Methylphenidate (MPH) is a leading treatment for Attention Deficit Hyperactivity Disorder (ADHD). Although this compound has been used for decades, the neural mechanisms underlying MPH's therapeutic actions are still unknown. Recent advances in our understanding of the neurobiology of ADHD, and the identification of appropriate MPH doses for use in rodents, now allow the examination of therapeutic actions in animals.
Converging evidence has demonstrated that ADHD symptoms arise from dysregulation of prefrontal cortical (PFC)/striatal and cerebellar circuits (reviewed in [1
]. The PFC uses working memory to guide behavior and attention, inhibiting inappropriate responses and sustaining attention over long delays, particularly under conditions of interference from distractors [2
]. Deficits in PFC function lead to poor impulse control, distractibility, hyperactivity, forgetfulness and poor organization and planning [4
]. There is general agreement that ADHD involves weakened PFC function e.g. [5
], and speculation that medications might strengthen PFC abilities. Imaging studies have shown that MPH produces more efficient PFC function in both ADHD patients [6
] and control subjects [7
], consistent with this view.
Many researchers have assumed that MPH acts by blocking dopamine (DA) transporters (reviewed in [8
]). Indeed, elegant PET imaging studies of DA transporter occupancy in striatum have shown that MPH acts at this site [9
]. However, the striatum contains very few noradrenergic (NE) transporters, and thus the important actions of MPH on the NE system have received far less attention. At the present time, imaging studies are unable to reliably visualize the low levels of NE and DA actions in cortex, although there is the suggestion that there may be fewer catecholamine terminals in the PFC of adults with ADHD [10
]. Thus, animal studies are of particular importance for understanding MPH actions in PFC.
Recent animal studies by Kuzcenski and Segal [11
] have identified the low, oral doses of MPH which 1) produce plasma levels in rats similar to those observed in children taking MPH, and 2) decrease locomotor activity in rats just as they do in humans. Oral administration was key, as MPH administration by injection produces much higher blood and brain MPH levels [12
]. Prior to appreciation of this research, MPH doses in rat studies were generally too high, and were usually administered by injection, producing kinetics and drug levels relevant to drug abuse but not to ADHD e.g. [13
]. These injected, effectively higher doses produce locomotor hyper
activity with stimulant treatment e.g. [16
], and it has been assumed that there were species differences that would impede research. Thus, the identification of the appropriate dose regimen for MPH treatment in rats opens a new field of research that may more quickly elucidate MPH therapeutic mechanisms.
Although previous research focused on MPH amplification of DA actions, more recent biochemical studies using low doses of MPH show more potent effects on hippocampal NE than on striatal DA [18
], while increasing both DA and NE release in the PFC ([19
] and C.W. Berridge, personal communication). Both NE and DA have a critical influence on PFC cognitive functioning. NE improves working memory, response inhibition and lessens distractibility through actions at post-synaptic α2A adrenoceptors in the PFC, while DA improves working memory through modest stimulation of D1 receptors in PFC (reviewed in [20
]). Although optimal levels of NE and DA are essential to proper PFC function, very high levels of NE and DA release, e.g. during stress, impair PFC function through α1, beta-1, D1 and possibly D4 receptors [22
The current study characterized the effects of low, oral doses of MPH on PFC function in rats. Rats were tested on a working memory task, spatial delayed alternation, a classic test of PFC function in rodents [23
]. MPH was found to have effects similar to those observed in patients: improving performance at moderate doses but producing perseverative errors at high doses. The second part of the study examined whether NE α2A adrenoceptor and/or DA D1 receptor actions contributed to the enhancing effects of MPH on PFC function.