NMDA receptors in the midbrain periaqueductal gray mediate hypothalamically evoked hissing behavior in the cat

The present study was designed to test the hypothesis that the descending pathway from the medial hypothalamus to the dorsal periaqueductal gray (PAG) is critical for the expression of defensive rage behavior in the cat and utilizes excitatory amino acids as a neurotransmitter. In the first phase of the study, monopolar stimulating electrodes were implanted into the medial hypothalamus from which defensive rage behavior could be elicited by electrical stimulation. For the entire study, the hissing response was used as a measure of defensive rage behavior. Cannula electrodes were implanted into the PAG from which defensive rage sites could be identified and were later used for microinfusion of the NMDA receptor antagonist, DL-2-amino-7-phosphoheptanoic acid (AP-7), into behaviorally identified sites within the PAG. Initially, intracerbral microinjections of the NMDA receptor antagonist, AP-7 (0.2, 2.0 nmol), which were placed directly into sites within the PAG from which defensive rage had been elicited, blocked the occurrence of hypothalamic hissing. Microinjections of similar doses of AP-7 into the PAG also blocked the facilitatory effects of medial hypothalamic stimulation upon hissing behavior elicited from the PAG. However, microinjections of 2 nmol into the PAG had no effect upon hissing that was also elicited from the region of the injection site. This finding indicates that AP-7 selectively blocks hissing elicited from the medial hypothalamus and that the suppressive effects of AP-7 cannot be the result of anesthetic or other nonselective properties of the drug. The next phase of the study, which employed immunohistochemical, receptor autoradiographic techniques, identified NMDA receptors to be present in highest concentrations in the dorsolateral aspect of the PAG where defensive rage is typically elicited. The final phase of the study, which employed a combination of retrograde labeling procedures following microinjections of Fluoro-Gold into defensive rage sites in the dorsal PAG and the immunocytochemical labeling of glutamatergic neurons, identified large numbers of neurons in the medial hypothalamus that were labeled positively for both Fluoro-Gold and glutamate. The overall findings of this study support the hypothesis that descending fibers of the medial hypothalamus that supply the dorsal aspect of the PAG mediate defensive rage behavior and utilize excitatory amino acids that act upon NMDA receptors within the dorsal PAG.