Activation of glutamate neurotransmission in the prefrontal cortex sustains the motoric and dopaminergic effects of phencyclidine.
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 behavioral effects of NMDA antagonists in the rodent is stereotyped motor activity. Although the major cellular correlate of this behavioral activation 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 prefrontal cortex (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 ventral tegmental area (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 cortical dopamine 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 principal site for the regulation of PCP-induced stereotypy and hyperlocomotion, and that this regulation is independent of accumbal dopamine activity.
Takahata
Ryuichi
R
Department of Psychiatry, Yale University School of Medicine, West Haven, CT 06516, USA.
Moghaddam
Bita
B
D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism* / Q000502:physiology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology*; D010622:Phencyclidine / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000502:physiology; D013239:Stereotyped Behavior / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
D018691:Excitatory Amino Acid Antagonists; D017470:Receptors, Glutamate; D018698:Glutamic Acid; D010622:Phencyclidine; D004298:Dopamine