Chapter 4: Psychosis, Schizophrenia, and the Neurotransmitter Networks Dopamine, Serotonin, and Glutamate

The prototypical psychotic disorder, schizophrenia, encompasses positive, negative, cognitive, aggressive, and affective symptom domains that extend beyond the classic positive symptom presentation. The chapter integrates three interconnected neurotransmitter hypotheses to explain psychotic pathology. The dopamine hypothesis proposes that mesolimbic dopamine hyperactivity at D2 receptors drives positive symptoms, while mesocortical dopamine deficiency accounts for cognitive and negative symptoms. The glutamate hypothesis suggests that N-methyl-D-aspartate receptor dysfunction at cortical GABAergic interneurons reduces inhibitory tone, paradoxically increasing downstream glutamate activity and triggering mesolimbic dopamine dysregulation. Glutamate receptor function depends on coactivation by glycine or D-serine at NMDA sites, with additional contributions from AMPA and kainate receptor systems. The serotonin hypothesis identifies hyperactivity or dysbalance at 5HT2A receptors in cortical regions as a psychosis mechanism, evident in hallucinogen-induced and Parkinson's disease psychosis presentations. Serotonin's extensive receptor subtype distribution enables modulation of nearly all other neurotransmitter networks throughout the brain. The etiology of schizophrenia reflects gene-environment interactions in which multiple genetic risk factors converge to disrupt normal neurodevelopmental processes. These molecular and cellular disruptions impair long-term potentiation and synaptic consolidation, culminating in aberrant synaptic elimination during the adolescent period of competitive refinement. This cascade initiates a progressive neurodegenerative trajectory characterized by progressive brain tissue loss and declining pharmacological treatment efficacy over time.