The Muscarinic Hypothesis of Schizophrenia

Since the discovery of dopamine(Drug information on dopamine) as a neurotransmitter in the late 1950s, schizophrenia has been associated with changes in the dopaminergic system. However, the dopamine hypothesis of schizophrenia cannot explain all the symptoms associated with this disorder. Therefore, research has also focused on the role of other neurotransmitter systems, including glutamate, g-aminobutyric acid, serotonin, and acetylcholine (ACh) in schizophrenia.

Recently, schizophrenia has been linked to changes in the muscarinic ACh system.^1,2 This review focuses on the muscarinic hypothesis of schizophrenia and the potential implications of ACh for the treatment of schizophrenia.

Acetylcholine as a neurotransmitter
For almost a century, ACh has been recognized as a neurotransmitter both in the CNS and in the peripheral nervous system (PNS). ACh plays a crucial role in a variety of CNS and PNS functions, including sensory perception, motor function, cognitive processing, memory, arousal, attention, sleep, nociception, motivation, reward, mood, psychosis, and neuroplasticity.

ACh is synthesized in neurons from acetyl-CoA and choline in a reaction catalyzed by the enzyme choline acetyltransferase (Figure restricted. Please see print version for content). In the synaptic cleft, ACh binds to presynaptic and postsynaptic receptors and is inactivated through hydrolysis by the enzyme cholinesterase. Choline is transported back into the presynaptic neuron through a specific choline transporter and is recycled into the synthesis of ACh.

Cholinergic neurons in the brain
Most cholinergic projection neurons are located in the basal forebrain and the brain stem. Basal forebrain cholinergic neurons (eg, nucleus basalis of Meynert) innervate the cerebral cortex and hippocampus. Brain stem cholinergic neurons project to the midbrain and brain stem, including dopaminergic cells in the substantia nigra and ventral tegmental area. Cholinergic interneurons are mainly located in the striatum and nucleus accumbens.

Muscarinic and nicotinic ACh receptors
The muscarinic and the nicotinic system are 2 distinct families of the ACh system. Muscarinic and nicotinic ACh receptors differ in function and structure. Nicotinic ACh receptors are ligand-gated ion channel receptors. The binding of ACh to the nicotinic receptor leads to an activation of the ion channel, resulting in a rapid inflow of sodium ions. In contrast, muscarinic ACh receptors are G-protein-coupled receptors. The activation of muscarinic receptors results in a slow- er but potentially more sustained response. Although nicotinic ACh receptors also play a role in the pathophysiology and treatment of schizophrenia, this review will focus on the role of the muscarinic system in schizophrenia.

Muscarinic ACh receptors
Muscarinic ACh receptors belong to the superfamily of G-protein-coupled receptors that either activate or inhibit message transduction systems, thus having an effect on the intracellular second messengers, such as cyclic adenosine(Drug information on adenosine) monophosphate or inositol triphosphate. Muscarinic ACh receptors can be found on cholinergic and noncholinergic cells in presynaptic and postsynaptic locations. There are 5 known muscarinic ACh receptors (M₁ through M₅). All 5 subtypes of the muscarinic ACh receptor are present in the human CNS, albeit in regionally varying concentrations. M₁, M₂, and M₄ are the predominant muscarinic ACh receptor subtypes in the CNS. Animal studies—genetically modified animals studies, in particular—have helped clarify the physiological role of the different mus-carinic receptor subtypes.³

The muscarinic hypothesis of schizophrenia
The muscarinic hypothesis of schizophrenia postulates that the muscarinic ACh system plays a crucial role in the pathology and treatment of schizophrenia. Data from clinical, postmortem, neuroimaging, and preclinical and clinical pharmacology studies support this hypothesis.

Postmortem and neuroimaging studies Postmortem studies have shown a decreased number of M₁ and M₄ muscarinic ACh receptors in persons with schizophrenia in several key areas, including caudate and putamen, hippocampus, anterior and posterior cingulate cortex, and prefrontal cortex. (For more information, see the work by Raedler and colleagues.¹) Similar changes were not found in persons with bipolar disorder or major depression.⁴ The levels of M₂ and M₄ muscarinic ACh receptors were unchanged in schizophrenia. These findings are supported by a single-photon emission CT (SPECT) study that found a significant decrease in vivo in the availability of muscarinic receptors in the cortex and basal ganglia in patients with schizophrenia compared with healthy controls.⁵

Pharmacological studies of the muscarinic system
Different pharmacological approaches (eg, increase of intrasynaptic ACh concentration; agonistic and antagonistic effects on muscarinic receptors) can be used to target the muscarinic system. Some of these approaches have been applied to schizophrenia and represent promising novel targets for its pharmacological treatment.

