Implantation of electrodes or cannulae into the brain is accompanied by a tissue response referred to as foreign body response. Adenosine triphosphate (ATP) is one of the signalling molecules released by injured cells which mediate the chemoattraction of microglial cells. The constitutive release of pro‐inflammatory and cytotoxic substances by microglial cells in chronic implants exacerbates neuronal cell death and the immune response. This study aimed to interfere with the initial events of the foreign body response in order to mitigate neurotoxicity and inflammation. For this purpose, the ATP‐hydrolysing enzyme apyrase and the antibiotic minocycline with a broad range of anti‐inflammatory, anti‐apoptotic and glutamate‐antagonist properties were locally infused during cannula implantation in the caudal forelimb area of the motor cortex in Lister Hooded rats. The rats’ motor performance was assessed in a skilled reaching task and the distribution of neurons and glial cells in the vicinity of the implant was examined 2 and 6 weeks post‐implantation. Apyrase as well as minocycline increased the number of surviving neurons and reduced microglial activation. Moreover, minocycline improved the motor performance and, additionally, caused a temporary reduction in astrogliosis, suggesting it as a possible therapeutic candidate to improve the biocompatibility of chronic brain implants.