of choice in the treatment of attention deficit hyperactivity disorder (ADHD) has seen a sharp uprising in recent years among both youth and adults for its cognitive enhancing effects and for recreational purposes. This uprise in illicit use has lead to many questions concerning the long-term consequences of MPD exposure. The objective of this study was to record animal behavior concomitantly with the caudate nucleus (CN) neuronal activity following acute and repetitive (chronic) dose response exposure to methylphenidate (MPD). A saline control and three MPD dose (0.6, 2.5, and 10.0mg/kg) groups were used. Behaviorally, the same MPD dose in some animals following chronic MPD exposure elicited behavioral sensitization and other animals elicited behavioral tolerance. Based on this finding, the CN neuronal population recorded from animals expressing behavioral sensitization was also evaluated separately from CN neurons recorded from animals expressing behavioral tolerance to chronic MPD exposure, respectively. Significant differences in CN neuronal population responses between the behaviorally sensitized and the behaviorally tolerant animals were observed for the 2.5 and 10.0mg/kg MPD exposed groups. For 2.5mg/kg MPD, behaviorally sensitized animals responded by decreasing their firing rates while behaviorally tolerant animals showed mainly an increase in their firing rates. The CN neuronal responses recorded from the behaviorally sensitized animals following 10.0mg/kg MPD responded by increasing their firing rates whereas the CN neuronal recordings from the behaviorally tolerant animals showed that approximately half decreased their firing rates in response to 10.0mg/kg MPD exposure. The comparison of percentage change in neuronal firing rates showed that the behaviorally tolerant animals trended to exhibit increases in their neuronal firing rates at ED1 following initial MPD exposure and oppositely at ED10 MPD rechallenge. While the behaviorally sensitized animals in general increased in their percentage change of firing rats were observed following acute 10.0mg/kg MPD and the behaviorally sensitized 10.0mg/kg MPD animals and a robust increase in neuronal firing rates at ED1 and ED10 rechallenge. These results suggest the need to first individually analyze animal behavioral activity, and then to evaluate the neuronal responses to the drug based on the animals behavioral response to chronic MPD exposure.

Concomitant behavioral and PFC neuronal activity recorded following dose-response protocol of MPD in adult male rats

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.

Single exposure of dopamine D1 antagonist prevents and D2 antagonist attenuates methylphenidate effect.

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.