Variability among Patients Receiving Methylphenidate

August 18, 2015 at 03:31 AM | categories: mph

Contents

1 Variability of Response to MPH treatment
2 MPH effect on DA levels
3 Effects of increased Dopamine

1 Variability of Response to MPH treatment

There is a large intersubject variability for methylphenidate (MPH) induced increases in extracellular dopamine (DA) and dopamine transporter (DAT) blockade with a fixed dose of MPH [12]. Some small children require high doses and some large children require small doses, so adjustment for weight does not account for this range [9]. Neither do differences in absorption and metabolism [9], since children who respond to low doses (5 mg per administration) have low serum concentrations of MPH (4 ng/mL to 5 ng/mL at Tmax) and those who respond to high doses (20 mg per administration) have high serum concentrations (12 ng/mL to 15 ng/mL).

2 MPH effect on DA levels

A relatively large therapeutic dose of oral MPH (60 mg) significantly blocked DATs in all subjects (measured using positron emission tomography (PET)) but did not increase extracellular DA in all of them [12]. Volkow et al. [12] suggests that individual differences in MPH-induced increases to DA may reflect differences in DA tone between subjects. Since the pharmacological responses to MPH will also depend on the sensitivity of DA regulated circuits, differences in sensitivity of these circuits to DA stimulation is also likely to contribute to the large intersubject variability in MPH’s effects [12]. This is consistent with the findings that homovanillic acid (HVA) levels in cerebrospinal fluid (CSF) (a marker of DA turnover in the central nervous system (CNS)) predicts response to MPH in children with ADHD: the higher the levels, the better the responses [3]. It also suggests a plausible mechanism that may underlie nonresponse to MPH, which occurs in 15 % to 30 % of children with attention-deficit/hyperactivity disorder (ADHD) [9], or the requirement for very high doses to produce clinical effects, which is required in about 20 % of those who are considered responsive to stimulants.

MPH-induced increases in DA declined as a function of age [10]. This could reflect the decrease in DAT that occurs with age. In fact, one could speculate that the age-associated decline in DAT could contribute to the decrease in symptomatology in most of the ADHD subjects as they grow older [2]. Alternatively the fact that the elevations of DAT in ADHD subjects were reported in adults [4] suggests that a failure to show DAT decline with age could account for the persistence of symptomatology in subjects with ADHD. This could also explain the therapeutic efficacy of MPH in adults with ADHD [8].

3 Effects of increased Dopamine

DA cells fire in response to salient events, which is a mechanism by which the brain signals that a stimulus is relevant and should be attended to, and indeed, increases in DA induced by MPH were linked to an enhanced perception of events as salient [14]. In Volkow et al. [11], the study evaluated the effects of MPH on appetitive stimuli using PET and [11C]raclopride to compare the changes in DA induced by food stimuli (visual and olfactory presentation of food in food-deprived individuals) versus neutral stimuli (description of family genealogy) when given with placebo or with MPH (20 mg oral) and in parallel evaluated the self-reports for the ‘desire for the food’ and for ‘hunger’ [11]. This study showed that MPH induced significant increases in DA in dorsal striatum when given with food stimuli but not when given with the neutral stimuli. In contrast, no differences in DA were found among placebo-treated subjects exposed to food stimuli, suggesting that stimulus presentation alone was not strong enough to induce a DA change large enough to be detected by PET. MPH also increased the ratings in self-reports for ‘desire for food’ and for ‘hunger’ when exposed to the food stimuli as compared with placebo. The increases in the perception of hunger and desire for food were correlated with MPH-induced increases in extracellular DA in dorsal striatum. These findings support the role of MPH in enhancing DA signal saliency for appetitive stimuli [14].

MPH also increased extracellular DA in the striatum when administered before subjects were required to perform a remunerated mathematical task, but not when MPH was administered before subjects passively viewed scenery cards [13]. MPH increases the ratings of cognitive tasks as being interesting, exciting, motivating, and less tiresome [7, 13]. This suggests that MPH amplifies small DA increases due to the task, and this may be the mechanism underlying this drug’s ability to make tasks more salient to the subject [13]. MPH’s therapeutic attentional effects may be secondary to its ability to enhance stimuli-induced DA increases, thus making them more motivationally salient and thereby improving performance [7, 13], which would explain why stimulants improve performance of a boring task in normal healthy individuals and why unmedicated ADHD children perform properly when the task is sufficiently salient to them [1, 5, 6].

Acronyms

ADHD
attention-deficit/hyperactivity disorder
CNS
central nervous system
CSF
cerebrospinal fluid
DAT
dopamine transporter
DA
dopamine
HVA
homovanillic acid
MPH
methylphenidate
PET
positron emission tomography

References

[1]    M. Aman, M. Vamos, and J. Werry. Effects of methylphenidate in normal adults with reference to drug action in hyperactivity. Australian and New Zealand Journal of Psychiatry, 18:86–88, 1984.

