Researchers at UQ’s Queensland Brain Institute (QBI) have highlighted how acetylcholine signalling interacts with dopamine pathways in the brain, findings that may help explain how a new class of schizophrenia treatments works.
The research team, led by Professor Darryl Eyles and Drs James Kesby and Xiaoying Cui, sought answers to how new schizophrenia drugs, which gained attention following favourable Phase 3 clinical trials, offer an alternative to traditional antipsychotics.
Professor Darryl Eyles explained that traditional drugs block dopamine receptors, reducing overactive dopamine synthesis, which is recognised as a biological feature in 2/3 of patients with schizophrenia.
“This new class of drugs target the acetylcholine system, a signalling system that helps regulate attention, learning, memory, and how brain circuits communicate,” Professor Darryl Eyles said.
“Using a novel preclinical model of hyperactive dopaminergic systems, we studied the interplay between acetylcholine and dopamine, two tightly interconnected systems.
“We selectively increased dopamine synthesis capacity in the dorsal striatum, which led to a doubling of baseline acetylcholine levels in this same brain region.
“This shift disrupted the normal relationship between acetylcholine and dopamine, potentially altering how dopamine is released in response to important or salient stimuli.”
The team’s work highlights the importance of revisiting long-standing neurochemical relationships considering new therapies. A cholinergic agonist drug called xanomeline was given decades ago to people with dementia, but the side effects were severe, and the research was discontinued; however, it was noted back then that the treatment improved end-stage psychosis.
Dr James Kesby said their team’s results provide a possible biological framework for understanding the action of the new drugs for schizophrenia.
“If baseline acetylcholine levels are elevated in patients who have increased capacity to release more dopamine in response to various stimuli, as our model suggests, then these drugs may work by restoring balance in this system,” Dr Kesby said.
“If this new antipsychotic acts to put a break on acetylcholine release within the striatum then this could normalise how dopamine is released from dopamine terminals within the striatum.
“We believe this may be how these new generation antipsychotics, which are cholinergic agonists, may act.”
“This mechanism could help explain why these therapies show antipsychotic effects without directly blocking dopamine receptors.
“Rather than suppressing dopamine activity outright, these treatments may fine-tune the release of dopamine in response to various stimuli.”
The study builds on the team’s previously developed “EDiPs” model (Enhanced Dopamine in Prodromal Schizophrenia), which mimics increased dopamine synthesis/release seen in patients with schizophrenia and allows researchers to explore downstream neurochemical changes.
While the findings are preliminary and clinical research is needed, the team says the work underscores the therapeutic potential of targeting acetylcholine systems in schizophrenia.
“In schizophrenia treatment, we are long overdue for new approaches,” Professor Eyles said.
“This study provides insights into how therapies acting on acetylcholine signalling might deliver clinical benefit, and it highlights the need to study these two systems together rather than in isolation.
“Understanding the balance between dopamine and acetylcholine could be crucial to developing the next generation of treatments for people living with schizophrenia, offering hope for improved outcomes with fewer side effects.”
This research was published in Molecular Psychiatry.
The Eyles lab’s work is funded by The Queensland Centre for Mental Health Research.
