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Electrical stimulation of the medial prefrontal cortex caused glutamate release in the ventral tegmental area (VTA) of freely moving animals. Cathodal stimulation was given through monopolar electrodes in 0.1-ms pulses at an intensity of 300 biA and frequencies of 4-120 Hz. Glutamate was measured in 10-min perfusate samples by HPLC coupled with fluorescence detection following precolumn derivatization with o-phthaldialdehyde/ß-mercaptoethanol. The stimulation-induced glutamate release was frequency dependent and was blocked by the infusion of the sodium channel blocker tetrodotoxin (10 1iM) through the dialysis probe. The stimulation also induced bilateral Fos-like immunoreactivity in ventral tegmental neurons, with a significantly greater number of Fos-positive cells on the stimulated side. These findings add to a growing body of evidence suggesting that the medial prefrontal cortex regulates dopamine release in the nucleus accumbens via its projection to dopamine cell bodies in the VTA. Key Words: Prefrontal cortexVentral tegmental area-Glutamate-Fos-like immunoreactivity-Microdialysis-Electrical stimulation. J. Neurochem. 70, 1503-1512 (1998).There has been considerable recent interest in the possibility that glutamatergic fibers from the medial prefrontal cortex (PFC) to the striatum might presynaptically regulate striatal dopamine release (Giorguieff et al., 1977;Chesselet, 1984;Cheramy et al., 1986;Romo et al., 1986b;Abercrombie and Zigmond, 1990;Grace, 1993;Greenamyre, 1993). Glutamate infusion into the striatum elevates extracellular dopamine, but this effect is insensitive to the perfusion of the sodium channel blocker tetrodotoxin (TTX) (Giorguieff et al., 1977;Roberts and Sharif, 1978;Roberts and Anderson, 1979; Marien et al., 1983;Clow and Jhamandas, 1989;Lonart and Zigmond, 1991; but see Youngren et al., 1993). Disinhibition of prefrontal cortex by local interference with GABAergic transmission (Karremann and Moghaddam, 1996) or by GABA infusion into the medial thalamus (Romo et al., 1986a,b) similarly increases striatal dopamine levels while, at least in the latter case, inhibiting the firing of the ventral tegmental dopaminergic neurons that project to the striatum. However, glutamate antagonists infused into the striaturn tend to have no effect (Carter et al., 1988;Imperato et al., 1990;Leviel et al., 1990; Moghaddarn and Gruen, 1991; Rao et al., 1991;Keefe et al., 1992; or tend to increase extracellular dopamine levels (Barbeito et al., 1990; Moghaddarn and Gruen, 1991). Moreover, prefrontal neurons do not appear to make synaptic contact with doparninergic terminals in the striatum; rather, glutamatergic and dopaminergic terminals each synapse primarily on medium spiny neurons, often on adjacent regions of the same dendritic spine (Bouyer et al., 1984;Sesack and Pickel, 1992;Smith et al., 1994). Thus, a number of groups have begun to look for alternate avenues by which glutamatergic projections from the frontal cortex might influence dopamine levels in the striatum.The PFC sends ...

Chlorisondamine, a quarternary nicotinic antagonist, was given in a dose that crosses the blood-brain barrier, is taken up and concentrated intracellularly by dopaminergic neurons, and induces long-term blockade of the locomotor stimulant and rewarding effects of nicotine. This treatment had no effect on the rewarding effects of lateral hypothalamic brain stimulation, failing to shift the function that relates reward strength to rate of responding (rate-frequency function). That the treatment regimen was sufficient to block nicotinic receptors in the reward system was confirmed by the fact that it completely blocked the ability of normally effective nicotine to potentiate the rewarding effects of stimulation (shift this function to the left). These data add evidence that the direct, endogenous cholinergic contribution to brain stimulation reward is muscarinic and fit with other evidence that the potentiation of brain stimulation reward by exogenous nicotine involves actions on nicotinic receptors native to dopaminergic neurons.

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