Activation of mGluR5 induces spike afterdepolarization and enhanced excitability in medium spiny neurons of the nucleus accumbens by modulating persistent Na+ currents.
The involvement of metabotropic glutamate receptors type 5 (mGluR5) in drug-induced behaviours is well-established but limited information is available on their functional roles in addiction-relevant brain areas like the nucleus accumbens (NAc). This study demonstrates that pharmacological and synaptic activation of mGluR5 increases the spike discharge of medium spiny neurons (MSNs) in the NAc. This effect was associated with the appearance of a slow afterdepolarization (ADP) which, in voltage-clamp experiments, was recorded as a slowly inactivating inward current. Pharmacological studies showed that ADP was elicited by mGluR5 stimulation via G-protein-dependent activation of phospholipase C and elevation of intracellular Ca(2+) levels. Both ADP and spike aftercurrents were significantly inhibited by the Na(+) channel-blocker, tetrodotoxin (TTX). Moreover, the selective blockade of persistent Na(+) currents (I(NaP)), achieved by NAc slice pre-incubation with 20 nm TTX or 10 \#956;m riluzole, significantly reduced the ADP amplitude, indicating that this type of Na(+) current is responsible for the mGluR5-dependent ADP. mGluR5 activation also produced significant increases in I(NaP), and the pharmacological blockade of this current prevented the mGluR5-induced enhancement of spike discharge. Collectively, these data suggest that mGluR5 activation upregulates I(NaP) in MSNs of the NAc, thereby inducing an ADP that results in enhanced MSN excitability. Activation of mGluR5 will significantly alter spike firing in MSNs in vivo, and this effect could be an important mechanism by which these receptors mediate certain aspects of drug-induced behaviours.
Institute of Human Physiology, Catholic University 'S. Cuore', Rome, Italy.
Marcello
M
D'Ascenzo
Maria Vittoria
MV
Podda
Tommaso
T
Fellin
Gian Battista
GB
Azzena
Philip
P
Haydon
Claudio
C
Grassi
D000200:Action Potentials; D000818:Animals; D002396:Catechols / Q000494:pharmacology; D055724:Electrophysiological Phenomena; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009714:Nucleus Accumbens / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism
D002396:Catechols; C578935:GRM5 protein, human; C578936:Grm5 protein, mouse; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D019831:Sodium-Calcium Exchanger; C099561:3,4-dihydroxyphenylglycine; D012964:Sodium; D005998:Glycine