Increase of Extracellular Glutamate and Expression of Fos‐Like Immunoreactivity in the Ventral Tegmental Area in Response to Electrical Stimulation of the Prefrontal Cortex

Abstract

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 ...

Ventral tegmental area involvement in pair bonding in male prairie voles

“…Since blockade of an excitatory influence results in an increase in dopamine release, it is likely that the glutamate receptors being impacted are on GABAergic interneurons [13]. Consistent with this idea is the suggestion that efferent (presumably glutamatergic [39]) projections from the PFC to the VTA may synapse on GABAergic interneurons that ultimately modulate dopamine release in the NAcc [7]. Our results are in accord with this interpretation since GABA receptor blockade also induced partner preferences.…”

Serotonin2C receptor localization in GABA neurons of the rat medial prefrontal cortex: Implications for understanding the neurobiology of addiction

“…Thus, release of GABA via activation of the 5-HT 2C R on parvalbumin-positive mPFC GABA interneurons would be expected to reduce excitatory output from the mPFC to the mesoaccumbens pathway, enabling mPFC 5-HT 2C R to indirectly regulate glutamate and DA levels in the NAc ( Figure 9). In support of this concept, iontophoretic application of the 5-HT 2C R agonist mCPP suppressed spontaneous and/or glutamate-activated firing of PFC neurons (Bergqvist et al, 1999), while electrical stimulation of the rat mPFC enhanced glutamate levels in the VTA (Rossetti et al, 1998) and NAc (You et al, 1998) as well as DA release in the NAc (You et al, 1998); but see (Jackson et al, 2001). Taken in conjunction with the observation that activation of mPFC GABA receptors inhibited both glutamate release in the VTA and NAc and DA release in the NAc (Karreman and Moghaddam, 1996;Harte and O'Connor, 2005), these data suggest that stimulation of mPFC 5-HT 2C R on parvalbumin-positive GABA interneurons would function to reduce excitatory glutamate output as well as subsequent DA neurotransmission within the mesoaccumbens pathway (Figure 9).…”

“…NIH-PA Author Manuscript NIH-PA Author Manuscript 1999), while electrical stimulation of the rat mPFC enhanced glutamate levels in the VTA (Rossetti et al, 1998) and NAc (You et al, 1998) as well as DA release in the NAc (You et al, 1998); but see (Jackson et al, 2001). Taken in conjunction with the observation that activation of mPFC GABA receptors inhibited both glutamate release in the VTA and NAc and DA release in the NAc (Karreman and Moghaddam, 1996;Harte and O'Connor, 2005), these data suggest that stimulation of mPFC 5-HT 2C R on parvalbumin-positive GABA interneurons would function to reduce excitatory glutamate output as well as subsequent DA neurotransmission within the mesoaccumbens pathway (Figure 9).…”

Basic fibroblast growth factor as a mediator of the effects of glutamate in the development of long-lasting sensitization to stimulant drugs: studies in the rat

“…Electrical stimulation of the PFC increases glutamate efflux in the VTA (Rossetti et al 1998), whereas excitotoxic lesions of the PFC prevent amphetamine-induced increases in glutamate efflux in the VTA (Wolf and Xue 1999). There is evidence suggesting that glutamatergic transmission in the PFC-VTA pathway is crucial in the development of sensitization.…”