[2]    J. Biederman. Attention-deficit/hyperactivity disorder: a life-span perspective. J Clin Psychiatry, 59 Suppl 7:4–16, 1998.

[3]    F. X. Castellanos, J. Elia, M. J. Kruesi, W. L. Marsh, C. S. Gulotta, W. Z. Potter, G. F. Ritchie, S. D. Hamburger, and J. L. Rapoport. Cerebrospinal fluid homovanillic acid predicts behavioral response to stimulants in 45 boys with attention deficit/hyperactivity disorder. Neuropsychopharmacology, 14(2):125–37, Feb 1996. doi: 10.1016/0893-_ 133X(95)00077-_Q.

[4]    D. D. Dougherty, A. A. Bonab, T. J. Spencer, S. L. Rauch, B. K. Madras, and A. J. Fischman. Dopamine transporter density in patients with attention deficit hyperactivity disorder. Lancet, 354(9196):2132–3, 1999. doi: 10.1016/S0140-_6736(99)04030-_1.

[5]    L. Grinspoon and S. B. Singer. Amphetamines in the treatment of hyperkinetic children. Harvard Educational Review, 43:515–555, 1973.

[6]    J. Rapoport and G. Inoff-Germain. Responses to methylphenidate in attention-deficit/hyperactivity disorder and normal children: update 2002. Journal of Attention Disorders, 6:S57–60, 2002.

[7]    D. Repantis, P. Schlattmann, O. Laisney, and I. Heuser. Modafinil and methylphenidate for neuroenhancement in healthy individuals: A systematic review. Pharmacol. Res., 62(3):187–206, Sep 2010.

[8]    M. V. Solanto. Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit hyperactivity disorder: a review and integration. Behavioural Brain Research, 94:127–152, 1998.

[9]     J. M. Swanson, D. Cantwell, M. Lerner, K. McBurnett, and G. Hanna. Effects of stimulant medication on learning in children with adhd. J Learn Disabil, 24(4):219–30, 255, Apr 1991.

[10]    N. D. Volkow, G. Wang, J. S. Fowler, J. Logan, M. Gerasimov, L. Maynard, Y. Ding, S. J. Gatley, A. Gifford, and D. Franceschi. Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain. J Neurosci, 21(2): RC121, Jan 2001.

[11]    N. D. Volkow, J. S. Fowler, G.-J. Wang, and R. Z. Goldstein. Role of dopamine, the frontal cortex and memory circuits in drug addiction: insight from imaging studies. Neurobiol Learn Mem, 78(3):610–24, Nov 2002.

[12]    N. D. Volkow, G.-J. Wang, J. S. Fowler, J. Logan, D. Franceschi, L. Maynard, Y.-S. Ding, S. J. Gatley, A. Gifford, W. Zhu, and J. M. Swanson. Relationship between blockade of dopamine transporters by oral methylphenidate and the increases in extracellular dopamine: therapeutic implications. Synapse, 43(3):181–7, Mar 2002. doi: 10.1002/syn.10038.

[13]    N. D. Volkow, G.-J. Wang, J. S. Fowler, F. Telang, L. Maynard, J. Logan, S. J. Gatley, N. Pappas, C. Wong, P. Vaska, W. Zhu, and J. M. Swanson. Evidence that methylphenidate enhances the saliency of a mathematical task by increasing dopamine in the human brain. Am J Psychiatry, 161(7):1173–80, Jul 2004.

[14]    N. D. Volkow, G.-J. Wang, J. S. Fowler, and Y.-S. Ding. Imaging the effects of methylphenidate on brain dopamine: new model on its therapeutic actions for attention-deficit/hyperactivity disorder. Biol Psychiatry, 57(11): 1410–5, Jun 2005. doi: 10.1016/j.biopsych.2004.11.006.

Actions of Methylphenidate in the Hippocampus

August 18, 2015 at 12:32 AM | categories: hippocampus, mph

Contents

1 Actions of MPH in the Hippocampus

1 Actions of MPH in the Hippocampus

Most of our knowledge of the therapeutic effects of stimulants comes from studies focused on the prefrontal cortex and striatum, but there is increasing evidence of the relevance of catecholaminergic modulation in limbic regions such as the amygdala and hippocampus in mediating the motivation-enhancing effects of stimulant drugs [8, 12]. methylphenidate (MPH) increases hippocampal norepinephrine (NE) and dopamine (DA) in vivo [7, 11], both of which are known to affect plasticity such as long-term potentiation (LTP) and long-term depression (LTD) [1–5, 9, 10]. MPH enhances rat hippocampal NE to an extent comparable to that of striatal DA in microdialysis studies following i.p. injection [6]. Also, oral administration of a low dose of MPH preferentially enhances hippocampal NE efflux without affecting DA in the nucleus accumbens (NAcc) [7].

