The involvement of the endogenous cannabinoid system has been implicated in the rewarding actions of several drugs of abuse. Recent evidence indicates that the transcription factor CREB (cAMP response element-binding protein) may be an important biochemical substrate for behavioral plasticity that has been associated with the chronic administration of drugs of abuse and addiction. Increased CREB activity was reported as a chronic effect of drugs of abuse in the neurons of the nucleus accumbens, a brain reward region that expresses high-density levels in the CB1 cannabinoid receptors. However, little is known whether a similar change occurs in the hippocampus, a region of the brain that also expresses high-density levels of the CB1 cannabinoid receptors and has intimate synaptic connections with the brain's reward regions. The present study revealed that CREB activities were present in the hippocampal neurons of cultured slice preparations in response to acute and chronic applications of endogenous cannabinoid, anandamide and R(+)-methanandamide (a non-hydrolyzing form of anandamide). When administered acutely at a dose effective for inducing self-administration in vivo, anandamide and R(+)-methanandamide stimulated the expression of pCREB in our hippocampal slice culture. Interestingly, a sub-threshold dose of R(+)-methanandamide, which was not effective in producing acute changes in the CREB activity, was also found to effectively increase pCREB when administered chronically for 10 days. These increases were blocked by the antagonist of the CB1 cannabinoid receptor. Present findings demonstrate: (1) the hippocampus is vulnerable to the direct chemical effect of anandamide and R(+)-methanandamide in isolation of synaptic influences from the midbrain reward neurons, and (2) the effect of R(+)-methanandamide is cumulative as evidenced by the sustained elevation of CREB activities in response to a chronic dosage that is too low and thus fails to exert any acute effect. The ability of hippocampal neurons to integrate a time-dependent effect on the endogenous cannabinoid signaling may be a key function of plasticity as related to the induction and maintenance of maladaptive learning and memory that underlies both cue-induced cravings as well as relapses in drug-seeking.