P72. Agonists and antagonists of specific serotonergic subreceptors and combined GABAA agonists and NMDA antagonists as a possible treatment of Alzheimers disease

Abstract

In Alzheimer’s disease, neurotransmitter alterations, for example acetylcholine deficiency and a surplus of the excitotoxic glutamate have been described and are associated with cognitive impairment. An interaction between acetylcholine deficiency and beta-amyloid formation has also been reported. Neurotransmitter imbalances between noradrenaline, dopamine and 5-HT on the one hand, and acetylcholine, GABA and glutamate on the other hand have been reported in the temporal cortex and hippocampus. Since serotonin plays an important role in cognitive processes a question arises, whether agonists or antagonists at specific serotonergic subreceptors, for example 5-HT4 or 5-HT7 agonists or 5-HT6 antagonists, can improve cognitive functions. The neural network, in the hippocampus and prefrontal cortex, involved in cognitive deficits in Alzheimer’s disease can be described as follows: hippocampal 5-HT2A serotonergic neurons (with a diminishing activity) activate GABAergic neurons, which weakly inhibit, via GABAA receptors, alpha1 noradrenergic neurons. The latter neurons - the activity of which is first high and then decreases more and more during the progression of the Alzheimer’s disease - activate glutamatergic neurons, which strongly inhibit, via NMDA receptors, 5-HT2A serotonergic neurons. In the prefrontal cortex, M1 muscarinic cholinergic neurons (with a low activity) activate GABAergic neurons, which weakly inhibit via GABAA receptors alpha1 noradrenergic neurons. The latter neurons activate glutamatergic neurons, which strongly inhibit via NMDA receptors M1 muscarinic cholinergic neurons. Hippocampal GABAergic neurons inhibit, via GABAA receptors, alpha1 noradrenergic located in the prefrontal cortex. Finally, glutamatergic neurons located in the prefrontal cortex inhibit, via NMDA receptors, hippocampal 5-HT2A serotonergic neurons. In clinical trials, the therapeutic effects of 5HT4, 5-HT7 agonists and 5-HT3, 5-HT6 antagonists have been examined to improve cognitive symptoms in Alzheimer’s disease. In these trials, 5-HT4 agonists and 5-HT6 antagonists showed a significant better effect in improving cognitive functions than placebo. The effect of such drugs on the formation of amyloid plaques is also examined. The clinical effects of 5-HT4 and 5-HT7 agonists or 5-HT3 and 5HT6 antagonists, which might slow down the development of senile plaques, should be examined in future clinical trials. Moreover, in the hippocampus and prefrontal cortex, we describe a neurotransmitter imbalance between GABAA GABAergic neurons (with hypoactivity) and NMDA glutaminergic neurons (with hyperactivity). The prophylactic effect of such drugs in Alzheimer’s disease, for example of combined GABAA agonists and NMDA antagonists should be examined in mild Alzheimer patients.