Acronyms

DA
dopamine
LTD
long-term depression
LTP
long-term potentiation
MPH
methylphenidate
NAcc
nucleus accumbens
NE
norepinephrine

References

[1]    W. F. Hopkins and D. Johnston. Frequency-dependent noradrenergic modulation of long-term potentiation in the hippocampus. Science, 226 (4672):350–352, Oct 1984.

[2]    S. E. Hyman, R. C. Malenka, and E. J. Nestler. Neural mechanisms of addiction: the role of reward-related learning and memory. Annu. Rev. Neurosci., 29:565–598, 2006.

[3]    Y. Izumi, D. B. Clifford, and C. F. Zorumski. Norepinephrine reverses N-methyl-D-aspartate-mediated inhibition of long-term potentiation in rat hippocampal slices. Neurosci Lett, 142(2):163–166, Aug 1992.

[4]    S. Jones and A. Bonci. Synaptic plasticity and drug addiction. Curr Opin Pharmacol, 5(1):20–25, Feb 2005.

[5]    J. A. Kauer. Learning mechanisms in addiction: synaptic plasticity in the ventral tegmental area as a result of exposure to drugs of abuse. Annu. Rev. Physiol., 66:447–475, 2004.

[6]    R. Kuczenski and D. S. Segal. Locomotor effects of acute and repeated threshold doses of amphetamine and methylphenidate: relative roles of dopamine and norepinephrine. J Pharmacol Exp Ther, 296(3):876–83, Mar 2001.

[7]    R. Kuczenski and D. S. Segal. Exposure of adolescent rats to oral methylphenidate: preferential effects on extracellular norepinephrine and absence of sensitization and cross-sensitization to methamphetamine. J Neurosci, 22(16):7264–7271, Aug 2002. doi: 20026690. URL http://dx.doi.org/20026690.

[8]    K. Lehmann, J. Lesting, D. Polascheck, and G. Teuchert-Noodt. Serotonin fibre densities in subcortical areas: differential effects of isolated rearing and methamphetamine. Brain Res Dev Brain Res, 147(1-2):143–52, Dec 2003.

[9]    J. E. Lisman and A. A. Grace. The hippocampal-VTA loop: controlling the entry of information into long-term memory. Neuron, 46 (5):703–713, Jun 2005.

[10]    M. J. Thomas, T. D. Moody, M. Makhinson, and T. J. O’Dell. Activity-dependent beta-adrenergic modulation of low frequency stimulation induced LTP in the hippocampal CA1 region. Neuron, 17(3): 475–482, Sep 1996.

[11]    P. Weikop, T. Yoshitake, and J. Kehr. Differential effects of adjunctive methylphenidate and citalopram on extracellular levels of serotonin, noradrenaline and dopamine in the rat brain. European Neuropsychopharmacology, 17:658–671, 2007.

[12]    T. E. Wilens, L. A. Adler, J. Adams, S. Sgambati, J. Rotrosen, R. Sawtelle, L. Utzinger, and S. Fusillo. Misuse and diversion of stimulants prescribed for ADHD: a systematic review of the literature. J Am Acad Child Adolesc Psychiatry, 47(1):21–31, Jan 2008.

Effects of Chronic Administration of Methylphenidate

August 18, 2015 at 12:06 AM | categories: mph

Contents

1 Chronic Actions of MPH

1 Chronic Actions of MPH

Although the acute effects methylphenidate (MPH) on human and animal behavior have been heavily studied, fewer studies have looked at longer-term effects and the consequences of long-term stimulant medication on the development of the adolescent brain is poorly understood [1]. With stimulant prescriptions to children and adolescents tripling during the 1990s, and seeing continued increases since then, there is a continued need to better understand the effects of MPH [1, 4, 7]. Clear reductions in symptoms justify treatment with stimulant medications [3], and in addition, untreated attention-deficit/hyperactivity disorder (ADHD) adolescents were at a 2-fold higher risk of developing drug abuse than medication-treated peers [10]; however, the long-term cognitive effects are less clear.

Long-term dopamine (DA) agonists often reduce the density of D2 receptors [6], and increase dopamine transporter (DAT) density [9], however, the effects of MPH and other stimulants on the density of DAT and D2 receptors depends on the experimental conditions used [7]. Despite the different ways in which drugs of abuse can affect DAT function, acute and long-term changes in the amount of the DAT at the cell surface emerge as a crucial mechanism in the chronic effects of drugs of abuse [11].

Pretreatment of rats with MPH (4 mg/kg i.p. bi-daily for four days) increases [3H]DA uptake and vesicular monamine transporter 2 (VMAT-2) levels in rat striatal vesicles ex vivo [5]. After 21 day treatment with 3 mg/kg MPH i.p., striatal DAT and basal DA levels were lower than saline treated spontaneously hypertensive rats (SHRs), an animal model of ADHD, however, K+-induced release and amphetamine (AMPH)-challenge induced higher DA release in the MPH treated rats [8]. In contrast, subcutaneous injection of adolescent mice for seven days with MPH (2.5 mg/kg to 80 mg/kg) did not show long-term behavioral effects, with no change in performance in open field, elevated plus maze or spatial learning paradigms [2].

