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 of / Graduate
| Identifer | oai:union.ndltd.org:UBC/oai:circle.library.ubc.ca:2429/6199 |
| Date | 11 1900 |
| Creators | Taber, Matthew Thomas |
| Source Sets | University of British Columbia |
| Language | English |
| Detected Language | English |
| Type | Text, Thesis/Dissertation |
| Format | 6744567 bytes, application/pdf |
| Rights | For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use. |
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