Chronic Methylphenidate Effects on Brain Gene Expression: An Exploratory Review

Figures & data

Table 1 Monoamine Receptor Genes Affected by MP

Gene / Subunit	Association	Brain Region	Result with MP	References
Grik2	Mutations associated with the motor and higher order cognitive function deficits	Dorsolateral, ventromedial caudate putamen and in the pre-frontal cortex	Long-term exposures cause ↑	[28]
Htr7	Association with impulsivity behaviors	Nucleus accumbens, pre-frontal cortex	Basal behavioral impulsivity ↓	[29]
ADRA2A	Associated with inattentiveness	Pre-frontal cortex, locus coeruleus, amygdala, hippocampus, septum	↑ of inattentive and hyperactive-impulsive symptoms	[30]
GABA	Association with impulsivity behaviors and inhibitory control	Pre-frontal cortex, medial pre-frontal cortex.	↑ age-dependent response responsivity and ↓ GABA levels in adulthood, impulsivity	[31]

Notes: ↑ upregulated/potentiated expression. ↓ downregulated expression. ⊘ no detection or change.

Table 2 Common Post Synaptic Density Genes Affected by MP

Gene / Subunit	Association	Brain Region	Result with MP	References
AMPA	Regulating synaptic transmission at excitatory synapses	Basal ganglia	High dose MP suppressed their receptor-mediated excitatory synaptic currents (EPSCs) via pre-synaptic mechanism	[32]
NMDA	Regulating synaptic transmission at excitatory synapses	Basal ganglia	Low dose MP ↑ ⇑ receptor-mediated EPSCs significantly via post-synaptic mechanism; ↑ ⇓ by high dose MP via pre-synaptic mechanism	[32]
Homer1a	Associated with neural in corticocortical circuits and synaptic plasticity	Hippocampus, PFC, striatum	↑ cognitive function	[33,34]
Zif268/Egr1	Associated with neural plasticity in corticocortical circuits and acts as a transcriptional factor	PFC, striatum	↑ Long-term gene blunting	[33,34]
Shank2	Associated with remodeling and dendritic spine formation, related the AMPAR and NMDAR functioning	Striatum, hippocampus	↑ Cognitive functioning and structure altered	[35]

Notes: ↑ upregulated/potentiated expression. ↓ downregulated expression. ⊘ no detection or change.

Table 3 Summary Results for MP on Gene Expression

Gene(s) Regulated	MP Dosage	Acute or Chronic	General Result	Reference
Neurotransmitter receptor: Grik2, Htr7, (Adr)α1b, GABAA, etc. PSD family: Homer1, Shaknk2, and MAGUK Other: Homer2, Homer3, PSD-95, Htr2a, Drd1, Drd2	0 or 2 mg/kg I.P. once daily	Subchronic; 16 days	Neurotransmitter receptors ↑ PSD family ↑ Other: ∅	[29]
Grik2, Htr7	2 mg/kg/day	Chronic	↑ of both	[28]
Zif268/ Egr1, c-fos, and Homer 1a with agonists: CP94253, 5-HT1B	MP and FLX 5 mg/kg	Acute	5-HT1B agonist: ∅ Homer 1a, ↑ zif268 and c-Fos	[36]
Htr-7, Grik2CAMKII, C-FOS	3 mg/kg MP or vehicle	Acute effects vs Chronic; 14 days	↑ of Htr7, Grik2 Gene expression; MPH ↓ expression of DA D1/D2 receptors, CAMKII and c-FOS	[35]
Zif268 and Homer 1a with D1R antagonist: SCH-23390	2 μg/kg or 10 μg/kg I.P.	10 days	SCH-23390: ↓ both	[37]
ADRA2A	0.5, 0.65 mg/kg	Acute	∅ for Arp2 mRNA or protein expression	[30]
IRSp53, Cdc42, Arp2 (genes associated with neuroplasticity)	2.0 mg/kg MP, twice daily for 15 days	Chronic; 15 days	IRSp53, Arc, IPSp53, Cdc42, Arp2 expression ↑ Arc and IRSp53 were ↓ in the cerebellum	[20]
Potassium channels (TASK-1, TASK-5), intracellular junctions, connexin30, neurotransmitter receptors (adrenergic alpha 1B, kainate 2, serotonin 7, GABA-A); Homer 1, MAGUK MPP3, Shank2	2 mg/kg	Sub-chronic; 16 days	↑ suggesting the therapeutic effects on behavioral plasticity but potentiating genes involved with synaptic plasticity and dendritic formation of dendritic spines	[38]
Homer 1a, Homer 2a/b, Homer 1b/c	2 mg/kg oral	Sub-chronic; 14 days	Homer 1a and Homer 2a/b ↑ in PFC, ∅ Homer 1b/c	[39]
Zif268/ Egr1, Homer1a	6 daily injections of 5 mg/kg; 5 mg/kg FLX; or MP+FLX for 14 days after cocaine challenge (25 mg/kg)	Chronic MP, acute cocaine administration; 14 days	MP alone- modest gene building, FLX alone – no effect Combined group – had pronounced potentiation of MP-induced blunting for both genes	[33]
Zif268/ Egr1, c-fos	5 mg/kg FLX, 2–5 mg/kg MP	Acute, 7 days	↑ both in the striatum and cortex (in 23 sectors)	[40]
Zif268/ Egr1, c-fos	5 mg/kg FLX, 2–5 mg/kg MP	Acute, 5 days	↑ striatum and cortex in the sensorimotor parts; regional specificity	[41]
Zif268/Egr1, Homer1a	0.5, 2, 5, 10 mg/kg MP, 0.02% ascorbic acid, 1 mL/kg, i.p.	Acute	↑ expression of both Homer 1a and Zif 268 in the cortex and striatum	[42]
NMDAR- and AMPAR-EPSCs	0.5mg/kg MP, 10 mg/kg MP	7 days	Low-dose MPH (0.5 mg/kg) ⇑ NMDAR-mediated excitatory synaptic current (EPSCs) via adrenergic receptor activation. High-dose MP ⇓ both NMDAR- and AMPAR-EPSCs	[32]
Glutamate subunits (NR1, NR2A, NRB2)	1 mg/kg IP	Acute	MP ↓ NR1 and NR2B, but not NR2A subunits, in juvenile prefrontal cortex. MP also ↓ NMDAR-EPSCs but increased AMPAR-mediated short-term plasticity. • MP ↑ the probability of LTP induction, but had a small effect on LTD.	[43]

Notes: ↑ upregulated/potentiated expression. ↓ downregulated expression. ∅ no detection or change.

Figure 1 MP pharmacological mechanism of action. A schematic depiction showing presynaptic neurons releasing neurotransmitters into the synapse, the post-synaptic neuron and receptors, and resulting in the elicitation of a response. MP inhibits the reuptake of these transporters on the pre-synaptic neuron, causing the synaptic concentrations of these neurotransmitters to be increased. The image on the far left, in red, shows the effect of MP increasing dopamine in the synaptic cleft. The middle image, in green, shows the same process that occurs with serotonin increasing in the synapse, and the far right, in orange, shows norepinephrine increasing in concentration in the synapse due to MP inhibiting the reuptake transporters.

Figure 2 MP on gene expression, both region and gene specific: circle = upregulated, square = downregulated; black = region of the brain, blue = monoamine neurotransmitter genes and receptors, red = postsynaptic density protein genes.

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