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Studies in Sprague-Dawley rats using intracerebral microdialysis combined with HPLC showed that presentation of the animals with a chamber in which they had previously acquired a conditioned reflex fear reaction (combination of a tone and electric shocks) led to increases in extracellular citrulline (a co-product of NO synthesis) in the medial segment of the nucleus accumbens. This increase was prevented by local administration of the NO synthase inhibitor 7-nitroindazole (0.5 mM). The increase was significantly smaller in amplitude than the increase in the citrulline level induced by combined presentation of the tone and the chamber but was no different from changes in citrulline levels seen during this test in the lateral segment of the nucleus accumbens. These data provide evidence that contextual danger signals activate neuronal NO synthase in the medial and perhaps the lateral segments of the nucleus accumbens, leading to increases in extracellular citrulline and, probably, increased NO production in this part of the brain.

Intracerebral microdialysis studies on Sprague-Dawley rats using HPLC showed that performance of a conditioned reflex fear reaction was accompanied by an increase in the extracellular citrulline (a co-product of nitric oxide synthesis) level in the nucleus accumbens. Administration of the selective D1 receptor antagonist SCH-23390 (100 microM) into the nucleus accumbens had no long-lasting effect on the extracellular citrulline level in this structure, but reduced the magnitude of the increase in the citrulline level seen on performance of the conditioned reflex fear reaction. These data suggest that the dopaminergic input of the nucleus accumbens acts via D1 receptors to increase NO synthase activity and nitric oxide production during performance of the conditioned reflex fear reaction.

Intracerebral microdialysis and high-performance liquid chromatography were used to demonstrate that the acquisition and execution of an emotional conditioned reflex in Sprague-Dawley rats are accompanied by increases in extracellular citrulline (a co-product of nitric oxide synthesis) levels in the nucleus accumbens. Injection of the selective NMDA glutamate receptor antagonist MK-801 (100 microM) into the nucleus accumbens significantly decreased the increase in extracellular citrulline seen in this structure on acquisition of the emotional conditioned reflex and completely blocked the increase induced by execution of the reflex. These data suggest that during the acquisition and execution of an emotional conditioned reflex, the glutamatergic input of the nucleus accumbens acts on NMDA receptors to stimulate nitric oxide production in this part of the brain.

In vivo microdialysis combined with high-performance liquid chromatography and electrochemical detection was used to study effects of intraaccumbal infusion of N -methyl- d -aspartate (NMDA) on the content of extracellular citrulline (a nitric oxide co-product) in the medial nucleus accumbens of Sprague–Dawley rats. The intraaccumbal NMDA infusion (10–1000 μM) dose-dependently increased the local dialysate citrulline levels (193 ± 7% and 258 ± 7% versus basal for the 100 and 1000 μM, respectively). The NMDA-induced increase of extracellular citrulline was completely prevented by intraaccumbal infusions through the dialysis probe both of 50 μM dizocilpine maleate (an NMDA antagonist) and of 0.5 mM N -nitro- l -arginine (a nitric oxide synthase inhibitor). Local infusion of N -nitro- l -arginine (0.5 mM) slightly decreased basal citrulline levels in the nucleus accumbens throughout the entire period of the infusion, whereas dizocilpine maleate (50 μM) had no long-lasting effect. These results suggest that NMDA receptor stimulation of the medial nucleus accumbens might cause a local nitric oxide synthase activation resulting in nitric oxide production in this brain area.

It was shown in Sprague-Dawley rats by means of in vivo microdialysis combined with HPLC analysis that presentations to the animals in a home cage of a tone previously paired with a footshock in an experimental chamber produced an increase in extracellular levels of citrulline (an NO co-product) in the medial n. accumbens. The increase was prevented by intraaccumbal infusions of 7-nitroindasole (0.5 mM), a neuronal NO synthase inhibitor and was not observed in rats previously exposed to unpaired tone and footshock presentations and in controls with microdialysis probes implanted into the lateral n. accumbens. The results indicate that sound signals of danger produce a neuronal NO synthase activation within the medial n. accumbens, which leads to citrulline formation and, very likely, to NO production in this brain area.

