Object memory impairment at post-drug Day 15 but not at Day 1 after a regimen of repeated treatment with oral methylphenidate.

Methylphenidate (MPH) is a dopamine and norepinephrine reuptake inhibitor that is widely used for the treatment of attention-deficit/hyperactivity disorder in children and adults. Its similarity to other psychostimulants suggests that, at certain doses, the drug may generate lasting neuroadaptations that can be detrimental to the recipient. Some investigators have found that, in rats, the residual effects of the drug (i.e., following a 10-14 day washout period) can interfere with memory for objects when the retention interval is 3h or more. The present experiment replicated this result and demonstrated the critical importance of the washout period. Long-Evans male rats treated with MPH (5.0mg/kg po b.i.d.) on 21 days (during a post-natal period ranging from Day 29 to Day 57) and then twice-assessed for their performance in an object recognition task were able to recognize a familiar object on Day 1 after the last dose of the drug had been administered, behaving the same as the untreated control group. However, on Day 15 post-drug, the same MPH group failed to distinguish between a familiar and a novel object, exploring both nearly equally, while the control group continued to investigate the novel object to a greater extent than the familiar one. This suggests that, if a test for object recognition is conducted too early after the MPH treatment period ceases, a memory impairment may not be detected. In general, this finding has implications for studies of other behavioral or neurophysiological consequences of MPH that may appear following a drug-free withdrawal period.

Chronic oral methylphenidate induces post-treatment impairment in recognition and spatial memory in adult rats.

Recent pre-clinical research has indicated that chronic treatment with methylphenidate (Ritalin) in young animals can result in lasting and potentially detrimental alterations in brain function that can persist into adulthood. Chronic methylphenidate-induced neuronal alterations may result in behavior and cognitive deficits that include increases in behavioral responses and impairment in recognition memory. This study compared the cognitive consequences following chronic treatment with two doses (5 and 10 mg/kg) of methylphenidate on recognition and spatial memory in adult male Long-Evans rats using an established oral dosing procedure. The animals were then tested in the Object Recognition test at 14 days post treatment and the Object Placement test at 21 days post treatment. The results indicate that repeated exposure to oral methylphenidate impaired the performance of rats in these tests. The current findings add to recent research demonstrating negative consequences in rats pre-treated with methylphenidate, and extend previous findings to include deficits in spatial recognition memory.

Inhibition in adults with attention deficit/hyperactivity disorder: event-related potentials in the stop task.

The core deficit in Attention Deficit/Hyperactivity Disorder (ADHD) may be a deficiency in executive functions, particularly the processes that are associated with the inhibition of predominant responses. To test this notion in the adult population, healthy undergraduate volunteers and students with ADHD symptoms performed a visual Stop Signal Task (Logan et al. J Exp Psychol: Hum Percept Perform 10:276-291, 1984) while Event-Related brain Potentials were recorded. The two groups did not differ on behavioral measures of performance, but there was a significant difference in the N2-P3 component. These results underline the robustness of an N2-P3 difference between healthy adults and people with ADHD symptoms that have persisted into young adulthood.

Chronic oral methylphenidate administration to periadolescent rats yields prolonged impairment of memory for objects.

Methylphenidate (MPD) is widely prescribed for the treatment of attention deficit disorders in children and has generally been thought to be free of significant side effects when administered at recommended therapeutic doses. However, recent behavioral research with laboratory rodents has indicated that, like other psychostimulants with which it shares neurotransmitter-modulating properties, chronically administered MPD can bring about lasting and potentially detrimental alterations in brain function. Some of these may involve changes in the neuromodulatory input from noradrenergic and dopaminergic systems that project to the prefrontal cortex and hippocampus, regions with significant roles in several cognitive functions, including those critical to memory formation. To investigate the possibility of cognitive impairment, the effects of a regimen of chronic MPD on the performance of an object recognition task known to rely on the integrity of systems involved in rodent memory was assessed. The drug, at doses of 2, 3 or 5mg/kg, was delivered twice daily to periadolescent rats via an oral administration technique on either 11 or 21 treatment days. Subsequent to this period, the animals were subjected to an object recognition test at 14, 28, and 42 days after their last MPD treatment. In each of these tests, exploration time for two objects, one novel and one previously encountered (3h earlier), was assessed. Longer exploration of the novel object was considered evidence of retained memory for the familiar object. It was found that rats exposed to 3 or 5mg/kg (b.i.d.) on 21 occasions exhibited no significant preference for exploration of the novel object at any of the three post-treatment intervals. This finding was interpreted as evidence of a persisting MPD-induced impairment of recognition memory in these animals.

Impairment of single-trial memory formation by oral methylphenidate in the rat.

High synaptic concentrations of dopamine and/or norepinephrine can impair the working memory function of the prefrontal cortex and impede attention and learning. Methylphenidate, a dopamine and norepinephrine transporter blocker known to facilitate these cognitive processes at low doses, was hypothesized to interfere with memory storage at doses that may raise concentrations of these neurotransmitters to systemically disruptive levels. In the present experiments, a dose of 10.0mg/kg of this drug was administered to female and male Long-Evans rats using a novel oral administration procedure designed to model the normal mode of delivery to humans. It was found to interfere with single-trial memory acquisition in a delayed object recognition test, a spontaneous learning task that involves no appetitive or aversive motivator. The time that the rats spent in overt exploration of the to-be-remembered objects during the acquisition trial was not affected, suggesting that the drug may have impaired processes of memory formation independently of interference with attention.

Behavioral reactivity to a noradrenergic challenge after chronic oral methylphenidate (ritalin) in rats.

Methylphenidate (Ritalin) is routinely used for the treatment of attention-deficit/hyperactivity disorder (ADHD). It is a psychomotor stimulant with pharmacodynamics similar to those established for cocaine and amphetamine with primary activation of the noradrenergic and dopaminergic systems. Long-term exposure to psychostimulants including methylphenidate (MPD) is believed to result in enduring functional changes along both these pathways and various behaviors mediated by these systems may be affected. In the present experiment, the effects of intermittent oral administration of methylphenidate (10 mg/kg) to rats over a 4-week period were subsequently (after a drug washout interval) assessed in three animal models sensitive to noradrenergic manipulation: the elevated plus-maze, predator odor avoidance, and social interaction tests. The behaviors of methylphenidate-experienced animals were compared with untreated controls. Thirty minutes prior to testing, half the animals with each of these histories received an injection of yohimbine hydrochloride (2.0 mg/kg), an alpha2-adrenoreceptor blocker intended to evoke noradrenergic system activation, while the remainder received a saline injection. Yohimbine was expected to reduce both exploration of novel stimuli and interaction with conspecifics, and it was predicted that methylphenidate would potentiate these effects. Relative to saline-tested controls, rats that received both the methylphenidate treatment and the yohimbine challenge exhibited the least exploration in the predator odor test and the lowest duration of interaction with an unfamiliar conspecific partner in the social interaction test. The behavior patterns observed in this group of rats suggest heightened emotionality and defensiveness that are typically seen when rats are administered drugs known to be anxiogenic in human subjects. In the plus-maze, exploratory locomotor activities remained unaltered by either drug while yohimbine decreased risk-assessment behaviors, an effect that remained uninfluenced by methylphenidate pretreatment.