A Balancing Act: Interacting Neurotransmitter Pathways in Schizophrenia

This foundational article examines schizophrenia as a multi-pathway disorder involving interacting dopamine, serotonin, glutamate, GABA, and acetylcholine systems, highlighting how distributed neurotransmitter dysfunction may contribute to positive, negative, and cognitive symptom domains. The article explores how these pathways intersect across neural circuits and supports a broader, disease-focused understanding of schizophrenia neurobiology beyond any single neurotransmitter. 

Neurotransmitter Dysfunction Associated With Schizophrenia

Schizophrenia is associated with positive symptoms (hallucinations, delusions), negative symptoms (blunted affect, avolition), and cognitive symptoms (impaired working memory, executive dysfunction).^1,2 Research suggests that disturbances across dopamine, serotonin, glutamate, GABA, and acetylcholine may be associated with the pathophysiology of schizophrenia.^1,2

Dopamine

Dopamine dysregulation remains one of the most replicated biological findings in schizophrenia.^1-3 Elevated dopamine release in the mesolimbic pathway (projecting to the striatum) is thought to be associated with positive symptoms such as hallucinations and delusions.^1,2 On the other hand, reduced dopaminergic activity in the mesocortical pathway (projecting to the prefrontal cortex) is thought to be linked to negative and cognitive symptoms.^1-3 The observed symptom variability across people with schizophrenia may point to the involvement of additional neurotransmitter systems, and current research continues to expand upon these historical hypotheses.^1-3

Serotonin

Serotonin, primarily acting at 5-HT_2A receptors on cortical glutamate neurons, represents another pathway implicated in schizophrenia.^1,2 Hyperactivation of 5-HT_2A receptors is hypothesized to increase excitatory glutamate release from projection neurons, which is thought to contribute to increases in mesolimbic dopamine signaling.^1,2 Preclinical and clinical studies have suggested that activating 5-HT_2A receptors may produce psychosis-like symptoms.¹ 

Glutamate

Glutamate, the primary excitatory neurotransmitter, plays a central role in cortical circuit function and synaptic plasticity.² Hypofunction of N-methyl-D-aspartate (NMDA) receptors—a subtype of glutamate receptor—has been proposed as a contributing mechanism in schizophrenia, based on observations that blocking NMDA receptors may induce psychosis-like symptoms in healthy individuals and exacerbate symptoms in people with schizophrenia.^1,4 NMDA receptor hypofunction may reduce the activation of inhibitory GABA interneurons, thereby disinhibiting excitatory signaling and contributing to increased downstream dopamine release.^1-3 Neurophysiologic studies have suggested impairments in excitatory cortical signaling in individuals with schizophrenia, consistent with this glutamatergic dysfunction.^1,2,4

GABA (gamma aminobutyric acid)

GABA is the primary inhibitory neurotransmitter and plays a critical role in regulating excitation–inhibition balance in the cortex.² Reduced GABA-mediated inhibition has been observed in schizophrenia, particularly involving GABA interneurons in the prefrontal cortex.^1,2,5 These fast-spiking interneurons coordinate signaling processes that are critical for working memory and cognitive control.² Loss of inhibitory tone from these GABA interneurons may amplify glutamate signaling and is thought to contribute to neuropathologic features, including increased mesolimbic dopamine synthesis.^1,2,5

Acetylcholine

The cholinergic system—including the neurotransmitter acetylcholine and its associated nicotinic and muscarinic receptors—contributes to synaptic plasticity, cortical signaling, and modulation of excitation–inhibition balance across neural circuits.^2,6,7 A systematic review and meta-analysis of 61 studies, which included 53 post-mortem studies and 8 in-vivo neuroimaging studies, reported alterations in cholinergic receptor expression in schizophrenia, including reductions in the expression of M1/M4 muscarinic and a7 nicotinic receptors in the striatum, hippocampus, and cortex.⁶ Muscarinic and nicotinic receptors are distributed across both excitatory and inhibitory neurons, suggesting acetylcholine has the potential to modulate both glutamatergic and GABAergic neurotransmission.^2,6,7 

Acetylcholine Within the Broader Neurotransmitter Network

Collectively, receptor-level, physiologic, and network-level findings support a model of schizophrenia as a disorder involving distributed dysfunction across interacting neurotransmitter systems.^1,2 Within this multi-system model, acetylcholine functions as a regulatory modulator that interfaces with dopaminergic, glutamatergic, and GABAergic pathways.^2,6,7 Experimental studies demonstrate reciprocal modulation between cholinergic interneurons and dopaminergic pathways: striatal cholinergic interneurons can dynamically promote dopamine release and influence motivational states.^1,8 On the other hand, dopamine D2 receptor activation may coordinate changes in striatal acetylcholine levels in response to environmental cues.^2,9 These interactions illustrate bidirectional integration between neurotransmitter pathways rather than unidirectional control of one pathway over another.

