Differential regulation of synaptic inputs by constitutively released endocannabinoids and exogenous cannabinoids

Shane T. Hentges, Malcolm J. Low, John Williams

Research output: Contribution to journalArticle

104 Citations (Scopus)

Abstract

Endocannabinoid release from a single neuron has been shown to cause presynaptic inhibition of transmitter release at many different sites. Here, we demonstrate that hypothalamic proopiomelanocortin (POMC) neurons release endocannabinoids continuously under basal conditions, unlike other release sites at which endocannabinoid production must be stimulated. The basal endocannabinoid release selectively inhibited GABA release onto POMC neurons, although exogenous administration of cannabinoid agonists also inhibited glutamate release. The CB1 cannabinoid receptor antagonist AM 251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H- pyrazole-3-carboxamide] blocked endocannabinoid-mediated inhibition of GABA release without affecting excitatory synaptic currents, whereas the CB1 receptor agonist WIN 55,212-2 [R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl] pyrol [1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl) methanone monomethanesulfonate] inhibited both inhibitory and excitatory synaptic currents in POMC neurons. These data demonstrate that endogenously released cannabinoids and exogenously applied CB1 receptor agonists can have markedly different effects on synaptic inputs. Furthermore, the data suggest a novel form of endocannabinoid-mediated retrograde inhibition, whereby the regulation of a subset of inputs requires either the removal of tonic presynaptic inhibition caused by endocannabinoids or the engagement of a mechanism that actively inhibits endocannabinoid production.

Original languageEnglish (US)
Pages (from-to)9746-9751
Number of pages6
JournalJournal of Neuroscience
Volume25
Issue number42
DOIs
StatePublished - Oct 19 2005

Fingerprint

Endocannabinoids
Cannabinoids
Pro-Opiomelanocortin
Neurons
Cannabinoid Receptor CB1
gamma-Aminobutyric Acid
Cannabinoid Receptor Antagonists
Cannabinoid Receptor Agonists
Glutamic Acid

Keywords

  • Food intake
  • GABA
  • Hypothalamus
  • POMC
  • Presynaptic
  • Retrograde

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Differential regulation of synaptic inputs by constitutively released endocannabinoids and exogenous cannabinoids. / Hentges, Shane T.; Low, Malcolm J.; Williams, John.

In: Journal of Neuroscience, Vol. 25, No. 42, 19.10.2005, p. 9746-9751.

Research output: Contribution to journalArticle

@article{1a7c0358c3104917b40eb78ae38f403f,
title = "Differential regulation of synaptic inputs by constitutively released endocannabinoids and exogenous cannabinoids",
abstract = "Endocannabinoid release from a single neuron has been shown to cause presynaptic inhibition of transmitter release at many different sites. Here, we demonstrate that hypothalamic proopiomelanocortin (POMC) neurons release endocannabinoids continuously under basal conditions, unlike other release sites at which endocannabinoid production must be stimulated. The basal endocannabinoid release selectively inhibited GABA release onto POMC neurons, although exogenous administration of cannabinoid agonists also inhibited glutamate release. The CB1 cannabinoid receptor antagonist AM 251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H- pyrazole-3-carboxamide] blocked endocannabinoid-mediated inhibition of GABA release without affecting excitatory synaptic currents, whereas the CB1 receptor agonist WIN 55,212-2 [R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl] pyrol [1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl) methanone monomethanesulfonate] inhibited both inhibitory and excitatory synaptic currents in POMC neurons. These data demonstrate that endogenously released cannabinoids and exogenously applied CB1 receptor agonists can have markedly different effects on synaptic inputs. Furthermore, the data suggest a novel form of endocannabinoid-mediated retrograde inhibition, whereby the regulation of a subset of inputs requires either the removal of tonic presynaptic inhibition caused by endocannabinoids or the engagement of a mechanism that actively inhibits endocannabinoid production.",
keywords = "Food intake, GABA, Hypothalamus, POMC, Presynaptic, Retrograde",
author = "Hentges, {Shane T.} and Low, {Malcolm J.} and John Williams",
year = "2005",
month = "10",
day = "19",
doi = "10.1523/JNEUROSCI.2769-05.2005",
language = "English (US)",
volume = "25",
pages = "9746--9751",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "42",

}

TY - JOUR

T1 - Differential regulation of synaptic inputs by constitutively released endocannabinoids and exogenous cannabinoids

AU - Hentges, Shane T.

AU - Low, Malcolm J.

AU - Williams, John

PY - 2005/10/19

Y1 - 2005/10/19

N2 - Endocannabinoid release from a single neuron has been shown to cause presynaptic inhibition of transmitter release at many different sites. Here, we demonstrate that hypothalamic proopiomelanocortin (POMC) neurons release endocannabinoids continuously under basal conditions, unlike other release sites at which endocannabinoid production must be stimulated. The basal endocannabinoid release selectively inhibited GABA release onto POMC neurons, although exogenous administration of cannabinoid agonists also inhibited glutamate release. The CB1 cannabinoid receptor antagonist AM 251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H- pyrazole-3-carboxamide] blocked endocannabinoid-mediated inhibition of GABA release without affecting excitatory synaptic currents, whereas the CB1 receptor agonist WIN 55,212-2 [R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl] pyrol [1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl) methanone monomethanesulfonate] inhibited both inhibitory and excitatory synaptic currents in POMC neurons. These data demonstrate that endogenously released cannabinoids and exogenously applied CB1 receptor agonists can have markedly different effects on synaptic inputs. Furthermore, the data suggest a novel form of endocannabinoid-mediated retrograde inhibition, whereby the regulation of a subset of inputs requires either the removal of tonic presynaptic inhibition caused by endocannabinoids or the engagement of a mechanism that actively inhibits endocannabinoid production.

AB - Endocannabinoid release from a single neuron has been shown to cause presynaptic inhibition of transmitter release at many different sites. Here, we demonstrate that hypothalamic proopiomelanocortin (POMC) neurons release endocannabinoids continuously under basal conditions, unlike other release sites at which endocannabinoid production must be stimulated. The basal endocannabinoid release selectively inhibited GABA release onto POMC neurons, although exogenous administration of cannabinoid agonists also inhibited glutamate release. The CB1 cannabinoid receptor antagonist AM 251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H- pyrazole-3-carboxamide] blocked endocannabinoid-mediated inhibition of GABA release without affecting excitatory synaptic currents, whereas the CB1 receptor agonist WIN 55,212-2 [R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl] pyrol [1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl) methanone monomethanesulfonate] inhibited both inhibitory and excitatory synaptic currents in POMC neurons. These data demonstrate that endogenously released cannabinoids and exogenously applied CB1 receptor agonists can have markedly different effects on synaptic inputs. Furthermore, the data suggest a novel form of endocannabinoid-mediated retrograde inhibition, whereby the regulation of a subset of inputs requires either the removal of tonic presynaptic inhibition caused by endocannabinoids or the engagement of a mechanism that actively inhibits endocannabinoid production.

KW - Food intake

KW - GABA

KW - Hypothalamus

KW - POMC

KW - Presynaptic

KW - Retrograde

UR - http://www.scopus.com/inward/record.url?scp=27144550404&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=27144550404&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.2769-05.2005

DO - 10.1523/JNEUROSCI.2769-05.2005

M3 - Article

VL - 25

SP - 9746

EP - 9751

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 42

ER -