DOI-Induced Activation of the Cortex: Dependence on 5-HT2AHeteroceptors on Thalamocortical Glutamatergic Neurons

A hallucinogenic drug that activates 5-HT2A receptors increases Fos protein expression in the rat somatosensory cortex. This effect depends on 5-HT2A, not 5-HT2C, receptors and requires intact thalamocortical connections. The drug does not act directly on cortical neurons but instead stimulates 5-HT2A receptors on thalamocortical neurons, increasing glutamate release, which then drives Fos expression in cortical neurons via AMPA receptors. Blocking AMPA/KA receptors or lesioning the ventrobasal thalamus reduces the effect. These findings illuminate how hallucinogens produce their effects through a thalamocortical glutamate pathway.

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Abstract

Administration of the hallucinogenic 5-HT 2A/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-HT 2A antagonist MDL 100,907 completely blocked DOI-elicited Fos expression, but pretreatment with the 5-HT 2C antagonist SB 206,553 did not modify DOI-elicited Fos expression. These data suggest that DOI acts through 5-HT 2A receptors to increase cortical Fos expression. However, we found that DOI did not induce Fos in cortical 5-HT 2A 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-HT 2A -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-HT 2A 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-HT 2A 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.