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Cited by 13Neurotransmitter Receptor Influence on BehaviorNeuroscience and Neuropharmacology ResearchAttention Deficit Hyperactivity Disorder

Glutaminergic signaling in the caudate nucleus is required for behavioral sensitization to methylphenidate

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King, Nicholas, Floren, Samuel, Kharas, Natasha, Thomas, Ming, Dafny, Nachum·2019·Pharmacology Biochemistry and Behavior
DOI 10.1016/j.pbb.2019.172737PMC PMC6692216
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Abstract

Methylphenidate (MPD) is a widely prescribed psychostimulant for the treatment of attention deficit hyperactivity disorder, and is growing in use as a recreational drug and academic enhancer. MPD acts on the reward/motive and motor circuits of the CNS to produce its effects on behavior. The caudate nucleus (CN) is known to be a part of these circuits, so a lesion study was designed to elucidate the role of the CN in response to acute and chronic MPD exposure. Five groups of n = 8 rats were used: control, sham CN lesions, non-specific electrolytic CN lesions, dopaminergic-specific (6-OHDA toxin) CN lesion, and glutaminergic-specific (ibotenic acid toxin) CN lesions. On experimental day (ED) 1, all groups received saline injections. On ED 2, surgeries took place, followed by a 5-day recovery period (ED 3-7). Groups then received six daily MPD 2.5 mg/kg injections (ED 9-14), then three days of washout with no injection (ED 15-17), followed by a re-challenge with the previous 2.5 mg/kg MPD dose (ED 18). Locomotive activity was recorded for 60 min after each injection by a computerized animal activity monitor. The electrolytic CN lesion group responded to the MPD acute and chronic exposures similarly to the control and sham groups, showing an increase in locomotive activity, i.e. sensitization. The dopaminergic-specific CN lesion group failed to respond to MPD exposure both acute and chronically. The glutaminergic-specific CN lesion group responded to MPD exposure acutely but failed to manifest chronic effects. This confirms the CN's dopaminergic system is necessary for MPD to manifest its acute and chronic effects on behavior, and demonstrates that the CN's glutaminergic system is necessary for the chronic effects of MPD such as sensitization. Thus, the dopaminergic and glutaminergic components of the CN play a significant role in differentially modulating the acute and chronic effects of MPD respectively.

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  1. Reid MS, Hsu KJ, Berger SP. Cocaine and amphetamine preferentially stimulate glutamate release in the limbic system: studies on the involvement of dopamine. Synapse 1997; 27: 95– 105. 9266771
  2. Wang H, Gracy KN, Pickel VM. μ-opioid and NMDA-type glutamate receptors are often colocalized in spiny neurons within patches of the caudate-putamen nucleus. J. Comp. Neurol 1999; 412: 132– 146. 10440715

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Authors
King, N., Floren, S., Kharas, N., Thomas, M., & Dafny, N.
Corresponding author
Dafny, Nachum
ORCID
Venue
Pharmacology Biochemistry and Behavior
Publisher
Elsevier BV
Published
2019-09
Volume
184
Pages
172737
ISSN
0091-3057 (ISSN-L)
DOI
10.1016/j.pbb.2019.172737
PMC
PMC6692216
OpenAlex
W2951926736
Cited by
13
References
131
Citations by year
2025: 2 · 2024: 3 · 2023: 2 · 2022: 4 · 2020: 1 · 2019: 1
FWCI
0.72
Type
journal article
Language
en
Open access
Licence
Locations
  • Pharmacology Biochemistry and Behavior (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
Keywords
methylphenidate, caudate nucleus, behavioral sensitization, dopaminergic system, ibotenic acid lesions, 6-hydroxydopamine lesion, locomotor activity, psychostimulants, chronic drug exposure, acute drug effects
MeSH terms
Central Nervous System Stimulants, Animals, Attention Deficit Disorder with Hyperactivity, Behavior, Animal, Caudate Nucleus, Dopamine, Dose-Response Relationship, Drug, Locomotion, Male, Methylphenidate, Motivation, Reward, Rats, Sprague-Dawley, Dopamine Agonists, Glutamic Acid, Rats

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