Systemic administration of relatively high doses of amphetamine or cocaine induces expression of c-fos in the rat striatum and nucleus accumbens. The doses of drugs used in such experiments are substantially higher than those needed to produce reward or sensitization. Therefore, it was determined if low doses of amphetamine capable of eliciting reward and sensitization increase levels of c-Fos protein in the nucleus accumbens. Amphetamine, 1 mg/kg, stimulated locomotor activity and increased the number of nucleus accumbens cells immunohistochemically positive for c-Fos protein to approximately 800 cells per section from a control of approximately 100 cells per section. Since glutamate antagonists modify various responses to amphetamine, it was then determined whether activation of glutamate receptors is involved in the induction of c-Fos protein by low doses of amphetamine. The NMDA receptor antagonist MK-801 by itself stimulated locomotor activity but did not alter baseline levels of c-Fos protein. When given before amphetamine, both locomotor activity and extent of c-fos induction were greater than from amphetamine alone. The AMPA receptor antagonist NBQX by itself had no effect on locomotor activity but increased slightly the number of cells positive for c-Fos protein in the nucleus accumbens. When given before amphetamine, locomotor activity was completely attenuated, and the extent of c-fos induction was greater than from amphetamine alone. We conclude that low doses of amphetamine do increase abundance of c-Fos protein in the nucleus accumbens. This action does not correlate with locomotor activity and is independent of activation of glutamate receptors.