Cholinesterase inhibitors
Cholinesterase inhibitors (donepezil, galantamine(Drug information on galantamine), and rivastigmine(Drug information on rivastigmine)) increase the intrasynaptic concentration of ACh through inhibition of the enzyme acetylcholinesterase. These inhibitors are used to improve cognitive function in dementia.

A series of studies in schizophrenia failed to show convincing improvement in cognitive function after the addition of cholinesterase inhibitors to antipsychotic medication.^1,6 More recently, a study of cotreatment with donepezil(Drug information on donepezil) in 250 patients with schizophrenia showed no advantage for donepezil over placebo.⁷

Galantamine differs from the other cholinesterase inhibitors. In addition to being a cholinesterase inhibitor, galantamine is an allosteric modulator at nicotinic receptors. This combined mechanism of action may be more beneficial in schizophrenia, and first add-on studies of galantamine have shown significant improvement in some aspects of cognitive function.⁸

Muscarinic antagonists
For several decades, anticholinergics such as benztropine, biperiden(Drug information on biperiden), and trihexyphenidyl have been beneficial for the prophylaxis and treatment of antipsychotic-induced motor adverse effects. At the same time, anticholinergics have been found to cause cognitive dysfunction in healthy controls as well as in patients with schizophrenia.^9,10 Anticholinergics have been associated with a worsening of positive symptoms and an improvement in negative symptoms of schizophrenia.¹¹ Patients with schizophrenia report activating effects of anticholinergics, which occasionally results in the misuse of these medications.¹² Because of these effects as well as potential adverse effects (eg, urinary retention, dry mouth, constipation), the use of anticholinergics has recently been viewed with a more critical eye. Because the muscarinic receptor antagonist scopolamine was recently associated with robust antidepressant effects, the spectrum of action of anticholinergics may need to be reevaluated.¹³

Antimuscarinic effects of antipsychotics
Several antipsychotics have antimuscarinic properties in vitro and can cause antimuscarinic adverse effects (eg, dry mouth, urinary hesitancy, constipation) in vivo. Looking at atypical antipsychotics, in vitrostudies show that clozapine and olanzapine(Drug information on olanzapine) have strong binding affinity for muscarinic ACh receptors, while quetiapine(Drug information on quetiapine) shows a moderately strong binding affinity.^14,15

SPECT-imaging can be used to assess the in vivobinding properties of antipsychotic medications to muscarinic receptors. Treatment with clozapine(Drug information on clozapine) and olanzapine results in a significantly decreased availability of muscarinic receptors.^16,17 In a direct comparison, the reduction of muscarinic receptor availability was shown to be significantly stronger after treatment with clozapine than with olanzapine.¹⁸

The anticholinergic properties of atypical antipsychotics may contribute to their reduced rate of treatment-induced motor adverse effects. However, recent studies have shown that muscarinic receptors, in particular M₃ muscarinic receptors, play a major role in blood sugar regulation.¹⁹ Thus, the binding profile of antipsychotics to muscarinic receptors may contribute to their risk of inducing diabetes mellitus.²⁰

Muscarinic agonists
Muscarinic agonists may be a beneficial new treatment approach in schizophrenia. Betel nut chewing is a widespread practice in some Asian and Pacific cultures. In schizophrenia, betel nut chewing has been associated with fewer positive and negative symptoms.²¹ These findings are of special interest in this context, as some psychoactive components of betel nut, in particular arecoline, are muscarinic agonists.

Xanomeline, a synthetic arecoline derivative, is an M₁/M₄ muscarinic ACh receptor agonist. Xanomeline was initially evaluated as a therapeutic agent for Alzheimer disease. It showed dose-dependent efficacy against psychotic symptoms (eg, agitation, delusions, hallucinations) in Alzheimer disease.²² In a small pilot study of schizophrenia, monotherapy with xanomeline resulted in an improvement in positive symptoms as well as in cognitive function.²³ In animal studies, xanomeline and other muscarinic agents (eg, BuTAC, PTAC) showed antipsychotic-like properties without any affinity to dopamine receptors.