In Spregue-Dawley rats by means of in vivo microdialysis combined with HPLC analysis, presentation of a chamber in which a conditioned fear response was previously acquired (tone(+) +footshock), resulted in an increase in extracellular level of citrulline (an NO co-product) in the medial nucleus accumbens. This increase was prevented by intraaccumbal infusion of 7-nitraindazole (0.5 mM), an NO synthase inhibitor. It was less than a rise in citrulline extracellular level induced by a combined presentation the chamber and the tone, but did not differ from citrulline changes occurring during the chamber presentation in the lateral nucleus accumbens. The data obtained indicate that conditioned signals of danger cause neuronal NO synthase activation in the medial and, probably, in the lateral nucleus accumbens which produces the rise in extracellular citrulline level and, likely, in NO formation in this brain area.

By means of in vivo microdialysis combined with HPLC analysis it was shown that levels of extracellular citrulline (NO co-product) in the rat n. accumbens increased during expression of a conditioned fear response. Intraaccumbal infusions of a D2 receptor antagonist raclopride (10 microM) decreased the rise of extracellular citrulline produced by expression of the response but did not change behavioral characteristics of conditioned freezing. The raclopride infusions increased exploratory activity inhibited by acquisition of conditioned fear but did not affect the exploration of control rats. These data suggest that dopaminergic input to the n. accumbens and D2 dopamine receptors regulate activity of the accumbal nitrergic system during conditioned fear response and possibly control fear transfer to another behavioral situation.

Nucleus accumbens (N.Acc) contains a subclass of nitric oxide (NO)-generating interneurons that are presumably regulated by the dopamine input. Receptor mechanisms underlying dopamine-NO interaction in the N.Acc are poorly understood. In the current study, we used in vivo microdialysis combined with high-performance liquid chromatography to examine participation of dopamine D1 receptors in regulation of extracellular levels of citrulline (an NO co-product) in the medial N.Acc of Sprague-Dawley rats during both pharmacological challenge and a conditioned fear response. The intraaccumbal infusion of the D1 receptor agonist SKF-38393 (100-500 microM) increased dose-dependently the local dialysate citrulline levels. The SKF-38393-induced increase in extracellular citrulline was prevented by intraaccumbal infusions of 500 microM 7-nitroindazole, a neuronal NO synthase inhibitor. In behavioral microdialysis experiment, the accumbal levels of extracellular citrulline markedly increased in rats given a mild footshock paired with tone. The presentation of the tone previously paired with footshock (the conditioned fear response) produced a "conditioned" rise of extracellular citrulline levels in the N.Acc which was attenuated by intraaccumbal infusion of 100 microM SCH-23390, a dopamine D1 receptor antagonist, and prevented by intraaccumbal infusion of 500 microM 7-nitroindazole. The results suggest that in the N.Acc, the dopamine D1 receptors might regulate the neuronal NO synthase activity; this dopamine-dependent mechanism seems to participate in activation of the neuronal NO synthase and probably NO formation in this brain area during the conditioned fear response.

In Spregue-Dawley rats, by means of in vivo microdialysis combined with HPLC analysis, it was shown that acquisition and expression of conditioned emotional response increased extracellular level of citrulline: a nitric oxide coproduct, in the nucleus accumbens. Intraaccumbal infusion of MK-801 (100 microM): an NMDA antagonist, markedly attenuated the increase in extracellular citrulline in the n. accumbens produced by acquisition of the response, and completely prevented its conditioned rise observed during expression of the response. The data obtained suggest that, during acquisition and expression of the conditioned emotional response, glutamatergic input to the n. accumbens might act via NMDA receptors to stimulate NO production within this brain area.

Intracerebral microdialysis/HPLC studies in Sprague-Dawley rats showed that the acquisition and execution of an emotional conditioned reflex was accompanied by an increase in the extracellular citrulline level in the nucleus accumbens; citrulline is a co-product of nitric oxide synthesis. The increase in the citrulline level evoked by execution of this reflex decreased after injection of 7-nitroindazole (0.5 mM), a selective inhibitor of neuronal NO synthase, into the nucleus accumbens, and was completely blocked by injection of N-nitroarginine (0.5 mM), a non-selective inhibitor NO synthase. The increase in the nucleus accumbens citrulline level seen during execution of the emotional conditioned reflex was prevented by administration of both of these NO synthase inhibitors. These data suggest that during the acquisition and execution of the emotional conditioned reflex, there is an increase in nitric oxide production in the nucleus accumbens, which arises predominantly as a result of activation of neuronal NO synthase.