The basal ganglia are primarily involved in the integration of input from cortical areas, particularly from the motor cortex. They modulate the activity of thalamocortical projections, thereby creating a cortico-striato-pallido-thalamo-cortical loop. Four groups of

densely packed neurons provide widespread projections to many brain areas: cholinergic neurons in the basal forebrain (BF) Inhibitors,research,lifescience,medical and brain stem; dopaminergic neurons in the substantia nigra (SN) and ventral tegmental area (VTA); noradrenergic neurons in the locus ceruleus (LC); and serotonergic neurons in the raphe nuclei (R). The anatomical organization of the human brain gives rise to several neural circuits, Inhibitors,research,lifescience,medical each affiliated with different aspects of brain function. Over the last 100 years of psychosis research, four major hypotheses have been put forward that propose abnormalities of these neural circuits in psychosis. (1) Beginning with Kraepelin, psychosis was thought to be

a dysfunction of the association cortex in the frontal lobe, the dorsolateral prefrontal cortex (DLPFC). (2) Based in part on the observation that temporal lobe seizures often present with hallucinations and delusions, abnormalities of the medial temporal lobe (MTL) were proposed to explain the positive symptoms of psychosis. (3) The occurrence Inhibitors,research,lifescience,medical of psychotic symptoms after the use of amphetamine and cocaine, and the discovery that neuroleptic drugs block dopamine D2 receptors, gave rise to the dopamine hypothesis. (4) More recently, the glutamatergic hypothesis, based

in part on the fact that N-methyl-D-aspartate (NMDA) receptor antagonists, such as ketamine and phencyclidine, can cause drug-induced psychotic states, has Inhibitors,research,lifescience,medical been put forward. We will review here the evidence that the four anatomical systems (the cortex, the thalamus, the basal ganglia, and the medial temporal lobe) and their modulation by the neurotransmitter-specific Inhibitors,research,lifescience,medical projection systems are abnormal in schizophrenia. Although other brain regions, eg, the cerebellum, have also been implicated in the pathology of find more schizophrenia,49 we will not review their role here. Cortex The association cortex of the human brain is a six-layered isocortex. Layers 2 and 4 are defined by a high density of small almost interneurons, ie, neurons that do not send long-ranging projections to other cortical or subcortical areas. In contrast, layers 3 and 5 are defined by a high density of pyramidal cells, which collect input through their dendrites and project to other cortical or subcortical areas. Interneurons are GABAergic cells (GABA: gamma-aminobu lyric acid) and exert an inhibitory influence on their targets (via GABAA receptors) whereas pyramidal cells are glutamatergic and have an excitatory influence. Normal cortical function depends on an intricate balance between GABAergic inhibition and glutamatergic excitation.