Inflammatory response in the Central Nervous System (CNS) induced by psychostimulants seems to be a crucial factor in the development and maintenance of drug addiction. The ventral hippocampus (vHp) is part of the reward system involved in substance addiction and expresses abundant G protein-coupled receptor 55 (GPR55). This receptor modulates the inflammatory response in vitro and in vivo, but there is no information regarding its anti-inflammatory effects and its impact on psychostimulant consumption. The aim of the present study was to investigate whether vHp GPR55 activation prevents both the inflammatory response induced by amphetamine (AMPH) in the vHp and the AMPH-induced conditioned place preference (A-CPP). Wistar adult male rats with a bilateral cannula into the vHp or intact males were subjected to A-CPP (5 mg/kg). Upon the completion of A-CPP, the vHp was dissected to evaluate IL-1β and IL-6 expression through RT-PCR, Western blot and immunofluorescence. Our results reveal that AMPH induces both A-CPP and an increase of IL-1β and IL-6 in the vHp. The GPR55 agonist lysophosphatidylinositol (LPI, 10 μM) infused into the vHp prevented A-CPP and the AMPH-induced IL-1β increase. CID 16020046 (CID, 10 μM), a selective GPR55 antagonist, abolished LPI effects. To evaluate the effect of the inflammatory response, lipopolysaccharide (LPS, 5 μg/μl) was infused bilaterally into the vHp during A-CPP acquisition. LPS strengthened A-CPP and increased IL-1β/IL-6 mRNA and protein levels in the vHp. LPS also increased CD68, Iba1, GFAP and vimentin expression. All LPS-induced effects were blocked by LPI. Our results suggest that GPR55 activation in the vHp prevents A-CPP while decreasing the local neuro-inflammatory response. These findings indicate that vHp GPR55 is a crucial factor in preventing the rewarding effects of AMPH due to its capacity to interfere with proinflammatory responses in the vHp.