A Comparison of the Effects of Different Doses of GABAB Receptor Ligands on Spatial Learning and Memory and Memory Flexibility

The principal inhibitory neurotransmitter in the brain, gamma amino-butyric acid (GABA), mediates several types of learning and memory. Of the two main receptor subtypes for GABA, the in vivo role of GABAB receptor in learning and memory is less well characterized and the current data often conflict. Based on the current literature, it is unclear, for instance, whether enhancing GABAergic activity via the GABAB receptor could be beneficial for or detrimental to learning and memory. Hippocampally-dependent learning and memory tasks are of particular interest due to their clinical relevance to patients with schizophrenia or Alzheimer’s disease, who exhibit impaired performance in hippocampally-dependent spatial tasks. Further, these clinical populations exhibit alterations to GABAergic and GABAB receptor markers throughout the brain, including the hippocampus. Before conclusions can be drawn regarding the effect these changes have on these clinical populations, it is crucial that the role of the GABAB receptor in learning and memory in an unaltered system is understood first. We examined the effect of altered GABAB receptor activity using several doses of a GABAB receptor agonist (baclofen) and a GABAB receptor antagonist (phaclofen) on performance in a hippocampally-dependent learning and memory task, the Morris water maze. Further, we examined the impact of these ligands on memory flexibility by utilizing reversal training in the Morris water maze. In our first experiment, Sprague-Dawley rats received a dose of baclofen that significantly impaired performance in the Morris water maze, whereas the animals receiving phaclofen exhibited significantly improved performance. Additionally, the phaclofen-treated group demonstrated increased learning flexibility when the rules of the task were changed during reversal training. The goal of the second experiment was to determine whether a lower dose of baclofen would decrease the deficit observed, or whether a higher dose of phaclofen could enhance the enhancement observed. The lower dose of baclofen failed to produce a behavioral deficit, and the higher dose of phaclofen impaired task performance. Interestingly, while the lower dose of baclofen did not affect time to find the hidden platform, it did produce a subtle enhancement of performance during reversal training. Finally, we examined protein levels to determine whether any alterations were related to task performance. Animals treated with a low dose of baclofen or phaclofen and exhibited improved performance during the reversal training also demonstrated a reduction in the glutamate receptor subunit AMPA GluR4 and the phosphorylated serine 892 on the GABAB2 receptor subunit. In addition to indicating a role for the GABAB receptor in memory flexibility and spatial learning and memory, these results suggest a finite range of GABAB receptor activity that is capable of improving learning