Acronyms

ADHD
attention-deficit/hyperactivity disorder
AMPH
amphetamine
DAT
dopamine transporter
DA
dopamine
MPH
methylphenidate
MTA
The Multimodal Treatment Study of Children with ADHD Cooperative Group
SHR
spontaneously hypertensive rat
VMAT-2
vesicular monamine transporter 2

References

[1]    K. C. F. Fone and D. J. Nutt. Stimulants: use and abuse in the treatment of attention deficit hyperactivity disorder. Curr Opin Pharmacol, 5(1):87–93, Feb 2005. doi: 10.1016/j.coph.2004.10.001.

[2]    M. P. McFadyen, R. E. Brown, and N. Carrey. Subchronic methylphenidate administration has no effect on locomotion, emotional behavior, or water maze learning in prepubertal mice. Dev Psychobiol, 41 (2):123–32, Sep 2002. doi: 10.1002/dev.10059.

[3]    The Multimodal Treatment Study of Children with ADHD Cooperative Group (MTA). A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry, 56: 1073–1086, 1999.

[4]    L. Robison, T. Skaer, D. Sclar, and R. Galin. Is attention deficit hyperactivity disorder increasing among girls in the us?: Trends in diagnosis and the prescribing of stimulants. CNS Drugs, 16(2):129–137, 2002.

[5]    V. Sandoval, E. L. Riddle, G. R. Hanson, and A. E. Fleckenstein. Methylphenidate redistributes vesicular monoamine transporter-2: role of dopamine receptors. J Neurosci, 22(19):8705–10, Oct 2002.

[6]    P. Seeman. Brain dopamine receptors. Pharmacol Rev, 32(3):229–313, Sep 1980.

[7]    P. Seeman and B. K. Madras. Anti-hyperactivity medication: methylphenidate and amphetamine. Mol Psychiatry, 3:386–396, 1998.

[8]    Y. Simchon, A. Weizman, and M. Rehavi. The effect of chronic methylphenidate administration on presynaptic dopaminergic parameters in a rat model for adhd. European Neuropsychopharmacology, 20(10): 714–720, 2010.

[9]    G. Wang, N. Volkow, T. Wigal, S. Kollins, J. Newcorn, F. Telang, J. Logan, C. Wong, J. Fowler, and J. Swanson. Chronic treatment with methylphenidate increases dopamine transporter density in patients with attention deficit hyperactive disorder. In Society of Nuclear Medicine Annual Meeting Abstracts, volume 50, page 1283. Soc Nuclear Med, 2009.

[10]    T. E. Wilens, S. V. Faraone, J. Biederman, and S. Gunawardene. Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? a meta-analytic review of the literature. Pediatrics, 111(1):179–85, Jan 2003.

[11]    J. Zhu and M. E. A. Reith. Role of the dopamine transporter in the action of psychostimulants, nicotine, and other drugs of abuse. CNS Neurol Disord Drug Targets, 7(5):393–409, Nov 2008.

Use of Methylphenidate in Attention/Deficit-Hyperactivity Disorder

August 16, 2015 at 11:53 AM | categories: mph, adhd

Contents

1 Use of MPH in ADHD
  1.0.1 Failures of Stimulant Drugs

1 Use of Methylphenidate in the Treatment of
Attention-Deficit/Hyperactivity Disorder

For near 50 years, the most widely used pharmacological treatment of attention-deficit/hyperactivity disorder (ADHD) is the racemic (50:50) mixture of d-threo-(R,R)-methylphenidate and l-threo-(S,S)-methylphenidate isomers. The clinical effectiveness of racemic methylphenidate (MPH) appears to reside primarily in the d-isomer, the l-MPH isomer of racemic MPH formulations has long been regarded as an inactive component [11]; because of stereospecific pre-systemic metabolism of oral MPH, l-MPH does not reach effective levels in plasma. However, more direct administration of the l-MPH isomer has been shown to inhibit the locomotor stimulation by d-MPH and other stimulants in rats in a dose-dependent fashion [1].

Stimulants have been prescribed to treat restlessness and ADHD symptoms in children since the 1930s, mostly mixed amphetamine (AMPH) salts until the synthesis of MPH in 1944, and the marketing of MPH as Ritalin®; in 1954 [2, 10]. Although newer drugs have been developed, including pure d-MPH, a transdermal patch, osmotic and slow release formulatins, racemic-MPH immediate release is still one of the most highly prescribed drugs for the treatment of ADHD [3]. Non-stimulant drugs have also been used to treat ADHD, however the average effect size for stimulants is greater than for non-stimulants, so non-stimulants are primarily used after stimulants have induced unwanted side-effects in individuals [6].

