Neurobiology of nAChRs and cognition: A mini review of Dr. Jerry J. Buccafusco's contributions over a 25 year career

Abstract

This review highlights some of the many contributions of the late Dr. Jerry J. Buccafusco to the neurobiology of nicotinic acetylcholine receptors (nAChRs) and cognition over a 25 year period. The article is written by two of Dr. Buccafusco's professional colleagues, one from academia and one from the pharmaceutical industry. While Dr. Buccafusco's expertise in the cholinergic field was extensive, his insights into the practical relevance of his work (with a long-term goal of formulating new drug development strategies) were unique, and a great asset to both the basic science community and pharmaceutical companies. In 1988, Dr. Buccafusco's laboratory was the first to report the cognitive enhancing action of low doses of nicotine in non-human primates. Since that time he studied a large number of novel pro-cognitive agents from several pharmacological classes in rodents as well as monkeys. Based on years of observing paradoxical effects of nicotinic ligands in vitro and in vivo, Dr. Buccafusco made the provocative argument that it might be possible to develop new chemical entities (with pro-cognitive actions) that have the ability to desensitize nAChRs without producing an antecedent agonist action. Some of his more recent work focused on development of single molecular entities that act on multiple CNS targets (including nAChRs) to enhance cognition, provide neuroprotection, and/or provide additional therapeutic actions (e.g., antipsychotic effects). Dr. Buccafusco's influence will live on in the work of the numerous graduate students, postdoctoral fellows, and junior faculty that he mentored over the years who now serve in prestigious positions throughout the world.

Nicotinic Receptor Agonists Reduce l-DOPA–Induced Dyskinesias in a Monkey Model of Parkinson's Disease

“…An extensive literature indicates that nicotine and nAChR drugs may enhance cognition in experimental animal models (Terry and Decker, 2011;Gao et al, 2012). The current data show that varenicline and TC-8831 did not influence performance on a working memory task in MPTP-lesioned monkeys.…”

Nicotinic Receptors in Neurodegeneration

“…ABT-418 administration improved verbal learning and immediate recall as well as spatial and recognition memory [132]. Unfortunately, ABT-418 did not reproduce these encouraging results in a phase II multi-center trial, likely because of poor pharmacokinetics and tolerability issues [133]. Recently, it has been described that ABT-418 significantly improves memory in an animal model of Attention-Deficit Hyperactivity Disorder (ADHD), increases the expression of the α4 and β2 subunits in the cortex and the expression of the α4 subunit in the hippocampus providing the bases for a possible use of ABT-418 in ADHD treatment [134].…”

“…In general terms, the study of the effect of other nAChR agonists with different affinities for distinct nAChR subunits suggests that α7 ligands seem to have more pronounced effects on memory while other nAChR ligands appear to have more robust effects on attention [133]. In addition, positive allosteric modulation of α7 nAChRs has emerged as an alternative approach to the use of direct agonists that could be beneficial in certain populations where smoking nicotine is prevalent [145].…”

“…Despite the efforts over the last twenty years to find new therapeutic strategies based on nAChRs for neurodegenerative disorders, only varenicline, a partial agonist of the α4ß2 nAChR and a full α7 agonist nAChR, has been approved for human administration, and only as a nicotine replacement therapy [133]. Other potential indications for nAChRs modulation are still pursued with full, partial agonist ligands or allosteric modulation that may gain increased attention in the future.…”