A major role for thalamocortical afferents in serotonergic hallucinogen receptor function in the rat neocortex

Activation of 5-hydroxytryptamine_2A (5-HT_2A) receptors by hallucinogenic drugs is thought to mediate many psychotomimetic effects including changes in affect, cognition and perception. Conversely, blockade of 5-HT_2A receptors may mediate therapeutic effects of many atypical antidepressant and antipsychotic drugs. The purpose of the present study was to determine the source of subcortical glutamatergic afferents, which would project widely throughout the anterior-posterior axis of the rat brain to the apical dendrites of layer V pyramidal cells of the medial prefrontal cortex, from which serotonin induces transmitter release via activation of 5-HT_2A receptors. Fiber-sparing chemical lesions of the medial thalamus selectively decreased the frequency of serotonin-induced excitatory postsynaptic currents recorded from layer V pyramidal cells in the prelimbic region of the medial prefrontal cortex by 60%. In contrast, large bilateral lesions of the amygdala did not alter the serotonin response. These thalamic lesions significantly decreased the amount of binding to either μ-opioid or metabotropic glutamate 2/3 receptors in the prelimbic region of the medial prefrontal cortex as expected from previous evidence that these agonists for these receptors suppress serotonin-induced excitatory postsynaptic currents by a presynaptic mechanism. Surprisingly, the amount of specific binding to cortical 5-HT_2A receptors was significantly increased by the medial thalamic lesions. Thus, these experiments demonstrate that activation of cortical 5-HT_2A receptors modulates transmitter release from thalamocortical terminals. Unexpectedly, lesioning the thalamocortical terminals also alters 5-HT_2A receptor binding in the prefrontal cortex. These findings are of interest with respect to understanding therapeutic effects of antidepressant/antipsychotic drugs and the known behavioral effects of thalamic lesions in humans.