Animal models of drug discrimination have been used to examine the subjective effects of addictive substances. The cAMP system is a crucial downstream signaling pathway implicated in the long-lasting neuroadaptations induced by addictive drugs. We examined effects of rolipram, nefiracetam, and dopamine D2-like receptor antagonists, all of which have been reported to modulate cAMP level in vivo, on the discriminative-stimulus effects of methamphetamine (METH) and morphine in rats. All these compounds inhibited the discriminative-stimulus effects of METH, while only rolipram and nefiracetam attenuated the discriminative-stimulus effects of morphine. In addition, neither nifedipine nor neomycin, two voltage-sensitive calcium channel blockers, was found to modulate the effect of nefiracetam on METH-associated discriminative stimuli, suggesting that the inhibitory effect of nefiracetam may not involve the activation of calcium channels. These findings suggest that the cAMP signaling cascade may play a key role in the discriminative-stimulus effects of METH and morphine and may be a potential target for the development of therapeutics to counter drugs of abuse.