Adult hippocampal neurogenesis is reported to be a target of antidepressants, drugs of abuse and animal models of depression, suggesting a role for this form of structural plasticity in psychopathology. Serotonergic neurotransmission, which is implicated in several psychiatric diseases, has been reported to regulate adult hippocampal neurogenesis. Amongst the serotonergic receptors, the serotonin2A/2C (5-HT2A/2C) receptors play an important role in the actions of antidepressants and the effects of hallucinogenic drugs of abuse. We have used the mitotic marker 5'-bromo-2-deoxyuridine to address the effects of the 5-HT2A/2C receptors on the proliferation of adult hippocampal progenitors following acute or chronic treatment with the hallucinogenic partial agonists, (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) and lysergic acid diethylamide (LSD) and the antagonist, Ketanserin. Acute, and chronic, DOI and LSD treatments induced a strong behavioral activation, but did not alter adult hippocampal progenitor proliferation. In striking contrast, Ketanserin treatment resulted in a biphasic regulation with a significant decline (22%) in progenitor proliferation following a single treatment, and a robust increase (46%) observed following chronic administration. These results indicate that hallucinogenic drugs that primarily target the 5-HT2A/2C receptors, in contrast to other drugs of abuse, may not alter adult hippocampal neurogenesis. In addition, our results that enhanced adult hippocampal progenitor proliferation results from a sustained blockade of the 5-HT2A/2C receptors suggest that the 5-HT2A/2C receptors may be an important target for the neurogenic effects of antidepressant treatment.