Research, including preclinical studies, suggests muscarinic and nicotinic receptors are distributed across both excitatory (glutamatergic) and inhibitory (GABAergic) neurons, providing a structural basis for acetylcholine to modulate both glutamatergic and GABAergic signaling simultaneously.^2,6,7For instance, through muscarinic receptor activation of GABA interneurons, acetylcholine can regulate inhibitory tone and may therefore influence excitation–inhibition balance across cortical circuits.⁶ At the network level, several imaging studies have reported associations between reduced muscarinic and nicotinic receptor availability and altered connectivity within brain regions thought to be associated with schizophrenia symptoms.⁶

Neurotransmitter Pathways and Symptom Domains

Clinically, schizophrenia encompasses multiple symptom domains, including positive (eg, hallucinations and delusions), negative (eg, avolition, social withdrawal, and blunted affect), and cognitive (eg, deficits in working memory, attention, and executive function).^1-3 Each domain is thought to involve contributions from multiple neurotransmitter systems.^1,2

Positive Symptoms

Positive symptoms, including hallucinations and delusions, are thought to be linked to the overactivity of mesolimbic dopaminergic circuits.^1,2 Elevated presynaptic dopamine synthesis and release in the striatum are among the most replicated findings in schizophrenia research.^1-3 However, serotonergic, glutamatergic, GABAergic, and cholinergic signaling are also thought to contribute to changes observed in these circuits.^1,2,7 Increased activity of serotonin 5-HT2A receptors in the cortex may contribute to increased striatal dopamine release through enhanced activation of cortico-striatal projections.^1,2 With regard to glutamatergic pathways, NMDA receptor hypofunction may indirectly disinhibit dopaminergic neurons, contributing to the increase in mesolimbic dopamine release.^1,2,4 Through reduced inhibition of excitatory circuits, GABA interneuron deficits may further contribute to increases in mesolimbic dopamine activity.^1,2,5 Cholinergic signaling also intersects with these neural pathways through M4 muscarinic receptor modulation of dopamine release in the striatum and M1 muscarinic receptor modulation of cortical GABA interneurons.^2,6,7 In some observational studies, reductions in muscarinic and nicotinic receptor availability have been associated with greater positive symptom severity, and further research in larger sample sizes is warranted to better understand this correlation. ⁶

Negative Symptoms

Negative symptoms, including blunted affect, alogia, avolition, and social withdrawal, are associated with reduced dopamine release in mesocortical circuits projecting to the prefrontal cortex.^2,3 This pathway is distinct from the mesolimbic circuit implicated in positive symptoms, and reduced cortical dopamine activity is thought to impair motivational drive and emotional expression.^1,3 Glutamatergic dysfunction may compound these effects by reducing the excitatory drive necessary for cortical engagement.² GABA interneuron deficits in the cortex reduce local inhibitory control, which may further contribute to this reduced cortical output.² In addition, cholinergic signaling may influence dopamine release in the prefrontal cortex through muscarinic receptor activity.^2,6,7 In observational studies, reductions in M1 muscarinic receptor availability have been associated with greater negative symptom severity, although additional studies are needed to characterize this association.⁶

Cognitive Symptoms

Cognitive symptoms in schizophrenia may precede the onset of overt psychosis and may persist through the disease trajectory.^2,3 Deficits in working memory, attention, processing speed, and executive function reflect distributed network abnormalities rather than a single neurotransmitter deficit.^1-3,5 Dopamine dysregulation in the cortex may contribute to deficits in cognitive flexibility and goal-directed behavior.³ Cortical glutamatergic and GABAergic dysfunction are thought to contribute to working memory impairments, as disrupted excitation–inhibition balance may be correlated with a reduction in the persistent firing patterns required for memory maintenance.^1,2,5 Acetylcholine may play a role in attention and memory consolidation by acting as a neuromodulatory agent in cortico-striato-thalamocortical circuits via muscarinic receptor activity.^2,6,7 In observational studies, reduced M1 muscarinic and a7 nicotinic receptors have been correlated with greater cognitive deficits, although follow-up studies are needed to fully characterize this observation.⁶

Conclusion

The pathophysiology of schizophrenia reflects the cumulative effects of distributed dysfunction across multiple interacting neurotransmitter systems, including dopamine, serotonin, glutamate, GABA, and acetylcholine.^1,2 Each system contributes to distinct but overlapping aspects of symptom expression, and no single pathway operates in isolation.^1,3 

Understanding schizophrenia as a multi-pathway disorder has practical implications for interpreting clinical presentations.^1,3 Symptom diversity across patients—and within individual patients over time—may reflect variations in the relative contributions of these interacting systems.^1,2 Ongoing research will continue to inform the mechanistic relationships among these pathways to further our knowledge of this disease.^2,3,6

References

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3. McCutcheon RA, Krystal JH, Howes OD. Dopamine and glutamate in schizophrenia: biology, symptoms, and treatment. World Psychiatry. 2020;19(1):15-33.
4. Kruse AO, Bustillo JR. Glutamatergic dysfunction in schizophrenia. Transl Psychiatry. 2022;12(1):500.
5. Zahid U, Onwordi EC, Hedges EP, Wall MB, Modinos G, Murray RM, et al. Neurofunctional correlates of glutamate and GABA imbalance in psychosis: a systematic review. Neurosci Biobehav Rev. 2023;144:105010.
6. Saint-Georges Z, MacDonald J, Al-Khalili R, Hamati R, Solmi M, Keshaven MS, et al. Cholinergic system in schizophrenia: a systematic review and meta-analysis. Mol Psychiatry. 2025;30(7):3301-3315.
7. Foster DJ, Bryant ZK, Conn PJ. Targeting muscarinic receptors to treat schizophrenia. Behav Brain Res. 2021;405:113201.
8. Mohebi A, Collins VL, Berke JD. Accumbens cholinergic interneurons dynamically promote dopamine release and enable motivation. Elife. 2023;12:e85011.
9. Martyniuk KM, Torres-Herraez A, Lowes DC, Rubinstein M, Labouesse MA, Kellendonk C. Dopamine D2Rs coordinate cue-evoked changes in striatal acetylcholine levels. Elife. 2022;11:e76111.

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