Cortical regulation of subcortical dopamine neurotransmission: contributions of glutamatergic mechanisms

Dysfunction in the cortical regulation of subcortical dopamine (DA) neurotransmission has been proposed to contribute to the pathophysiology of schizophrenia. However, before such a hypothesis can be fully described, it is necessary to establish the normal functional interactions of these systems. To this end, in vivo microdialysis was used to measure extracellular subcortical DA concentrations during electrical stimulation of the prefrontal cortex (PFC) and during feeding in rats. Because excitatory amino acids such as glutamate (Glu) are thought to be the predominant neurotransmitters used by cortical projection neurons, assessing the contributions of Glu receptors to DA release evoked by cortical stimulation and feeding has been the primary focus of these experiments. Bilateral electrical stimulation of the PFC produced a rapid, current-dependent increase in DA release in the striatum and nucleus accumbens (NAc). This response was not affected by local application of the ionotropic Glu receptor antagonist kynurenic acid (KYN). In contrast, local application of the metabotropic Glu receptor agonist ACPD blocked the effects of cortical stimulation. Application of the ionotropic Glu receptor antagonists, AP5 and CNQX, in the ventral tegmental area (VTA) blocked the effect of stimulation on accumbal DA release. Thus, the PFC modulates subcortical DA release and this effect relies on Glu receptors in the VTA but not the NAc. Given that electrical stimulation is an artificial stimulus, it was deemed worthwhile to investigate the role of glutamatergic mechanisms in regulating DA release occurring under natural conditions, i.e. during feeding. Thus, in rats deprived of food for 18 hours, feeding resulted in substantial increases in DA release in the NAc. This effect was potentiated by local application of KYN and was blocked by local ACPD application. The effect of feeding was also markedly attenuated by application of ionotropic Glu receptor antagonists in the VTA. Thus, the neurochemical mechanisms regulating feeding-evoked DA release are consistent with those regulating cortical stimulation-evoked DA release. These results demonstrate that Glu receptor mechanisms in the VTA mediate increases in DA transmission in the NAc evoked by a variety of stimuli. Secondary to this effect, local Glu receptors inhibit basal and evoked DA release in the NAc.Medicine, Faculty ofGraduat