Cholinergic Neurotransmission’s Role in Schizophrenia Symptoms

Cholinergic neurotransmission remains an overlooked key critical to our survival. It helps with muscle movement, ocular function, gastrointestinal motility, temperature regulation, and cognitive ability. Scientists recognized cholinergic neurotransmission as a potential therapeutic target for schizophrenia patients decades ago. But drug developers have been reluctant to pursue its potential beyond its management of extrapyramidal side effects.

And even though the use of antipsychotics in treating schizophrenia has worked wonders, their effectiveness relies on obstructing dopaminergic neurotransmission.

But another target in schizophrenia — cholinergic neuropathology — opens the door to targeting a variety of other receptors. 

Understanding the roles of specific subtypes of muscarinic receptors, and the crucial role of cholinergic neurotransmission in modulating dopaminergic and (gamma-aminobutyric acid) GABA-ergic functions could explain the importance of cholinergic neurotransmission in the management of schizophrenia symptoms.

Cholinergic Neurotransmission in Schizophrenia

Cholinergic neurotransmitters appear as one of two subtypes: nicotinic and muscarinic receptors.  Nicotinic receptors certainly play a role in schizophrenia. But evidence suggests that muscarinic receptors are a singular breed. And researchers based that on how they interact with neurotransmitters, including the excitatory neurotransmitter glutamate and the inhibitory neurotransmitter GABA. 

Additionally, muscarinic receptor stimulation and inhibition pathways in the central nervous system affect both dopaminergic and serotonergic neurotransmission through projections across specific brain regions. And cholinergic receptors within the muscarinic and nicotinic categories vary. Researchers have identified five subtypes of muscarinic receptor subtypes, labeled M1 through M5. These variants differ in expression throughout the brain and nervous system]. Similarly, nicotinic receptor subtypes include N1, and N2, with N1 present on skeletal muscle and N2 present within the central and peripheral nervous system.

The role of central cholinergic neurotransmission in schizophrenia relies on several lines of evidence:

1. Multiple postmortem studies and a neuroimaging study of people living with schizophrenia show reduced muscarinic receptor expression.
2. Brain tissue from patients with schizophrenia showed increased binding of the alpha-4 beta-2 nicotinic drug epibatidine compared to individuals without schizophrenia.
3. Researchers have implicated the alpha 7 nicotinic receptor in deficiencies in sensory gating – the ability to ignore irrelevant sensory input – in people with schizophrenia, a characteristic feature of the disorder. Decreased levels of a specific alpha-7 nicotinic receptor splice variant and decreased expression of mRNA that encodes this receptor in patients with schizophrenia further support this relationship.

Pharmacologic Evidence for Cholinergic Pathophysiology

Although many pondered the potential of cholinergic drugs in the 1940s, disappointing initial results and a lack of understanding of the nuanced role of specific receptors in the brain hampered progress. Interest in muscarinic receptors flared back when studies in the late 1990s and early 2000s. The research focused on mice with deficient expression of muscarinic receptors. Researchers also noted that the effect of muscarinic receptors on dopamine release varied by brain region and muscarinic receptor subtype.

These studies also showed the important role of muscarinic receptors in modulating dopamine release in specific areas of the brain. For example, in the striatum, inhibition of M3 receptors inhibits dopamine output. In contrast, inhibition of M4 dopamine receptors promotes dopaminergic neurotransmission, reflecting highly specialized functions of specific muscarinic receptors further specialized by brain region.

The Toxic Relationship Between Nictone and Schizophrenia

Epidemiologic evidence also highlighted the critical role of cholinergic neurotransmission in the pathophysiology of schizophrenia. Years ago, researchers identified a strong link between psychosis and tobacco use. According to one meta-analysis, more than half of patients with a first episode of psychosis – 58.9 percent – used tobacco regularly. That same meta-analysis identified roughly six-fold higher odds of development of psychosis in patients with psychosis versus a control group. Nicotine exposure potentially improves cognitive and negative symptoms, which would seem to reinforce tobacco use in schizophrenia patients. Consistent with this hypothesis, patients with schizophrenia who smoked inhaled more deeply and for longer periods than other smokers.

In addition to dopamine and dopaminergic pathways, nicotine modulates the release of multiple other neurotransmitters, including glutamate, noradrenaline, serotonin, opioids, acetylcholine, and gamma-aminobutyric acid.

The pharmacologic effects of the short-acting cholinergic agonist nicotine in schizophrenia include a potential amelioration of extrapyramidal symptoms of antipsychotic medications. Nicotine exposure might help alleviate extrapyramidal symptoms of antipsychotic medications by increasing dopamine levels in the mesolimbic pathway.

Consequently, increasing dopaminergic activity could antagonize the effect of antipsychotic drugs, potentially increasing positive symptoms. This is consistent with a study identifying higher rates of positive symptoms in heavy smokers with schizophrenia versus other smokers.

However, heavy smokers in this study also had lower negative symptom scores. A more recent study of nicotine dependence and schizophrenia also uncovered a relationship between nicotine dependence and schizophrenia symptoms, with higher negative subscale scores of the Positive and Negative Syndrome Scale (PANSS) in patients with mild or moderate dependence on nicotine than in patients with severe nicotine dependence. These findings point to the potential role of cholinergic pathways in addressing negative symptoms.

Bezel Nuts

Further pharmacologic evidence of the role of cholinergic neurotransmission in the management of schizophrenia was identified with a different cholinergic agonist — arecoline, a psychoactive alkaloid present in betel nut primarily active on M1 and M3 receptors. A cross-sectional study of patients with schizophrenia using betel nuts versus patients who didn’t show lower scores on both positive and negative PANSS subscales. Researchers found no significant effect of betel nut use on the severity of tardive dyskinesia or extrapyramidal symptoms.

Although cholinergic drugs remain important pharmacologic targets in schizophrenia, it’s important to note that cigarette and tobacco use are responsible for up to half of excess mortality in schizophrenia. As a result, smoking cessation is an important goal of therapy to improve overall health and lifespan. Similarly, the use of betel nut is a major risk factor for oral cancer due to the formation of carcinogenic nitrosamines. While we should still discourage tobacco and betel nut use, evidence highlights the role of cholinergic drugs in schizophrenia management. These findings have paved the way for the development of cholinergic therapeutics for schizophrenia.

Conclusions

Half a century of progress in schizophrenia with dopaminergic blockade has improved outcomes immensely for patients. Use of both typical and atypical antipsychotics – for the most part – targets schizophrenia’s positive symptoms. Unfortunately, antipsychotics have left negative symptoms largely unaddressed.

Through a greater understanding of cholinergic neural pathways and specific roles and subtypes of cholinergic receptors, scientists have identified novel cholinergic targets involved in the pathophysiology of schizophrenia. These findings could pave the way for novel therapeutic options in schizophrenia management active on cholinergic pathways.

Further Reading

Schizophrenia’s Acute Psychosis Crisis Calls for Novel Treatments

Beyond Dopamine: Evaluating the Pipeline for Schizophrenia

FDA Approves First New Schizophrenia Drug in Years