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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