Though it was once assumed that the beneficial effects of stimulant medications on individuals with ADHD were paradoxical, studies have demonstrated that the direction of response is often the same in healthy individuals without ADHD [15]. Stimulant medications elicit a biphasic action in humans; low doses reduce locomotor activity and distractibility; high doses lead to nervousness, sleeplessness, and anorexia; overdoses show signs of excessive central nervous system stimulation including excessive agitation and anxiety as well as dizziness, nausea, palpitations, increased heart rate, and psychosis [16]. At some doses and on some tasks [5], stimulant drugs may have the same direction of effect (cognitive enhancement) in some individuals without ADHD [4] as well as in those with ADHD.

In Europe, where the prescription of stimulants has been restricted by custom and by law, clinical guidelines recommend an initial rigorous trial of multiple psychosocial interventions such as behaviour modification, cognitive therapy, family therapy and teacher consultation. In North America, where the prescription of stimulants has been accepted for decades and some restrictions have been relaxed, clinical guidelines recommend an initial rigorous pharmacological trial [20]. Over the past decade, the prescriptions for these stimulants (MPH and AMPH) have increased from less that 2 million in 1991 to over 10 million in 2001, and now it is estimated that approximately 6 % of school-age children are identified and treated with these drugs (about 3 million/year in the US) [21].

In the The Multimodal Treatment Study of Children with ADHD Cooperative Group (MTA) [14], the largest and longest study of children with ADHD combined type, aged 7 years to 9.9 years, were randomly assigned to 14 months of treatment in four groups: rigorous medication management; intensive behavioral treatment; the two combined; or standard community care (2∕3 treated with medication). All groups in the study showed reduction of symptoms over time [14]. However, the children in the combined treatment and the medication management groups showed further reduction in core ADHD symptoms than those in behavioral alone, or community care groups [14]. This validates the clinical experience that children who largely adhere to a well-titrated regimen of stimulants continue to benefit significantly for at least 14 months [9]. After the MTA study completed, the caregivers/children determined their continued treatment. Interestingly, most children who were treated with stimulants did not continue this treatment. After 8 years, only 32.5 % of ADHD cases were being treated with stimulant medications [19]. By the 3 year follow-up assessment point, the initial relative benefits of assignment to the medication conditions and of current medication use were no longer significant [8, 12, 17]. In an 8 year follow-up [13], treatment-related improvements during the study were generally maintained, but differential treatment efficacy was lost. There were no differences between the four initially assigned treatment groups on repeated measures of psychiatric symptoms, academic function, and social functioning [13]. There was also no difference between groups for long-term outcomes, e.g. substance use or delinquency [12, 13]. This suggests that the relative benefits of childhood treatment with stimulant medication, compared with non-pharmacological treatments—improvement in cognitive deficits as well as reductions in symptom severity—may dissipate after a 2 year to 3 year period, whether or not the medication component of treatment is continued or withdrawn [13, 17, 18].

In a different long-term study, where subjects had self-selected medication status for 9 years, groups separated into medicated > 1 year (average 5.3 years) or no treatment/short-term treatment, differed on 3 measures of academic achievement and on grade point average, with the medicated group outperforming the non-medicated group regardless of current medication status [19]. Compared with non-ADHD controls, the subgroup of ADHD adolescents not taking medication at follow-up had a more pervasive pattern of significant deficits than the subgroup of ADHD adolescents taking medication. The ADHD subgroup on medication had better performance on sustained attention and verbal learning tests [19].

1.0.1 Failures of Stimulant Drugs

A meta-analysis found that stimulants have a three-fold greater benefit on behaviour ratings than on attention as measured by performance on academic tests [20].

The effect of stimulant drugs can sometimes fade over time. This return of symptoms is usually attributed to drug tachyphylaxis or placebo relapse, and in the case of MPH and other reuptake inhibitors, Hinz et al. [7] suggests that this reduction of drug effect is due to systemic depletion of monoamines and a moderate relative nutritional deficit. When the diet was adjusted to include more of the monoamine precursors l-tryptophan and l-tyrosine and monoamine levels had returned to the normal reference range of the population the problem was corrected and the drug effects returned to previous levels. 97 % of subjects who experienced waning of initial drug effects were suffering from monoamine depletion and monoamine electrical dysfunction secondary to developing a relative nutritional deficit [7].

Acronyms

ADHD
attention-deficit/hyperactivity disorder
AMPH
amphetamine
MPH
methylphenidate
MTA
The Multimodal Treatment Study of Children with ADHD Cooperative Group

References

[1]    R. Baldessarini and A. Campbell. Method of dopamine inhibition using l-threo-methylphenidate, Apr. 2001. US Patent 6,221,883.

[2]    C. Bradley. The behavior of children receiving benzedrine. American Journal of Psychiatry, 94(3):577–585, 1937.

