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Where is dopamine high in schizophrenia?

Schizophrenia is a chronic and severe mental disorder characterized by disruptions in thoughts, emotions, and perceptions. One of the leading hypotheses about the neurobiology of schizophrenia involves dopamine dysfunction, specifically hyperdopaminergia – excess levels of the neurotransmitter dopamine – in certain brain regions. Dopamine is a neurotransmitter that plays important roles in motor control, motivation, pleasure, and cognitive functions. In schizophrenia, elevated dopamine activity has been associated with the positive symptoms of the illness, including delusions, hallucinations, and disorganized thinking and behavior. Understanding where dopamine levels are abnormally high in the brain in schizophrenia can provide insight into the underlying pathophysiology and inform targeted treatments.

The Dopamine Hypothesis of Schizophrenia

The dopamine hypothesis of schizophrenia emerged in the 1960s and 1970s based on several key findings:

  • Drugs that block dopamine receptors, known as antipsychotics, were found to reduce positive symptoms of schizophrenia.
  • Drugs that increase dopamine levels, such as amphetamines and cocaine, can sometimes trigger psychosis in healthy people and exacerbate symptoms in schizophrenia.
  • PET and SPECT imaging revealed elevated dopamine transmission in the brains of patients with schizophrenia.

Together, these discoveries pointed to excess dopamine activity as a key contributor to schizophrenia symptoms. While the dopamine hypothesis has been updated and expanded over the decades, it remains one of the predominant neurochemical models of schizophrenia.

Brain Regions with Elevated Dopamine in Schizophrenia

Research utilizing post-mortem studies and brain imaging techniques has localized some of the brain regions where dopamine levels and activity appear to be abnormal in schizophrenia:


The striatum is part of the basal ganglia system involved in motor control, motivation, and habit formation. It includes the caudate nucleus and putamen. Multiple studies have found elevated dopamine levels and increased dopamine receptor binding in the striatum of schizophrenia patients compared to healthy controls. This hyperdopaminergic state may drive issues with motor function and motivation.

Prefrontal cortex

The prefrontal cortex (PFC) is the anterior part of the frontal lobes and is essential for complex cognitive functions, decision-making, and executive control. Some studies have found elevated baseline dopamine levels in the PFC of schizophrenia patients. This dysregulation may underlie cognitive deficits and disorganized thinking associated with the illness.

However, other studies suggest more complex dopamine alterations in the PFC, such as reduced dopamine receptor activity. More research is needed to clarify the nature of dopamine changes in the PFC in schizophrenia.

Mesolimbic pathway

The mesolimbic pathway connects the ventral tegmental area (VTA) in the midbrain to the limbic system, including the nucleus accumbens, amygdala, and hippocampus. It is central to the brain’s reward and motivation circuitry. Hyperdopaminergia in the mesolimbic pathway may drive the positive symptoms of schizophrenia. The mesolimbic pathway is also targeted by drugs of abuse, which may explain why substance use can exacerbate psychosis.

Temporal lobe

The temporal lobes house primary auditory processing centers. Increased dopamine activity in temporal regions may underpin auditory hallucinations, a core feature of schizophrenia. Both post-mortem and neuroimaging studies point to altered dopamine signaling in the temporal cortices of schizophrenia patients who experience auditory hallucinations.

Evidence from Neuroimaging Studies

In vivo molecular imaging techniques like PET and SPECT have provided additional evidence that dopamine dysfunction in schizophrenia is localized to specific neuroanatomical pathways and brain regions:

  • PET and SPECT scans show increased dopamine synthesis and release in the striatum of schizophrenia patients, particularly in the associative and sensorimotor striatum which connect to frontal, temporal, and limbic areas.
  • PET studies reveal increased dopamine receptor binding and dopamine release in response to amphetamine challenge in the striatum.
  • Elevated dopamine synthesis and release has been detected in the mesolimbic regions, including the hippocampus, amygdala, and nucleus accumbens.
  • Some PET studies have found increased resting dopamine levels in the PFC of schizophrenia patients.
  • In medicated patients, D2 dopamine receptor occupancy by antipsychotics is highest in the striatum and temporal cortex.

This molecular imaging evidence bolsters post-mortem findings and highlights the role of hyperdopaminergia in striatal-frontal, mesolimbic, and temporal lobe pathways in schizophrenia.

Theories on How Dopamine Dysfunction Drives Symptoms

How might excess dopamine activity in these regions drive the characteristic symptoms of schizophrenia? A few key theories have been proposed:

  • Hyperdopaminergia in the mesolimbic pathway may lead to abnormal assignment of salience and meaning to external stimuli and internal representations, resulting in hallucinations and delusions.
  • Increased dopamine transmission along striatal-frontal connections may disrupt appropriate filtering of thoughts and perceptions, manifesting as disorganized thinking.
  • Elevated temporal lobe dopamine activity could account for auditory hallucinations.
  • Cognitive deficits in schizophrenia may stem from imbalanced dopamine signaling between subcortical and prefrontal regions involved in cognitive control and working memory.

While excess dopamine activity correlates with positive symptoms of schizophrenia, dopamine deficiencies in frontal and limbic regions may also contribute to negative and cognitive symptoms. The complex interplay between different dopamine pathways likely leads to the heterogeneous symptoms across schizophrenia patients.

Implications for Treatment

The dopamine hypothesis of schizophrenia has shaped many treatment approaches over the past 50 years. All currently approved antipsychotic medications have affinity for D2 dopamine receptors and act at least partially by dampening dopamine signaling through blockade of these receptors. PET studies reveal that clinically effective dosing of antipsychotics leads to occupancy of 50-80% of D2 receptors, particularly in the striatum and temporal cortex.

While dopamine antagonism underlies the therapeutic effects of antipsychotics, it is also linked to debilitating movement side effects due to actions on nigrostriatal dopamine pathways controlling motor function. To reduce motor side effects, newer “atypical” antipsychotics have been designed to target both dopamine and serotonin receptors.

Some emerging treatment strategies aim to normalize rather than simply block dopamine activity in schizophrenia. For example, partial dopamine agonists may help stabilize dopamine neurotransmission. Researchers are also investigating glutamate, GABA, and acetylcholine-based therapies that indirectly influence dopamine function through effects on other neurotransmitter systems.


In summary, converging evidence from post-mortem, animal, and neuroimaging studies points to hyperdopaminergia localized to the striatum, mesolimbic pathway, prefrontal cortex, and temporal lobe as a pathophysiological hallmark of schizophrenia. Elevated dopamine neurotransmission in these regions may drive positive symptoms, cognitive deficits, and other characteristic features of schizophrenia. These insights have shaped antipsychotic drug development over decades. While dopamine lies at the heart of schizophrenia biology, an array of complex and interconnected neurotransmitter and circuit disturbances are also likely involved. Ongoing research promises to further unravel the role of dopamine and other neurochemical imbalances to pave the way for more targeted and effective treatments. Understanding where dopamine dysfunction is focused in the schizophrenia brain remains an essential piece of this neurobiological puzzle.