Methylphenidate amplifies long-term plasticity in the hippocampus via noradrenergic mechanisms

Abstract

Methylphenidate treatment is used for Attention Deficit Hyperactivity Disorder and can improve learning and memory. Previously, improvements were considered a by-product of increased attention; however, we hypothesize that methylphenidate directly alters mechanisms underlying learning and memory, and therefore examined its effects on hippocampal long-term potentiation and long-term depression. Methylphenidate enhanced both mechanisms in the absence of presynaptic changes and in a noradrenalin ␤-receptor-dependent manner. These findings can explain both the improved learning and memory and decreased learning selectivity found with methylphenidate treatment and constitute the first demonstration of direct actions of methylphenidate on mechanisms implicated in cognition.Attention Deficit Hyperactivity Disorder (ADHD) affects 8%-12% of children (Biederman and Faraone 2005) and is characterized by inattention, hyperactivity, and impulsivity. Consequences of the disorder include poorer academic performance, employment records, social relationships, and a higher risk of drug abuse (Doggett 2004). While behavioral, cognitive, and psychosocial therapies exist for ADHD, they are often ineffective unless combined with pharmacological treatment , the most common of which is the psychostimulant, methylphenidate (Ritalin, Concerta). Methylphenidate is known to increase extracellular dopamine and noradrenalin Segal 1997, 2002), but not serotonin (Kuczenski and Segal 1997) suggesting that therapeutic efficacy relates to alterations in dopamine and noradrenalin. Despite knowledge of these neurochemical effects, the mechanisms contributing to the effectiveness of methylphenidate are unclear (Safer and Allen 1989; National Institutes of Health Consensus Development Conference Statement 2000;Greenhill 2001).One clue to mechanisms of efficacy can be found at a behavioral level, where methylphenidate improves academic performance (Yang et al. 2004;McGough et al. 2006), working (Wright and White 2003) and visual (Rhodes et al. 2004) memory, nonverbal (O'Toole et al. 1997) and visuospatial (Bedard et al. 2004) learning, and reading skills (Keulers et al. 2007), which may explain why, in addition to its medicinal use, it is used illegally by healthy students to aid study (Teter et al. 2006). Despite evidence of methylphenidate-induced changes in learning and memory, the mechanisms underlying these changes have received little focus and are commonly assumed to be a by-product of improved attention. However, we suggest that these findings are the result of direct actions of methylphenidate on learning and memory mechanisms.In support of this hypothesis, methylphenidate has been shown to increase hippocampal noradrenalin in vivo (Kuczenski and Segal 2002), and such changes are known to impact on plasticity such as long-term potentiation (LTP) and long-term depression (LTD) (Hopkins and Johnston 1984;Izumi et al. 1992;Sah and Bekkers 1996;Thomas et al. 1996;Izumi and Zorumski 1999;Schimanski et al. 2007;Lin et al. 2008), both of which a...

Methylphenidate has long-lasting metaplastic effects in the prefrontal cortex of adolescent rats

“…In the present study, the modulation of synaptic plasticity through acutely applied MPH, as demonstrated previously in vitro [11,12], could be shown here in vivo, with an approximate doubling of the LTP induced. Surprisingly, 15-18 days after the last injection of MPH we found that the LTP increase was not only preserved, but further augmented.…”

“…Recently, it has been shown that MPH changes synaptic plasticity as assessed by its capacity to influence the induction of long-term potentiation (LTP) and/or long-term depression (LTD) in the hippocampus [11] and in the prefrontal cortex (PFC) [12]. The latter region is where MPH appears to exert effects on the expression of ADHD-related features such as the control of impulsivity [13].…”

Animal model of methylphenidate's long-term memory-enhancing effects

“…Substantial evidence does exist that MPH acts on cellular substrates implicated in LTM; for example, MPH enhances long-term potentiation and depression (Dommett et al 2008;Tye et al 2010). Recently, acute administration of MPH in rats has been shown to facilitate plasticity in the amygdala via an increase in AMPA receptor-mediated currents following a cue-reward learning task (Tye et al 2010).…”

Neuromodulatory Neurotransmitters Influence LTP-Like Plasticity in Human Cortex: A Pharmaco-TMS Study

“…MPH enhances LTP in rat hippocampus and this effect is mediated by b-adrenergic receptor activation (Dommett et al, 2008). MPH effects on neocortical LTP have never been examined, and the only study on NE modulation of neocortical LTP also demonstrated LTP enhancement via b-adrenergic receptor activation in rat visual cortex (Bröcher et al, 1992).…”