[3]    G. Chai, L. Governale, A. W. McMahon, J. P. Trinidad, J. Staffa, and D. Murphy. Trends of outpatient prescription drug utilization in US children, 2002-2010. Pediatrics, 130(1):23–31, Jul 2012.

[4]    P. L. Clatworthy, S. J. G. Lewis, L. Brichard, Y. T. Hong, D. Izquierdo, L. Clark, R. Cools, F. I. Aigbirhio, J.-C. Baron, T. D. Fryer, and T. W. Robbins. Dopamine release in dissociable striatal subregions predicts the different effects of oral methylphenidate on reversal learning and spatial working memory. J Neurosci, 29(15):4690–6, Apr 2009. doi: 10.1523/JNEUROSCI.3266-_08.2009.

[5]    C. M. Dodds, U. Müller, L. Clark, A. van Loon, R. Cools, and T. W. Robbins. Methylphenidate has differential effects on blood oxygenation level-dependent signal related to cognitive subprocesses of reversal learning. J Neurosci, 28(23):5976–82, Jun 2008. doi: 10.1523/JNEUROSCI.1153-_08. 2008.

[6]    S. V. Faraone and T. Wilens. Does stimulant treatment lead to substance use disorders? J Clin Psychiatry, 64 Suppl 11:9–13, 2003.

[7]    M. Hinz, A. Stein, and T. Uncini. Monoamine depletion by reuptake inhibitors. Drug Healthc Patient Saf, 3:69–77, 2011. doi: 10.2147/DHPS. S24798.

[8]    P. S. Jensen, L. E. Arnold, J. M. Swanson, B. Vitiello, H. B. Abikoff, L. L. Greenhill, L. Hechtman, S. P. Hinshaw, W. E. Pelham, K. C. Wells, C. K. Conners, G. R. Elliott, J. N. Epstein, B. Hoza, J. S. March, B. S. G. Molina, J. H. Newcorn, J. B. Severe, T. Wigal, R. D. Gibbons, and K. Hur. 3-year follow-up of the nimh mta study. J Am Acad Child Adolesc Psychiatry, 46(8):989–1002, Aug 2007. doi: 10.1097/CHI. 0b013e3180686d48.

[9]    G. Kaplan and J. H. Newcorn. Pharmacotherapy for child and adolescent attention-deficit hyperactivity disorder. Pediatr Clin North Am, 58(1):99–120, xi, Feb 2011. doi: 10.1016/j.pcl.2010.10.009.

[10]    K. W. Lange, S. Reichl, K. M. Lange, L. Tucha, and O. Tucha. The history of attention deficit hyperactivity disorder. Atten Defic Hyperact Disord, 2(4):241–55, Dec 2010. doi: 10.1007/s12402-_010-_0045-_8.

[11]    J. S. Markowitz, C. L. DeVane, L. K. Pestreich, K. S. Patrick, and R. Muniz. A comprehensive in vitro screening of d-, l-, and dl-threo-methylphenidate: an exploratory study. J Child Adolesc Psychopharmacol, 16(6):687–98, Dec 2006. doi: 10.1089/cap.2006.16.687.

[12]    B. S. G. Molina, W. E. Pelham, E. M. Gnagy, A. L. Thompson, and M. P. Marshal. Attention-deficit/hyperactivity disorder risk for heavy drinking and alcohol use disorder is age specific. Alcohol Clin Exp Res, 31 (4):643–54, Apr 2007. doi: 10.1111/j.1530-_0277.2007.00349.x.

[13]    B. S. G. Molina, S. P. Hinshaw, J. M. Swanson, L. E. Arnold, B. Vitiello, P. S. Jensen, J. N. Epstein, B. Hoza, L. Hechtman, H. B. Abikoff, G. R. Elliott, L. L. Greenhill, J. H. Newcorn, K. C. Wells, T. Wigal, R. D. Gibbons, K. Hur, P. R. Houck, and MTA Cooperative Group. The mta at 8 years: prospective follow-up of children treated for combined-type adhd in a multisite study. J Am Acad Child Adolesc Psychiatry, 48(5):484–500, May 2009. doi: 10.1097/CHI.0b013e31819c23d0.

[14]    MTA. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry, 56: 1073–1086, 1999.

[15]    J. Rapoport and G. Inoff-Germain. Responses to methylphenidate in attention-deficit/hyperactivity disorder and normal children: update 2002. Journal of Attention Disorders, 6:S57–60, 2002.

[16]    P. Seeman and B. K. Madras. Anti-hyperactivity medication: methylphenidate and amphetamine. Mol Psychiatry, 3:386–396, 1998.

