The Journal of Neuroscience, December 1, 2000, 20(23):8846-8852
DOI-Induced Activation of the Cortex: Dependence on
5-HT2A Heteroceptors on Thalamocortical Glutamatergic
Neurons
Jennifer L.
Scruggs*,
Sachin
Patel*,
Michael
Bubser, and
Ariel Y.
Deutch
Departments of Psychiatry and Pharmacology and Center for Molecular
Neuroscience, Vanderbilt University School of Medicine, Nashville,
Tennessee 37212
Administration of the hallucinogenic 5-HT2A/2C agonist
1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) induces
expression of Fos protein in the cerebral cortex. To understand the
mechanisms subserving this action of DOI, we examined the consequences
of pharmacological and surgical manipulations on DOI-elicited Fos expression in the somatosensory cortex of the rat. DOI dose-dependently increased cortical Fos expression. Pretreatment with the selective 5-HT2A antagonist MDL 100,907 completely blocked
DOI-elicited Fos expression, but pretreatment with the
5-HT2C antagonist SB 206,553 did not modify DOI-elicited
Fos expression. These data suggest that DOI acts through
5-HT2A receptors to increase cortical Fos expression.
However, we found that DOI did not induce Fos in cortical
5-HT2A immunoreactive neurons but did increase expression in a band of neurons spanning superficial layer V to deep III, within
the apical dendritic fields of layer V
5-HT2A-immunoreactive cells. This band of Fos
immunoreactive neurons was in register with anterogradely labeled axons
from the ventrobasal thalamus, which have previously been shown to be
glutamatergic and express the 5-HT2A transcript. The
effects of DOI were markedly reduced in animals pretreated with the
AMPA/KA antagonist GYKI 52466, and lesions of the ventrobasal thalamus
attenuated DOI-elicited Fos expression in the cortex. These data
suggest that DOI activates 5-HT2A receptors on
thalamocortical neurons and thereby increases glutamate release, which
in turn drives Fos expression in cortical neurons through an AMPA
receptor-dependent mechanism. These data cast new light on the
mechanisms of action of hallucinogens.
Key words:
AMPA receptor; DOI; Fos; glutamate; hallucinogen; pyramidal cell; serotonin; somatosensory cortex; thalamus; 5-HT2A receptor
*
J.L.S. and S.P. contributed equally to the work.
Correspondence should be addressed to Ariel Y. Deutch, Psychiatric
Hospital at Vanderbilt, Suite 313, 1601 23rd Avenue South, Nashville,
TN 37212. E-mail:
ariel.deutch{at}mcmail.vanderbilt.edu.
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