Mechanisms of Cortical Activation during Hallucinations

Hallucinations are accompanied by cortical activation. Hallucinogens such as LSD are potent agonists at 5-HT2A/C receptors, while atypical antipsychotic drugs are potent antagonists at 5-HT2A/C receptors. We are exploring the mechanisms that subserve cortical activation by hallucinogens such as LSD and DOI. We found that hallucinogens induce expression of the Fos, the protein product of the immediate-early gene c-fos, in cortical neurons through a 5-HT2A-dependent process. We were surprised to observe that DOI does not induce Fos in layer V pyramidal cells that express the 5-HT2A receptor. Instead, Fos is induced in a band of cells concentrated in layer IV (in sensory cortices); these cells lie within the apical dendritic fields of 5-HT2A layer V pyramidal cells. Layer IV receives a glutamatergic input derived from the thalamus, and both AMPA/KA receptor antagonists and lesions of the thalamic input block the cortical activation seen in response to hallucinogens. We interpret these findings to indicate that hallucinogens activate the cortex by targeting 5-HT2A heteroceptors present on thalamocortical neurons to elicit glutamate release, which in turn drives cells of the cortex through AMPA receptor activation.

Recent microdialysis data from our lab supports this view, revealing that both systemic and intracortical DOI increase extracellular glutamate levels through a 5-HT2A-dependent process. One other possibility, however, is that 5-HT2A pyramidal cells of the cortex elaborate a retrograde signal that drives the neurons of layer IV. We are actively exploring this possibility.