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J Neurophysiol 96: 524-525, 2006; doi:10.1152/jn.00373.2006
0022-3077/06 $8.00
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EDITORIAL FOCUS

Staying in Touch With Methylphenidate: AHDH and Sensory Processing. Focus on "Methylphenidate Enhances Noradrenergic Transmission and Suppresses Mid- and Long-Latency Sensory Responses in the Primary Somatosensory Cortex of Awake Rats"

Drouin et al. (this issue of J. Neurophysiol. p. 622–632) provide the first analysis of the neurochemical and neurophysiological effects of the stimulant medication, methylphenidate (MPH), in sensory cortex of freely behaving animals. MPH has been prescribed to children and adults with Attention Deficit Hyperactivity Disorder for decades (under the brand name Ritalin), yet little is known about how this compound alters sensory processing. Drouin et al. utilized a well-characterized system—the barrel field somatosensory cortex (S1) in rats—to examine how MPH alters cortical response to whisker stimulation. They administered saline, or a relatively low (1 mg/kg ip) or moderate (5 mg/kg ip) dose of MPH while measuring extracellular norepinephrine (NE) levels in S1, recording neuronal activity in S1, and assessing locomotor behavior in freely moving rats. The authors found that the lower dose of MPH increased NE release in S1 and suppressed long-latency neuronal responses without altering locomotor behavior. The higher dose similarly increased NE and suppressed the long-latency responses but also induced locomotor activation and had complex interactions on the initial excitatory responses of S1 neurons. As therapeutic doses of MPH do not increase locomotor activity in children, it is likely that the lower dose is the more relevant to current ADHD therapy. Suppression of longer-latency responses may be of particular relevance to interactions of S1 with other brain regions. The authors suggest that MPH may improve sensory attention by increasing NE release in S1 cortex and suppressing "noise. " This interpretation is consistent with the clinical literature, as ADHD patients are often tactile defensive and exhibit disinhibited somatosensory evoked potentials (Parush et al. 1997Go) and increased regional cerebral blood flow in S1 that is normalized by stimulant medication (Lee et al. 2005Go).

Stimulant medications such as MPH are currently being prescribed to ~2.5 million children in the United States, yet there has been surprisingly little research on the mechanism of action of these compounds. For years it was assumed that MPH had a paradoxical effect in ADHD children—a stimulant having calming actions. However, it is now well established that this is not a paradoxical effect in ADHD but rather an effect of dose, and that low, oral doses of MPH focus behavior and attention in normal individuals as well as those with ADHD (Rapoport and Inoff-Germain 2002Go). Another myth was that stimulants showed species differences, focusing behavior in humans but increasing locomotor activation in rodents. It is now known that the doses of MPH given in most previous rodent studies were too high and that low doses (especially when given orally) actually reduce or have no effect on locomotor activity (Kuczenski and Segal 2002Go) and improve prefrontal cortical cognitive abilities in rats as well as in humans (Arnsten and Dudley 2005Go; C. Berridge, personal communication). The current study found that a low dose of MPH—one that had no effect on locomotor activity—suppressed the long-latency responses of S1 neurons. This study in behaving animals provides a link between the clinical use of MPH and previous in vitro studies of NE actions in S1 slice preparations that similarly found suppressive effects with beta adrenergic receptor stimulation e.g., (Devilbiss and Waterhouse 2000Go). The results are also consistent with a classic finding by Foote and colleagues showing that NE increases the signal to noise ratio of responding in auditory cortex, mostly by suppressing noise (Foote et al. 1975Go).

