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The acute self-stimulation of the medial forebrain bundle was reported to induce the expression of c-Fos, the protein product of c-fos, an immediate early gene, in the central nervous system. In the present study, we examined regional changes in c-Fos expression in several reward-related areas of rat brain in response to short- and long-term exposure to self-stimulation of the medial forebrain bundle. Short-term one-hour stimulation of the medial forebrain bundle for one day after training, which evoked steady self-stimulation behavior, significantly increased the number of c-Fos-positive neurons bilaterally in all of 15 brain structures assayed, as compared to the non-stimulation control. Among them, structures showing a larger number of the stained neurons on the stimulated side were the anterior olfactory nucleus, amygdala, medial caudate-putamen complex, lateral septum, bed nucleus of the stria terminals, ventral pallidum, substantia innominata, lateral preoptic area, medial preoptic area, lateral hypothalamus rostral to the stimulating electrodes, and substantia nigra. Long-term stimulation of the medial forebrain bundle once daily for five successive days, which maintained consistently stable self-stimulation behavior, also increased the number of c-Fos-positive neurons in the aforementioned structures, as compared to the control. However, the long-term rewarding stimulation diminished the increased number of labeled neurons, as compared to the short-term rewarding stimulation. Seven areas, medial caudate-putamen complex, ventral pallidum, substantia innominata, lateral preoptic area, medial preoptic area, rostral lateral hypothalamus and substantia nigra, showed asymmetrical, ipsilateral predominance after the short- and long-term stimulation. However, the stained neuron count in those areas after the long-term stimulation was reduced to less than 50% of that found after the short-term stimulation with the exception of lateral preoptic area and rostral lateral hypothalamus. The results suggest that the development of desensitization of c-Fos response may differ among the reward-relevant brain regions as a consequence of repeated self-stimulation. They also indicate that a larger portion of neurons in the lateral preoptic area and rostral lateral hypothalamus may be implicated in both short- and long-term self-stimulations of the medial forebrain bundle.

Basal expression of the protein products of the inducible immediate early genes (IEGs), c-Fos and Zif268, was investigated in five regions of the rat basal ganglia using immunohistochemistry. In particular, high basal levels of Zif268 but very low levels of c-Fos were seen in the caudate-putamen (CPu). Double immunostaining revealed that many of the constitutively expressed Zif268-positive neurons were GABAergic but very few were cholinergic or neuronal nitric oxide synthase (nNOS)-positive, and some of the Zif268-positive neurons were also immunopositive for a glutamate NMDA receptor subunit NR1 or NR2A. No regional difference between the medial and lateral parts of the CPu was observed in the cellular phenotypes of Zif268-positive neurons. Almost no basal levels of Zif268 were seen in the other four regions: the globus pallidus, entopeduncular nucleus, subthalamic nucleus and substantia nigra pars reticulata. As in the CPu, negligible levels of c-Fos were seen in these four regions. Differential expression of these two IEGs may suggest gene-specific and region-specific functions of c-Fos and Zif268 in the basal ganglia. Constitutive expression of Zif268 existing mainly in the GABAergic neurons in the CPu may at least in part be maintained by glutamatergic afferents.

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