Role of nitric oxide in the periaqueductal gray in defensive behavior in mice: Influence of prior local N-methyl-D-aspartate receptor activation and aversive condition.

Abstract

Glutamate N-methyl-D-aspartate (NMDA) receptor activation within the dorsal column of the periaqueductal gray (dPAG) leads to antinociceptive, autonomic, and behavioral responses characterized as the fear reaction. Activation of NMDA receptors in the brain increases nitric oxide (NO) synthesis, and NO has been proposed to be a mediator of the aversive action of glutamate. This paper reviews a series of studies investigating the effects of neuronal NO synthase (nNOS) inhibition in the dPAG of mice in different aversive conditions. nNOS inhibition by infusion of Nω-propyl-L-arginine (NPLA) prevents fear-like reactions (e.g., jumping, running, freezing) induced by NMDA receptor stimulation within the dPAG and produces anti-aversive effects when injected into the same midbrain site in mice confronted with a predator. Interestingly, nNOS inhibition within the dPAG does not change anxiety-like behavior in mice exposed to the elevated plus maze (EPM), but it reverses the effect of an anxiogenic dose of NMDA injected into the same site in animals subjected to the EPM. Altogether, the results support a role for glutamate NMDA receptors and NO in the dPAG in the regulation of defensive behaviors in mice. However, dPAG nitrergic modulation of anxiety-like behavior appears to depend on the magnitude of the aversive stimulus. Keywords: periaqueductal gray matter (PAG), NMDA receptors, neuronal nitric oxide synthase (nNOS), elevated plus maze (EPM), rat exposure test (RET), mouse.

Ventrolateral periaqueductal gray matter integrative system of defense and antinociception

“…On the other hand, the antinociception that follows the behavioral defensive responses may be related to the activation of the entire circuit underlying fear [ 3 , 14 ]. In fact, time of effect of NMDA into the vlPAG lasts approximately 5 min [ 36 ], as observed in the tail-flick test immediately after the injections of 0.1 nmol NMDA and after 0.3- and 0.6-nmol treatment evaluated in behavioral and respiratory responses. Altogether, these results are consistent with the hypothesis that nociceptive reflexes and immobility may not occur simultaneously [ 35 ].…”