Vol. 282, Issue 2, 699-706, 1997

Direct Injection of 5-HT_2A Receptor Agonists into the Medial Prefrontal Cortex Produces a Head-Twitch Response in Rats¹

David L. Willins and Herbert Y. Meltzer²

Department of Psychiatry, Case Western Reserve University, School of Medicine, Cleveland, Ohio

The serotonin (5-HT)_2A/2c agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), the 5-HT_2C agonist 6-chloro-2-[1-piperazinyl]-pyrazine and the 5-HT_2A partial agonist m-chloro-phenylpiperazine (mCPP) were injected bilaterally into the medial prefrontal cortex of male rats. DOI and mCPP, but not 6-chloro-2-[1-piperazinly]-pyrazine, elicited a dose-dependent head-twitch response (HTR). DOI-induced HTR had an ED₅₀ of 12.8 nmoles/0.5 µl/side and was inhibited by the 5-HT_2A antagonists ketanserin and MDL 100,907 but was not blocked by pretreatment with the selective 5-HT_2C/2B antagonist SDZ SER 082. The HTR to mCPP demonstrated a bell-shaped dose-response curve with an ED₅₀ of 1.5 nmoles/0.5 µl/side and a peak effect after 3 nmoles/side. The response to mCPP was greatly diminished by both ketanserin and MDL 100,907 and was partially reversed by SDZ SER 082. These findings suggest that the HTR produced by the direct injection of serotonergic agonists into the medial prefrontal cortex is, in part, mediated by the activation of 5-HT_2A receptors. Pretreatment of rats with the 5-HT_1A agonist (±)-8-hydroxy-dipropylaminotetralin hydrobromide inhibited the HTR to DOI. This is consistent with other evidence that suggests a functional antagonism between 5-HT_1A and 5-HT_2A receptor activation. The HTR to DOI was potentiated by the novel 5-HT_1A selective antagonist WAY 100,635, which suggests that 5-HT^1A receptors tonically regulate this behavioral response to stimulation of cortical 5-HT_2A receptors.