Antagonism of the 5-HT6 receptor – Preclinical rationale for the treatment of Alzheimer's disease

Abstract Antagonism of the 5-HT 6 receptor is a promising approach for the symptomatic treatment of Alzheimer's disease (AD). There is compelling preclinical evidence for the procognitive potential of 5-HT 6 receptor antagonists and several compounds are in clinical development, as adjunct therapy to acetylcholinesterase inhibitors (AChEIs). This manuscript summarizes the scientific rationale for the use of 5-HT 6 receptor antagonists as AD treatment, with some focus on the selective and high-affinity 5-HT 6 receptor antagonist idalopirdine (Lu AE58054). The 5-HT 6 receptor is enriched in brain regions that mediate cognition, where expression predominates on glutamatergic and GABAergic neurons and subsets of GABAergic interneurons. It is proposed that 5-HT 6 receptor antagonism modulates the balance between neuronal excitation (glutamate) and inhibition (GABA), which may have widespread implications for neurotransmission and neuronal activity. This is supported by preclinical studies showing that 5-HT 6 receptor antagonists increase concentrations of multiple neurotransmitters, and strengthened by recent evidence that idalopirdine facilitates neuronal oscillations and contributes to the recruitment of several neuronal networks relevant in cognition. Some of these effects are observed with idalopirdine monotherapy, whereas others require concomitant treatment with an AChEI. Several hypotheses for the mechanism underlying the synergistic actions between 5-HT 6 receptor antagonists and AChEIs are discussed. Collectively, the current evidence suggests that 5-HT 6 receptor antagonism adds a unique, complementary mechanism of action to that of AChEIs. The facilitation of multiple neurotransmitters and neuronal activity in brain regions that mediate cognition, and the synergy with AChEIs, are proposed to mediate the procognitive effects of 5-HT 6 receptor antagonists in AD patients.