Activation of glutamate neurotransmission in the prefrontal cortex sustains the motoric and dopaminergic effects of phencyclidine

Ryuichi Takahata, Bita Moghaddam

Research output: Contribution to journalArticlepeer-review

117 Scopus citations

Abstract

N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) produce schizophrenia-like symptoms in healthy individuals, thus generating interest in understanding the mechanisms by which these drugs modify behavior. The hallmark of the behavioraleffects of NMDA antagonists in the rodent is stereotyped motor activity. Although the major cellular correlate of this behavioralactivation is thought to be an increase in dopamine neurotransmission in the nucleus accumbens (NAc), recent evidence suggests that NAc dopamine is neither necessary nor sufficient to elicit NMDA antagonist-induced motor effects. Based on our previous observation that NMDA antagonists increase glutamate efflux in the prefrontalcortex (PFC), and thus increase non-NMDA receptor glutamatergic neurotransmission in this region, we hypothesized that an increase in PFC efferent activity would activate motor pathways, independent of dopamine neurotransmission in the NAc. We tested this hypothesis by measuring dopaminergic and motoric effects of PCP while blocking non-NMDA receptors in the PFC, or in the ventraltegmentalarea (VTA) and NAc. Both VTA and NAc receive direct glutamatergic input from the PFC, and are implicated in the regulation of motor behavior. Blocking non-NMDA receptors in the PFC, NAc, or the VTA inhibited PCP-induced locomotion and stereotypy. This blockade was accompanied by an inhibition of PCP’s effect on corticaldopamine release. However, the PCP-induced increase in NAc dopamine was not diminished, despite the behavioral inhibition. These findings suggest that the PFC may be a principalsite for the regulation of PCP-induced stereotypy and hyperlocomotion, and that this regulation is independent of accumbaldopamine activity.

Original languageEnglish (US)
Pages (from-to)1117-1124
Number of pages8
JournalNeuropsychopharmacology
Volume28
Issue number6
DOIs
StatePublished - Jun 2003
Externally publishedYes

Keywords

  • Locomotion
  • Microdialysis
  • NMDA receptor
  • Prefrontalcortex
  • Schizophrenia
  • Stereotypy

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

Fingerprint Dive into the research topics of 'Activation of glutamate neurotransmission in the prefrontal cortex sustains the motoric and dopaminergic effects of phencyclidine'. Together they form a unique fingerprint.

Cite this