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nAChR 2009: Nicotinic AChRs—Mechanistic Basis for New Drug Discovery?

Adapted from a story that originally appeared on the Alzheimer Research Forum.

This story concludes a three-part series. See also Parts 1 and 2.

7 November 2009. All too often, basic science findings that initially seem promising never translate into viable pharmaceutical approaches, or when they do, fail miserably in clinical trials. Amid such tales of disappointment, it’s refreshing to hear about studies showing clear convergence between biology, drug action, and behavior, all in the space of a few seconds, no less. At a satellite symposium on therapeutic approaches targeting nicotinic acetylcholine receptors (nAChRs), which took place days before the Society of Neuroscience’s annual meeting in Chicago last month, Martin Sarter of the University of Michigan, Ann Arbor, had such a story to tell. His lab developed a way to record neurotransmitter release at sub-second resolution in freely moving animals. Using this technology, the researchers identified an electrophysiological readout for key attention tasks in rodents. Better yet, treatment with nicotine or nAChR agonists can tweak this readout and, correspondingly, affect task performance. “The neuroscience and the pharmacology come together,” Sarter told ARF. “That’s something you don’t see very often in this business.” The findings could have implications for screening new nAChR-targeting drugs.

Noting its role in regulating sleep/wake cycles and other types of arousal setting, scientists had presumed that the cholinergic system operates on the level of minutes, even tens of minutes. But once Sarter and colleagues pioneered their technology for listening to neurotransmitter release in real time, they made a surprising discovery. By recording acetylcholine release from presynaptic terminals in the prefrontal cortex of rats engaged in a cue detection task, the researchers saw characteristic “transients”—bursts of cholinergic activity—that mediated task performance on a timescale not of minutes, but of seconds (Parikh et al., 2007). “That’s really, really short,” Sarter said. “It was a whole new story.”

The rats in these studies wore surgically implanted, choline-sensitive microelectrodes, and were trained to perform a sustained attention task involving repeated rounds of pressing one lever if a cue light went on and pressing another lever if the light remained off. The researchers measured the accuracy of cue detection as well as response speed and other parameters. When they treated the rats with mecamylamine to block nACh receptors, the cue detection rate dropped considerably; this indicates that the nAChR system is required for this attention task and for generating the underlying electrophysiological signature, that is, the rapid transients. Quicker detection rates were found to be associated with larger amplitudes and faster decay rates of cholinergic transients, Sarter said.

For the next phase of analysis, the researchers made the attention task harder by introducing a distractor—for example, house lights flashing on and off. This lowered the baseline task performance and made the system more useful for determining how well various treatments influence the transients and, in turn, improve behavior. With the lower baseline, behavior was measured in terms of how long it took the rats to recover normal (i.e., distractor-free) levels of performance. The researchers found that nicotine helped the rats detect cues faster; importantly, this corresponded with larger amplitudes on their transients compared to vehicle treatment. Treatment with Abbott’s α4β2 agonist ABT-089 improved task performance even more, and further sharpened the transients—that is, gave them higher amplitude and faster decay rate. However, treatment with an α7 agonist did not help attention, and increased the duration of acetylcholine release. The readout for this was cholinergic transients with a longer “tail.”

Astute readers will recall from Part 1 of this series that Abbott has discontinued development of ABT-089 for AD and ADHD, in part because the α4β2 agonist failed to show efficacy in a recent Phase 2 AD trial. Sarter does not necessarily find these clinical disappointments inconsistent with his rat studies, where the compound has shown promise. “It is difficult to see how such a compound would work in AD, given that the prefrontal ‘cue detection network’ including the glutamatergic-cholinergic interactions and the prefrontal output neurons that are required for mediation of the performance effects (in the rat cue detection task) are quite disrupted,” he wrote in an e-mail to ARF. “To use a simple analogy, it is difficult to enhance the workings of a component of a circuit if the circuit is in a state of advanced disintegration.” As for the α7 agonist (ABT-107), the fact it did not improve task performance in the rat studies does not imply these compounds would be ineffective in other cognitive domains, such as memory, he said.

Despite these nuances, Sarter believes his animal set-up could be useful in screening for nAChR-stimulating cognition enhancers. “The rats do the detection task. You see the transients. You give the drug. You see what it does to transients and performance at the same time,” he said. “You look for drugs that make (transients) bigger and sharper.” When it comes to targeting the cholinergic system for therapeutics, it is too simplistic to think in terms of having too much or too little neurotransmitter, he said. Compounds should work if they allow proper orchestration of the transients.

Sarter’s team has preliminary data suggesting that the transients could have relevance in a disease context. In a rat neurodevelopmental model for schizophrenia that performs poorly in attention tasks, nicotine treatment failed to generate cholinergic transients. Thus far, standard antipsychotics also have been unable to bring back these transients. Any compound that could restore the cholinergic bursts could thus be interesting to pursue, Sarter said.—Esther Landhuis.

This story concludes a three-part series. See also Parts 1 and 2.

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