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

Antagonism of the 5-HT6 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-HT6 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-HT6 receptor antagonists as AD treatment, with some focus on the selective and high-affinity 5-HT6 receptor antagonist idalopirdine (Lu AE58054). The 5-HT6 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-HT6 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-HT6 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-HT6 receptor antagonists and AChEIs are discussed. Collectively, the current evidence suggests that 5-HT6 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-HT6 receptor antagonists in AD patients. •Antagonism of the 5-HT6R is a promising approach for the treatment of AD.•5-HT6R antagonism modulates the balance between neuronal excitation and inhibition.•5-HT6R antagonism facilitates activity in neuronal networks mediating cognition.•5-HT6R antagonists increase concentrations of multiple neurotransmitters.•5-HT6R antagonism adds a complementary mechanism of action to that of AChEIs.