The authors note that MPH is administered systemically in this study, thus blocking catecholamine reuptake and facilitating catecholamine transmission throughout the neuroaxis. Thus drug effects on S1 neurons may also arise from MPH actions in other brain regions connected with the S1 cortex. Drouin et al. raise the possibility that some of these actions may occur in VPM thalamus, which receives a dense NE innervation and projects directly to S1. They posit that the suppression of the long-latency excitation may involve beta adrenergic receptor-mediated effects on cAMP/Ih mechanisms in thalamus (McCormick and Pape 1990Go). MPH also may indirectly affect S1 through actions in prefrontal cortex (PFC), facilitating PFC gating of S1 responses. Low doses of MPH increase extracellular levels of both NE and dopamine in PFC and improve PFC cognitive function (Arnsten and Dudley 2005Go). The PFC projects back to sensory cortices where it has a "top-down" gating influence on sensory processing. Thus patients with PFC lesions, like ADHD patients, have disinhibited somatosensory evoked potentials (Yamaguchi and Knight 1990Go). Low doses of MPH may strengthen PFC regulatory output and thereby inhibit responses to irrelevant sensory stimulation.

It would be interesting to determine how S1 neurons would respond in the presence of MPH if the animals were required to attend to the whisker stimulation, e.g., perform a somatosensory discrimination. It is possible that under these conditions low doses of MPH might facilitate the initial excitatory response of S1 neurons and perhaps decrease the suppression at longer latencies as well.

In summary, new research with low doses of MPH in animals has begun to reveal the mechanisms by which stimulant medications may alter attentional processing in humans. MPH may have both direct effects in S1 as well as indirect effects through bottom up (VPM thalamus) and top-down (PFC) influences on S1 responsivity. The excellent correspondence between findings in animals and patients encourages the relevance of the basic research to human drug actions.

A.F.T. Arnsten and S. Vijayraghavan

Department of Neurobiology, Yale University School of Medicine, New Haven Connecticut

Address for reprint requests and other correspondence: A. Arnsten, Yale Univ School of Medicine- Neurobiology, 333 Cedar St, New Haven, CT 06510 (E-mail: amy.arnsten{at}yale.edu)

REFERENCES

Arnsten AFT and Dudley AG. Methylphenidate improves prefrontal cortical cognitive function through a2 adrenoceptor and dopamine D1 receptor actions: relevance to therapeutic effects in Attention Deficit Hyperactivity Disorder. Behav Brain Funct 1: 2, 2005.[CrossRef][Medline]

Devilbiss DM and Waterhouse BD. Norepinephrine exhibits two distinct profiles of action on sensory cortical neuron responses to excitatory synaptic stimuli. Synapse 37: 273–282, 2000.[CrossRef][Web of Science][Medline]

Drouin C, Page M, and Waterhouse B. Methylphenidate enhances noradrenergic transmission and suppresses mid- and long-latency sensory responses in the primary somatosensory cortex of awake rats. J Neurophysiol 96: 622–632, 2006.[Abstract/Free Full Text]

Foote SL, Freedman FE, and Oliver AP. Effects of putative neurotransmitters on neuronal activity in monkey auditory cortex. Brain Res 86: 229–242, 1975.[CrossRef][Web of Science][Medline]

Kuczenski R and Segal DS. Exposure of adolescent rats to oral methylphenidate: preferential effects on extracellular norepinephrine and absence of sensitization and cross-sensitization to methamphetamine. J Neurosci 22: 7264–7271, 2002.[Abstract/Free Full Text]

Lee JS, Kim BN, Kang E, Lee DS, Kim YK, Chung JK, Lee MC, and Cho SC. Regional cerebral blood flow in children with attention deficit hyperactivity disorder: comparison before and after methylphenidate treatment. Hum Brain Mapp 24: 157–164, 2005.[CrossRef][Web of Science][Medline]

McCormick DA and Pape HC. Noradrenergic and serotonergic modulation of a hyperpolarization-activated cation current in thalamic relay neurones. J Physiol 431: 319–342, 1990.[Abstract/Free Full Text]

Parush S, Sohmer H, Steinberg A, and Kaitz M. Somatosensory functioning in children with attention deficit hyperactivity disorder. Dev Med Child Neurol 39: 464–468, 1997.[Web of Science][Medline]

Rapoport JL and Inoff-Germain G. Responses to methylphenidate in Attention-Deficit/Hyperactivity Disorder and normal children: update 2002. J Atten Disord 6: S57–60, 2002.

Yamaguchi S and Knight RT. Gating of somatosensory input by human prefrontal cortex. Brain Res 521: 281–288, 1990.[CrossRef][Web of Science][Medline]




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