Prefrontal stimulation of GABAA receptors counteracts the corticolimbic hyperactivity produced by NMDA antagonists in the prefrontal cortex of the rat.
BACKGROUND
The hypofunction of NMDA receptors in the prefrontal cortex (PFC) has been suggested to produce corticolimbic hyperactivity through the reduction of cortical GABA transmission.


OBJECTIVE
The present study investigates the effects of injections of the NMDA antagonist 3-[(R)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid (CPP) into the PFC on (1) the release of dopamine and/or acetylcholine in the amygdala and hippocampus, (2) the levels of corticosterone in the hippocampus and (3) spontaneous motor activity. Also, the stimulation of GABA(A) receptors, by prefrontal injections of muscimol, on the effects produced by NMDA antagonists on these same neurochemical, hormonal and behavioural parameters was evaluated.


METHODS
Male Wistar rats were implanted with guide cannulae to perform bilateral microinjections into the PFC and microdialysis experiments in the amygdala and/or ventral hippocampus, simultaneously. Spontaneous motor activity was monitored in the open field.


RESULTS
Injections of CPP (1 μg/0.5 μl) into the PFC increased dialysate concentrations of dopamine and acetylcholine in the amygdala, acetylcholine and free corticosterone in the hippocampus and also motor activity. Simultaneous injections of muscimol (0.5 μg/0.5 μl) into the PFC counteracted the increases of dopamine and acetylcholine in the amygdala and hippocampus and also significantly reduced the peak increase of corticosterone in the hippocampus. Injections of muscimol (0.05 and 0.5 μg/0.5 μl) reduced the increases of motor activity produced by prefrontal NMDA antagonists.


CONCLUSIONS
These results suggest that the hypofunction of NMDA receptors in the PFC produces corticolimbic hyperactivity through the activation of prefrontal efferent projections to subcortical/limbic areas.
Del Arco
Alberto
A
Department of Physiology, Faculty of Medicine, Universidad Complutense, Avda. Complutense s/n, 28040, Madrid, Spain. adelarco@med.ucm.es
Ronzoni
Giacomo
G
Mora
Francisco
F
D000109:Acetylcholine / Q000378:metabolism; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003345:Corticosterone / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008032:Limbic System / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects; D009118:Muscimol / Q000008:administration & dosage / Q000494:pharmacology*; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors
D018691:Excitatory Amino Acid Antagonists; D058785:GABA-A Receptor Agonists; D010879:Piperazines; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D009118:Muscimol; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D000109:Acetylcholine; D004298:Dopamine; D003345:Corticosterone