Male C57BL/6 and DBA/2 mice were intrahippocampally microinjected with muscimol (0.5μg), given 15 min prior to individual 20-min exploration tests in a novel environment, and compared to saline controls. The GABA agonist reduced various exploratory acts and locomotor activity in strain C57BL/6 and increased the scores in DBA/2. In conjunction with similar opposite effects previously found with intra-hippocampal methylscopolamine and naloxone, these findings suggest that the opioid modulation of the hippocampal cholinergic mechanism which facilitates behavioral responses to novelty in mice is effectuated indirectly through an inhibitory GABAergic system. The functioning of these regulatory systems appears to depend on genotype.