6 This, in turn, suggested that NMDA receptors are inactive in the normal regulation of mesocortical dopamine neurons, and pointed to a possible explanation for why patients with schizophrenia exhibit negative, affective, and cognitive symptoms. This theory arose in response to the finding that phenylciclidine and ketamine, two noncompetitive NMDA/glutamate antagonists, induce schizophrenia-like symptoms. 1Īnother theory for the symptoms of schizophrenia involves the activity of glutamate, the major excitatory neurotransmitter in the brain. The newer compounds were found to be effective in alleviating both the positive and negative symptoms of schizophrenia. 1 Subsequent research led to the development of drug compounds that blocked both dopamine and serotonin receptors, in contrast to older medications, which affected only dopamine receptors. The serotonin hypothesis for the development of schizophrenia emerged as a result of the discovery that lysergic acid diethylamide (LSD) enhanced the effects of serotonin in the brain. A decrease or blockade of tuberoinfundibular dopamine results in elevated prolactin levels and, as a result, galactorrhea, ammenorrhea, and reduced libido. The tuberoinfundibular pathway projects from the hypothalamus to the pituitary gland. Negative symptoms and cognitive deficits in schizophrenia are thought to be caused by low mesocortical dopamine levels. 1 The mesocortical pathway extends from the VTA to the cortex. 1 The mesolimbic pathway, extending from the ventral tegmental area (VTA) to limbic areas, may play a role in the positive symptoms of schizophrenia in the presence of excess dopamine. Low dopamine levels within this pathway are thought to affect the extrapyramidal system, leading to motor symptoms. 4, 5 The nigrostriatal pathway originates in the substantia nigra and ends in the caudate nucleus. Four dopaminergic pathways have been implicated ( Figure 1). 1Ībnormal activity at dopamine receptor sites (specifically D 2) is thought to be associated with many of the symptoms of schizophrenia. Other theories implicate aspartate, glycine, and gamma-aminobutyric acid (GABA) as part of the neurochemical imbalance of schizophrenia. Most of these theories center on either an excess or a deficiency of neurotransmitters, including dopamine, serotonin, and glutamate. Abnormalities in neurotransmission have provided the basis for theories on the pathophysiology of schizophrenia.
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