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Sleep loss is known to potently suppress adult hippocampal cell proliferation and neurogenesis. Whether sleep suppression following acute administration of stimulant drugs also decreases hippocampal cell proliferation is not known. The present study examined the effect of three mechanistically distinct stimulants (caffeine, methamphetamine, and modafinil) on cell proliferation. To maximize sleep suppression, these drugs were administered to rats (three i.p. injections, once every 4 hours) during their sleep period (i.e., 12-h light phase). At the end of the light phase, 5-bromo-2′-deoxyuridine (200 mg/kg, i.p.) was injected and animals were sacrificed 2 hours later. Polygraphic recordings and locomotor activity measurements confirmed the wakepromoting/sleep-suppressing action of each treatment. Results indicate that caffeine (20 mg/kg), methamphetamine (1.5 mg/kg) and modafinil (300 mg/kg) differentially suppressed sleep (45%-91%) and selectively reduced cell proliferation in the hilus (12%-44%), which was significant for both caffeine and modafinil. When the same experiment was repeated in the dark (active) phase, the suppressant effect on hippocampal cell proliferation was either absent or greatly attenuated. In a further experiment, the effect of acute modafinil treatment in the light phase was shown to persist three weeks after BrdU administration. We hypothesize that the differential effect of the stimulant drugs in the light versus dark phase is attributable primarily to sleep suppression in the light. Since abuse of stimulant drugs invariably leads to disrupted sleep in humans, our results suggest that they may, at least in part, decrease hippocampal neurogenesis via sleep loss, and thereby adversely affect hippocampal-dependent processes.

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