cAMP and Extracellular Signal-Regulated Kinase Signaling in Response to D-Amphetamine and Methylphenidate in the Prefrontal Cortex in Vivo: Role of β1-Adrenoceptors
Abstract
d-Amphetamine and methylphenidate are widely used in the treatment of attention-deficit/hyperactivity disorder. Both drugs increase extracellular norepinephrine and dopamine in the prefrontal cortex, where they are believed to exert their therapeutic effects. However, the molecular mechanisms underlying their action are poorly understood. To investigate the intracellular signaling pathways activated by d-amphetamine and methylphenidate in the prefrontal cortex in vivo in mice, we measured the cAMP-dependent Ser845 phosphorylation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluR1 subunit and the active form of extracellular signal-regulated kinase (ERK). Administration of d-amphetamine (5-10 mg/kg) or methylphenidate (10-20 mg/kg) increased phosphorylation of GluR1. Basal and d-amphetamine-induced GluR1 phosphorylation was reduced by propranolol, a general beta-adrenoceptor antagonist, and betaxolol, a beta1-antagonist, but not by (+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol (ICI-118,515), a beta2-antagonist. The effect of methylphenidate was also blocked by propranolol and betaxolol. The d-amphetamine effect was slightly potentiated by prazosin, an alpha1-adrenoceptor antagonist, and mimicked by yohimbine, an alpha2 antagonist. Blockade of dopamine or N-methyl-d-aspartate (NMDA) receptors or serotonin depletion had no effect on d-amphetamine-induced GluR1 phosphorylation. d-amphetamine but not methylphenidate in…
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MPH modulates several other proteins including adrenergic, DA and glutamate receptors (ADRA2A, ADRA2B, ADRB1, DRD1, DRD5, DRD2, GRIA1).
“First, other NT pathways have been reported to be stimulated by MPH, including adrenergic, DA and glutamate receptors (e.g. alpha-2A adrenergic receptor [ADRA2A] and alpha-2B adrenergic receptor [ADRA2B], beta-1 adrenergic receptor [ADRB1], DA receptor 1A [DRD1], DA receptor 1B [DRD5], DA receptor 2 [DRD2]) and glutamate receptor 1 (GRIA1) [142–144].”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [143]
MPH upregulates ADRA2A, ADRA2B and ADRD1B receptors located in postsynaptic neurons.
“MPH also upregulates ADRA2A, ADRA2B and ADRD1B receptors located in postsynaptic neurons.”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [143]
The stimulation of these receptors probably leads to the GRIA1 receptor phosphorylation promoted by MPH, as described by Pascoli et al.
“The stimulation of these receptors probably leads to the GRIA1 receptor phosphorylation promoted by MPH, as described by Pascoli et al. [143].”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [143]
The assessment of the effect of MPH on the two major signalling pathways (PKA and ERK) in PFC showed no activation of ERK2 phosphorylation.
“The assessment of the effect of MPH on the two major signalling pathways (cAMP-dependent protein kinase [PKA] and extracellular signal-regulated kinase [ERK]) in PFC [143] showed no activation of ERK2 phosphorylation.”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [143]
MPH effects on these signalling pathways were totally inhibited using ADRD1B blockers, showing that ADRD1B mediates the phosphorylation of PKA signalling through MPH in the PFC.
“However, the MPH effects on these signalling pathways were totally inhibited using ADRD1B blockers, showing that ADRD1B mediates the phosphorylation of PKA signalling through MPH in the PFC [143].”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [143]
MPH has a broader range of modulation encompassing dopaminergic and adrenergic neurotransmission, inducing activation of ADRB1 and DRD2, modulating proteins involved in neuronal survival such as BCL2, BAX, CASP3 and CYC1, acting as an immunoregulator owing to its effect on TNF, and affecting circadian rhythm through CREB1.
“MPH has a broader range of modulation encompassing dopaminergic and adrenergic neurotransmission, inducing the activation of ADRB1 and DRD2 [143, 144] and modulating proteins involved in neuronal survival such as BCL2, BAX, CASP3 and CYC1 [147], acting as an immunoregulator owing to its effect on TNF [148] and affecting circadian rhythm through CREB1, involved in its synchronization [148].”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [143]
d-Amphetamine activated the phosphorylation of both PKA and ERK pathways through ADRD1B.
“d-Amphetamine activated the phosphorylation of both pathways through ADRD1B [143].”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [143]
ADRA blockers did not inhibit the ERK phosphorylation although its effect was slightly reduced; this reflects the major role of DRD in ERK activation by d-amphetamines with a slight contribution of ADRA2.
“ADRA blockers did not inhibit the ERK phosphorylation although its effect was slightly reduced; this reflects the major role of DRD in ERK activation by d-amphetamines with a slight contribution of ADRA2 [143].”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [143]
d-Amphetamine phosphorylates GRIA and, as with MPH, it could derive from the stimulation of dopamine D1/D5 receptors.
“Moreover, d-amphetamine phosphorylates GRIA and, as with MPH, it could derive from the stimulation of dopamine D1/D5 receptors [143].”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [143]
NE neurotransmission seemed also to be modulated via ADRA1 and ADRA2.
“In this sense, NE neurotransmission seemed also to be modulated via ADRA1 and ADRA2 [143].”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [143]
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Methylphenidate and cocaine: the same effects on gene regulation?
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“However, the MPH effects on these signalling pathways were totally inhibited using ADRD1B blockers, showing that ADRD1B mediates the phosphorylation of PKA signalling through MPH in the PFC [143].”
BackgroundInfluential
- Authors
- Pascoli, V., Valjent, E., Corbillé, A.-G., Corvol, J.-C., Tassin, J.-P., Girault, J.-A., & Hervé, D.
- Affiliations
- Inserm (FR)
- ORCID
- Venue
- Molecular Pharmacology
- Publisher
- Elsevier BV
- Published
- 2005-08
- Volume
- 68
- Issue
- 2
- Pages
- 421-429
- ISSN
- 0026-895X (ISSN-L)
- OpenAlex
- W2140736710
- Cited by
- 59
- References
- 4
- Citations by year
- 2025: 4 · 2023: 3 · 2022: 2 · 2020: 2 · 2019: 3 · 2018: 2 · 2017: 5 · 2016: 1 · 2015: 5 · 2014: 1 · 2013: 2 · 2012: 5
- FWCI
- 1.56
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Novartis
- Novartis Pharma
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- d-amphetamine, methylphenidate, prefrontal cortex, cAMP signaling, ERK1/2 phosphorylation, beta1-adrenergic receptor, GluR1 phosphorylation, AMPA receptors, adrenergic signaling, attention deficit hyperactivity disorder, hyperlocomotion, propranolol, betaxolol, prazosin, yohimbine
- MeSH terms
- Cyclic AMP, Animals, Dextroamphetamine, Male, Methylphenidate, Mice, Inbred C57BL, Prefrontal Cortex, Receptors, Adrenergic, beta-1, MAP Kinase Signaling System, Extracellular Signal-Regulated MAP Kinases, Mice
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