Modulation of learned helplessness by 5-hydroxytryptamine(2A) receptor antisense oligodeoxynucleotides

Serotonergic systems have been implicated in the pathogenesis of major depression in humans as well as in learned helplessness (LH), an animal model of depression. To understand the significance of neuronal responses in depression and LH that are mediated by serotonin (5-hydroxytryptamine, 5HT) receptors, we used intracerebroventricular injections to introduce a unique antisense oligonucleotide (ASO) to the 5HT(2A) receptor and determined its effect on LH behavior in Sprague-Dawley rats as determined by an escape-avoidance strategy. Of the rats injected with the 5HT(2A) receptor ASO, 8/16 rats met criteria for LH. By contrast, only 1/15 of the control group injected with 5HT(2A) sense oligonucleotide (SO) met criteria for LH. Quantitative receptor autoradiography revealed significant differences in 5HT(2A) receptor density between ASO and control sense oligonucleotides (SO), in close proximity to the injection site. Significant decreases in 5HT(2A) receptor density caused by of oligonucleotide blockade were found in the CA3 hippocampal region. These data support the view that central 5HT, mediated by the 5HT(2A) receptor, participates in regulating behaviors that are affected by inescapable stress, and that the induction of behavioral depression may be specifically regulated via serotonergic pathways that terminate in this hippocampal subfield.