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Brain Processes in Discounting: Consequences of Adolescent Methylphenidate Exposure

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Behavioral Neuroscience of Attention Deficit Hyperactivity Disorder and Its Treatment

Part of the book series: Current Topics in Behavioral Neurosciences ((CTBN,volume 9))

Abstract

Traits of inattention, impulsivity, and motor hyperactivity characterize children diagnosed with attention-deficit/hyperactivity disorder (ADHD), whose inhibitory control is reduced. In animal models, crucial developmental phases or experimental transgenic conditions account for peculiarities, such as sensation-seeking and risk-taking behaviors, and reproduce the beneficial effects of psychostimulants. An “impulsive” behavioral profile appears to emerge more extremely in rats when forebrain dopamine (DA) systems undergo remodeling, as in adolescence, or with experimental manipulation tapping onto the dopamine transporter (DAT). Ritalin® (methylphenidate, MPH), a DAT-blocking drug, is prescribed for ADHD therapy but is also widely abused by human adolescents. Administration of MPH during rats’ adolescence causes a long-term modulation of their self-control, in terms of reduced intolerance to delay and diminished proneness for risk when reward is uncertain. Exactly the opposite profile emerges when exogenous alteration of DAT levels is achieved via lentiviral transfection. Both adolescent MPH exposure and DAT-targeting transfection lead to enduring hyperfunction of dorsal striatum and hypofunction of ventral striatum. Together with upregulation of prefronto-cortical phospho-creatine, striatal upregulation of selected genes (like serotonin 7 receptor gene) suggests that enhanced inhibitory control is generated by adolescent MPH exposure. Operant tasks, which assess the balance between motivational drives and inhibitory self-control, are thus useful for investigating reward-discounting processes and their modulation by DAT-targeting tools. In summary, due to the complexity of human studies, preclinical investigations of rodent models are necessary to understand better both the neurobiology of ADHD-like symptoms’ etiology and the long-term therapeutic safety of adolescent MPH exposure.

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Abbreviations

5-HT:

5-Hydroxytryptamine (serotonin)

5-HT7:

5-Hydroxytryptamine (serotonin) receptor 7 (protein)

ADHD:

Attention-deficit/hyperactivity disorder

BOLD:

Blood-oxygen level-dependent

CBF:

Cerebral blood flow

CBV:

Cerebral blood volume

DA:

Dopamine

DAT:

Dopamine transporter

DBH:

Dopamine-β-hydroxylase

dStr:

Dorsal striatum

fMRI:

Functional magnetic resonance imaging

H-MRS:

Proton magnetic resonance spectroscopy

Htr7 :

5-Hydroxytryptamine (serotonin) receptor 7 (gene)

ID:

Intolerance-to-Delay (task)

mITI:

Mean inter-trial interval

MPH:

Methylphenidate

NAcc:

Nucleus accumbens

NET1:

Norepinephrine transporter (for uptake 1 (neuronal))

PD:

Probabilistic-Delivery (task)

PFC:

Prefrontal cortex

phMRI:

Pharmacological magnetic resonance imaging

pnd:

Postnatal day

RT:

Response time

RTT:

Response-time task

SERT:

Serotonin transporter

SNAP-25:

Synaptosomal-associated peptide-25

SSRI:

Selective serotonin reuptake inhibitor

TO:

Timeout

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Acknowledgments

This study was supported by the “ADHD-sythe” young-investigator grant and by the “NeuroGenMRI” ERAnet project, “Prio-Med-Child” call (to WA), Italian Ministry of Health; ERARE-EuroRETT Network ERAR/6 (to GL). The authors wish to thank the European Mind and Metabolism Association (EMMA, www.emmaweb.org), L.T. Bonsignore and N. Francia for technical support.

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  1. Section of Behavioural Neuroscience, Department of Cell Biology & Neurosciences, Istituto Superiore di Sanitá, Viale Regina Elena 299, I-00161, Rome, Italy

    Walter Adriani, Francesca Zoratto & Giovanni Laviola

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  1. Walter Adriani
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  2. Francesca Zoratto
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  3. Giovanni Laviola
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Correspondence to Walter Adriani .

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  1. , Dept of Neurosci, Physiol & Pharmacol, University College London, Gower Street, London, WC1E6BT, United Kingdom

    Clare Stanford

  2. , Human Development & Applied Psychology, The Ontario Institute for Studies in Edu, Bloor Street West 252, Toronto, M5S1V6, Canada

    Rosemary Tannock

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Adriani, W., Zoratto, F., Laviola, G. (2011). Brain Processes in Discounting: Consequences of Adolescent Methylphenidate Exposure. In: Stanford, C., Tannock, R. (eds) Behavioral Neuroscience of Attention Deficit Hyperactivity Disorder and Its Treatment. Current Topics in Behavioral Neurosciences, vol 9. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7854_2011_156

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