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Mechanisms of Action of Methylphenidate in the Brain

August 15, 2015 at 04:57 PM | categories: mechanisms, mph

Contents

1 Mechanisms of Action of MPH in the Brain
2 MPH Effects on DA
 2.1 Changes in phasic/tonic DA release
3 MPH Effects on NE
4 MPH Effects on 5-HT

1 Mechanisms of Action of MPH in the Brain

methylphenidate (MPH) dose-dependently increases extracellular dopamine (DA) and norepinephrine (NE) indirectly, by blocking the transporters, dopamine transporter (DAT) and norepinephrine transporter (NET) [8, 22, 30, 32]. MPH has higher affinity for the human DAT than NET [9]: Ki of MPH with DAT: 34 nm; Ki of MPH with NET: 339 nm; Ki of MPH with serotonin transporter (5-HTT): > 10,000nm; although there are some differences in NET and DAT affinity by study, it has been widely shown that MPH has very low affinity for the 5-HTT [24]. MPH significantly increases extracellular DA concentrations in the prefrontal cortex, striatum, and nucleus accumbens (NAcc) at roughly similar levels [9, 24]. Although prefrontal regions express low DAT levels [52], the NET has similar affinities for NE and DA [44], and DA is taken up by NETs, as well as co-released by NE neurons [13], which contributes to DA reuptake and mediates DA increases in prefrontal cortex [10, 15, 39, 58, 68]. Under conditions of reduced DAT expression, the NET in NAcc can take over clearance of extracellular DA [11]. Selective NE uptake inhibitors will also increase extracellular DA and NE in prefrontal cortex, but not in NAcc [9, 36, 57] or striatum, under normal conditions [9, 10, 15].

2 MPH Effects on DA

Under physiological conditions, synaptic levels of DA and NE act primarily as neuromodulators, changing the efficacy and activity of other transmitter signals [28] as a function of ongoing neuronal activity [48]. In the striatum, applications of DA reduce the activity of spontaneously active neurons to a greater extent than glutamate-activated neurons [29]. This relative increase in glutamate-induced excitation is assumed to improve signal-to-noise neuronal activation [47].

The effect of stimulant medications on overall DA levels in the brain has been controversial [56]. There are DA deficit hypotheses [35], where MPH works to increase synaptic and extrasynaptic DA, and also DA excess hypotheses [53], where blockade of DAT by MPH activates DA D2 receptors, reducing DA release by DA neurons, with a net effect of reducing DA overall. Later positron emission tomography (PET) studies show that oral MPH increases extrasynaptic DA, suggesting more that clinical MPH doses produce their therapeutic effects by increasing DA and correcting an underlying DA deficit [59, 60, 63]. However, with a lot of focus on DA theories of attention-deficit/hyperactivity disorder (ADHD), it is noteworthy that the majority of drugs shown to be effective in treating ADHD in both stimulant and non-stimulant classes have important effects on NE transmission [12].

Downstream DA effects of stimulants depend on the dose and rate of entry of the drug into the brain, which regulates the time-course of the increase in extracellular DA, the magnitude of the stimulant effect as well as the abuse liability [5, 33, 49]. In the prefrontal cortex, MPH causes large increases in extracellular NE and DA [9, 38]. Similarly, imaging studies in humans have shown that MPH increases extracellular levels of DA in the striatum [62]. MPH-induced increases in extracellular DA in the dorsal striatum and the NAcc may mediate the MPH-induced increases in locomotor activity, stereotyped behaviors, and motor disturbances (such as tics in humans), as well as the rewarding aspects of high doses of the drug [9, 30, 31].

2.1 Changes in phasic/tonic DA release

Stimulant drugs raise extracellular DA concentration, but do not increase pulsatile DA release as much relative to the basal level, in effect reducing the pulsatile peak in relation to the new, higher baseline concentration [49]. MPH [14], dextroamphetamine (D-AMPH) [43], as well as cocaine [26, 43] all increase the level of extracellular DA in the DA-rich regions of the brain, as measured directly by means of intracerebral dialysis. MPH and cocaine block the DAT, slowing reuptake and increasing the extracellular level of DA. D-AMPH also inhibits the DAT, but directly releases DA from intracellular stores [66]. MPH and cocaine do not have this direct releasing action [66]. In addition to impacting the DAT, a recent study shows that MPH also indirectly affects DA transport by the vesicular monamine transporter 2 (VMAT-2) [65]. Importantly, MPH increases DA transport into the membrane-associated vesicles rather than transport into cytoplasmic vesicles, increasing the amount of DA per vesicle [65]. MPH and cocaine have a similar in vitro affinity for the rat DAT [46], and clinical PET studies report that MPH and cocaine have similar in vivo affinity for the DAT in humans as well [61, 63, 64].

