Activation of lateral hypothalamic group III metabotropic glutamate receptors suppresses cocaine-seeking following abstinence and normalizes drug-associated increases in excitatory drive to orexin/hypocretin cells

Jiann W. Yeoh, Morgan H. James, Cameron D. Adams, Jaideep S. Bains, Takeshi Sakurai, Gary Aston Jones, Brett A. Graham, Christopher V. Dayas

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The perifornical/lateral hypothalamic area (LHA) orexin (hypocretin) system is involved in drug-seeking behavior elicited by drug-associated stimuli. Cocaine exposure is associated with presynaptic plasticity at LHA orexin cells such that excitatory input to orexin cells is enhanced acutely and into withdrawal. These changes may augment orexin cell reactivity to drug-related cues during abstinence and contribute to relapse-like behavior. Studies in hypothalamic slices from drug-naïve animals indicate that agonism of group III metabotropic glutamate receptors (mGluRs) reduces presynaptic glutamate release onto orexin cells. Therefore, we examined the group III mGluR system as a potential target to reduce orexin cell excitability in-vivo, including in animals with cocaine experience. First, we verified that group III mGluRs regulate orexin cell activity in behaving animals by showing that intra-LHA infusions of the selective agonist L-(+)-2-Amino-4-phosphonobutyric acid (L-AP4) reduces c-fos expression in orexin cells following 24 h food deprivation. Next, we extended these findings to show that intra-LHA L-AP4 infusions reduced discriminative stimulus-driven cocaine-seeking following withdrawal. Importantly, L-AP4 had no effect on lever pressing for sucrose pellets or general motoric behavior. Finally, using whole-cell patch-clamp recordings from identified orexin cells in orexin-GFP transgenic mice, we show enhanced presynaptic drive to orexin cells following 14d withdrawal and that this plasticity can be normalized by L-AP4. Together, these data indicate that activation of group III mGluRs in LHA reduces orexin cell activity in vivo and may be an effective strategy to suppress cocaine-seeking behavior following withdrawal. These effects are likely mediated, at least in part, by normalization of presynaptic plasticity at orexin cells that occurs as a result of cocaine exposure. This article is part of the Special Issue entitled ‘Hypothalamic Control of Homeostasis’.

Original languageEnglish (US)
Pages (from-to)22-33
Number of pages12
JournalNeuropharmacology
Volume154
DOIs
StatePublished - Aug 1 2019

Fingerprint

Metabotropic Glutamate Receptors
Cocaine
Lateral Hypothalamic Area
Pharmaceutical Preparations
Drive
Orexins
Drug-Seeking Behavior
Food Deprivation
Transgenic Mice
Cues
Sucrose
Glutamic Acid
Homeostasis

All Science Journal Classification (ASJC) codes

  • Cellular and Molecular Neuroscience
  • Pharmacology

Keywords

  • Discriminative stimuli
  • Plasticity
  • Reinstatement
  • Withdrawal
  • mglur

Cite this

Yeoh, Jiann W. ; James, Morgan H. ; Adams, Cameron D. ; Bains, Jaideep S. ; Sakurai, Takeshi ; Aston Jones, Gary ; Graham, Brett A. ; Dayas, Christopher V. / Activation of lateral hypothalamic group III metabotropic glutamate receptors suppresses cocaine-seeking following abstinence and normalizes drug-associated increases in excitatory drive to orexin/hypocretin cells. In: Neuropharmacology. 2019 ; Vol. 154. pp. 22-33.
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abstract = "The perifornical/lateral hypothalamic area (LHA) orexin (hypocretin) system is involved in drug-seeking behavior elicited by drug-associated stimuli. Cocaine exposure is associated with presynaptic plasticity at LHA orexin cells such that excitatory input to orexin cells is enhanced acutely and into withdrawal. These changes may augment orexin cell reactivity to drug-related cues during abstinence and contribute to relapse-like behavior. Studies in hypothalamic slices from drug-na{\"i}ve animals indicate that agonism of group III metabotropic glutamate receptors (mGluRs) reduces presynaptic glutamate release onto orexin cells. Therefore, we examined the group III mGluR system as a potential target to reduce orexin cell excitability in-vivo, including in animals with cocaine experience. First, we verified that group III mGluRs regulate orexin cell activity in behaving animals by showing that intra-LHA infusions of the selective agonist L-(+)-2-Amino-4-phosphonobutyric acid (L-AP4) reduces c-fos expression in orexin cells following 24 h food deprivation. Next, we extended these findings to show that intra-LHA L-AP4 infusions reduced discriminative stimulus-driven cocaine-seeking following withdrawal. Importantly, L-AP4 had no effect on lever pressing for sucrose pellets or general motoric behavior. Finally, using whole-cell patch-clamp recordings from identified orexin cells in orexin-GFP transgenic mice, we show enhanced presynaptic drive to orexin cells following 14d withdrawal and that this plasticity can be normalized by L-AP4. Together, these data indicate that activation of group III mGluRs in LHA reduces orexin cell activity in vivo and may be an effective strategy to suppress cocaine-seeking behavior following withdrawal. These effects are likely mediated, at least in part, by normalization of presynaptic plasticity at orexin cells that occurs as a result of cocaine exposure. This article is part of the Special Issue entitled ‘Hypothalamic Control of Homeostasis’.",
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Activation of lateral hypothalamic group III metabotropic glutamate receptors suppresses cocaine-seeking following abstinence and normalizes drug-associated increases in excitatory drive to orexin/hypocretin cells. / Yeoh, Jiann W.; James, Morgan H.; Adams, Cameron D.; Bains, Jaideep S.; Sakurai, Takeshi; Aston Jones, Gary; Graham, Brett A.; Dayas, Christopher V.

In: Neuropharmacology, Vol. 154, 01.08.2019, p. 22-33.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Activation of lateral hypothalamic group III metabotropic glutamate receptors suppresses cocaine-seeking following abstinence and normalizes drug-associated increases in excitatory drive to orexin/hypocretin cells

AU - Yeoh, Jiann W.

AU - James, Morgan H.

AU - Adams, Cameron D.

AU - Bains, Jaideep S.

AU - Sakurai, Takeshi

AU - Aston Jones, Gary

AU - Graham, Brett A.

AU - Dayas, Christopher V.

PY - 2019/8/1

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