An Investigation of the Role of GABAb Ligands on Cued and Contextual Fear Conditioning

GABA is the primary inhibitory neurotransmitter in the brain and mediates several processes, including learning and memory. Activating or inhibiting GABA receptors allows for the examination of the effects of altered GABAergic signaling on these processes. The two main receptors, GABA A and GABA B , each have a different mechanism of action when activated, thus they may contribute differentially to learning and memory. The metabotropic GABA B receptor responds with the activation of several intracellular signaling cascades, which provide long-lasting inhibitory effects that primarily mediate network function. Conversely, the GABA A receptor is an ion channel that contributes more immediate inhibitory effects through the movement of ions across the cell membrane. While there is more research regarding the role of the GABA A receptor in learning and memory because it was discovered first, the data on the role of the GABA B receptor in learning and memory are more varied and inconsistent. Because of the discrepancies in the literature, it is necessary to better characterize the effects contributed by the GABA B receptors to learning and memory. We examined the effects of a GABA B agonist (baclofen) and a GABA B antagonist (phaclofen) on the associative learning and memory task, cued and contextual fear conditioning, as well as the extinction of the learned associations. Using two protocols that vary in complexity and iv differentially recruit brain regions to learn the associations, we were able to evaluate whether the GABA B ligands produce different behavioral effects based on task in our first experiment. In a second experiment, we then investigated whether the results seen in the previous two experiments could be attributed to how well the task was learned initially by delaying the onset of ligand administration. Further, we investigated whether administration of the ligands altered GABA receptor protein levels in the neurological regions associated with the behavioral tasks. While baclofen treatment impaired the extinction of both the cued and contextual fear associations in both experiments, phaclofen treatment did not alter the acquisition or extinction of any of the associations. Interestingly, we found task-dependent shifts in GABA B receptor protein levels in both baclofen-and phaclofen-treated animals in several brain regions. In some instances, significant differences in protein levels were found in delay-trained groups that were not evident even in a non-significant trend in the trace-trained groups. These protein differences suggest that the administration of GABA B ligands alters behavior and …