The normal resting or basal level of extracellular DA is approximately 4 nm [20, 27], and transiently rises over 60-fold to about 250 nm during a single nerve-impulse. The level of extracellular DA quickly falls back to 4 nm, primarily by diffusion [20] but assisted by the DAT. Uptake through DATs on the plasma membrane of DA neurons is the primary mechanism for regulating the baseline extracellular DA concentration ([DA]o), and thus, the most effective means of restricting DA actions at pre- and post-synaptic receptors [4, 19]. Low doses of stimulant drugs increase the resting [DA]o far more than they increase the nerve-impulse-associated output of DA [23, 49]. The higher baseline levels of DA can effect downstream changes to reduce DA release and make more of the DA receptors low affinity, desensitizing the receptors, which would decrease the sphere of influence of phasic bursting [45, 49, 50], thereby reducing psychomotor activity. However, elevated doses of stimulants can overwhelm the pre- and post-synaptic inhibitory action of DA, saturating and overstimulating postsynaptic DA receptors, leading to hyperdopaminergic somatic, behavioral, and psychological signs and symptoms [49].

3 MPH Effects on NE

Although present theories emphasize the role of the DA system in mediating the anti-hyperactivity action of MPH and other stimulants, there is considerable evidence that these medications have substantial effects on noradrenergic neurotransmission [21, 30, 55]. The noradrenergic system is involved in attentional processes and has been shown to prime the prefrontal cortex for response to sensory stimuli [2, 7, 51]. NE has also been proposed to play a key role in the pathophysiology and pharmacotherapy of ADHD [1, 8, 42, 69]. Low therapeutic doses of MPH might increase NE and DA in the prefrontal cortex by action on the NET to a greater extent than DA increases in the striatum [6, 32]. Similar signal-to-noise adjustments seen in the DA system may also help prefrontal NE signaling to improve attentional, arousal, and cognitive processes [42] by facilitating excitatory transmission through the depression of basal levels of activity [67].

The enhancement of DA and NE neurotransmission in the prefrontal cortex by psychostimulants [9, 38] and NE uptake inhibitors may play a pivotal role in the efficacy of these drugs in ADHD [8, 54].

4 MPH Effects on 5-HT

No acute or chronic dose of MPH altered extracellular concentrations of serotonin [30, 31], consistent with the relatively low affinity of MPH for the 5-HTT [9]. In contrast, Markowitz et al. [37] replicated previous binding experiments showing no or negligible binding of MPH to the serotonin transporter (5-HTT), however they found modest, yet stereoselective, binding of d-MPH to the serotonin 1A receptor (5-HT1A) and serotonin 2B receptor (5-HT2B) receptors. 5-HT1A receptors are localized dendritically as inhibitory autoreceptors on serotonergic cell bodies of the median raphe nucleus, which predominantly innervate the dorsal hippocampus, septum, and hypothalamus, as well as the dorsal raphe nucleus, which provides input to the frontal cortex, ventral hippocampus, and striatum [3] Furthermore, postsynaptic 5-HT1A sites are abundant in the frontal cortex, hippocampus, and other corticolimbic structures. Accordingly, both pre- and postsynaptic 5-HT1A receptors are likely to contribute to the MPH induced modulation of mood, cognition, and motor behavior [3]. At present, relative to 5-HT1A, much less is known about the 5-HT2B receptor, its brain distribution, or general neuropharmacology [3].

It has also recently been shown that MPH alters superior colliculus responsiveness in a stimulation intensity-dependent fashion [16]. The superior colliculus is important in directing saccadic eye movement, and therefore directing attention [34]. In the presence of MPH, evoked responses elicited by low intensity stimulation were reduced in amplitude while those elicited by higher intensity stimulation were largely unaffected [16]. The effects of MPH on response amplitude were mimicked by the application of 1 μm serotonin (5-HT), while a higher concentration (10 μm) of 5-HT produced almost universal response suppression, but still, this was more pronounced at low intensities [16]. Prior application of a 5-HT receptor antagonist blocks these effects, confirming the role of 5-HT [16]. Previously reported examples of monoamine-mediated changes in the signal-to-noise ratio [29, 47], including those caused by 5-HT, have all arisen because of suppression of spontaneous background activity, producing a net increase in signal size [16]. MPH increased the signal-to-noise ratio in the superior colliculus by differentially affecting the impact of weak and strong activations (rather than signal and background), suppressing weak signals and retaining strong signals [16].

These results provide insight into the mechanism by which MPH might act in the superior colliculus to decrease distractibility and improve sustained attention in normal and ADHD subjects. There is suggestion that the colliculus may be dysfunctional in ADHD [41], and consistent with the recognized role of 5-HT transmission in many psychiatric disorders [25, 40], 5-HT selective drugs, such as fluoxetine, have shown therapeutic efficacy in ADHD [16, 18], as well as the associations between 5-HT genes and ADHD, [17].

Acronyms

5-HT1A
serotonin 1A receptor
5-HT2B
serotonin 2B receptor
5-HTT
serotonin transporter
5-HT
serotonin
ADHD
attention-deficit/hyperactivity disorder
D-AMPH
dextroamphetamine
DAT
dopamine transporter
DA
dopamine
MPH
methylphenidate
NAcc
nucleus accumbens
NET
norepinephrine transporter
NE
norepinephrine
PET
positron emission tomography
VMAT-2
vesicular monamine transporter 2

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