α7 nicotinic acetylcholine receptors as therapeutic targets in schizophrenia: Update on animal and clinical studies and strategies for the future

Abstract

Schizophrenia is a devastating mental illness and its effective treatment is among the most challenging issues in psychiatry. The symptoms of schizophrenia are heterogeneous ranging from positive symptoms (e.g., delusions, hallucinations) to negative symptoms (e.g., anhedonia, social withdrawal) to cognitive dysfunction. Antipsychotics are effective at ameliorating positive symptoms in some patients; however, they are not reliably effective at improving the negative symptoms or cognitive impairments. The inability to address the cognitive impairments is a particular concern since they have the greatest long-term impact on functional outcomes. While decades of research have been devoted to the development of pro-cognitive agents for schizophrenia, to date, no drug has been approved for clinical use. Converging behavioral, neurobiological, and genetic evidence led to the identification of the α7-nicotinic acetylcholine receptor (α7-nAChR) as a therapeutic target several years ago and there is now extensive preclinical evidence that α7-nAChR ligands have pro-cognitive effects and other properties that should be beneficial to schizophrenia patients. However, like the other pro-cognitive strategies, no α7-nAChR ligand has been approved for clinical use in schizophrenia thus far. In this review, several topics are discussed that may impact the success of α7-nAChR ligands as pro-cognitive agents for schizophrenia including the translational value of the animal models used, clinical trial design limitations, confounding effects of polypharmacy, dose-effect relationships, and chronic versus intermittent dosing considerations. Determining the most optimal pharmacologic strategy at α7-nAChRs: agonist, positive allosteric modulator, or potentially even receptor antagonist is also discussed. article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology'.

Keywords: Attention; Cholinergic; Cognition; Executive function; Pro-cognitive; Psychosis.

Fig 1.

Diagram illustrating several domains of cognition and other behaviors often targeted in drug discovery programs for schizophrenia and other neuropsychiatric disorders. The homomeric, low affinity α7-nicotinic acetylcholine receptor (α7-nAChR) is abundant in regions of the brain (e.g., hippocampus, prefrontal cortex) that are important for cognitive function. The receptor consists of five subunits arranged around a central channel that opens when endogenous ligands such as acetylcholine or exogenous ligands (nicotine) bind at the orthosteric site allowing cations (e.g., Ca⁺⁺) to flow through the channel into the neuron causing depolarization. Allosteric sites are the target of positive allosteric modulators (PAMs) and they are located at a site which is distinct from the orthosteric where they serve to indirectly influence (modulate) the effects of the agonist.