Dopamine Hypothesis The most widely accepted original hypothesis of the etiology of schizophrenia and of the action of antipsychotic

drugs has implicated the neurotransmitter dopamine (DA). Dopaminergic neurons arise from two midbrain nuclei: (1) The nigrostriatal tract originates in the substantia nigra, terminates in the striatum, and is involved in modulation of motoric behavior, cognition, and sensory gating; and (2) the mesolimbic and mesocortical tracts originate in the ventral tegmental area and terminate in limbic and cortical structures, respectively, affecting cognitive, motivational, and reward systems. The dopamine 1 (D1) receptor family, which includes D1 and D5 receptors, is present in high concentration in the cortex and striatum. The dopamine 2 (D2) receptor family consists of D2, D3, and D4 receptors and is concentrated in the limbic and striatal regions. Presynaptic DA receptors (ie, D2 and D3) can consist of either somatodendritic autoreceptors localized to cell bodies in the substantia nigra and ventral tegmental area or terminal autoreceptors limited to axons of these DA cells. The somatodendritic and terminal autoreceptors affect firing of DA cells and synthesis and release of DA, respectively. Decreased DA activity in the prefrontal cortex may mediate the negative symptoms and cognitive dysfunction associated with schizophrenia. The DA hypothesis of schizophrenia, as originally postulated, proposed that schizophrenia was due to an excess of DA activity in limbic brain areas, especially the nucleus accumbens, as well as the stria terminalis, lateral septum, and olfactory tubercle. This hypothesis was based on evidence that chronic administration of the stimulant D -amphetamine produced a psychosis that resembled paranoid schizophrenia. D -Amphetamine increased the release of DA and norepinephrine (NE) and inhibited their reuptake. Isomers of D -amphetamine with different effects on the availability of NE and DA in rodents were used to show that increased locomotor activity, which correlates best with psychosis in humans, was due to an increased release of DA rather than NE. The second line of evidence relating DA to schizophrenia was that drugs that proved to be antipsychotics decreased DA activity by receptor blockade (reserpine) and depletion (neuroleptics). The most compelling evidence that linked DA to the positive symptoms of schizophrenia was the finding that chlorpromazine was an effective antipsychotic drug and that it blocked DA receptors in vivo, which inhibited the effect of D -amphetamine on locomotor activity. The discovery that a number of different chemical classes of DA-receptor antagonists were effective as antipsychotic drugs and that there was a high correlation between the drug's average daily dosage and its affinity for the D2 receptor family led to the view that increased stimulation of these receptors caused schizophrenia. The concept of increased DA activity as the core deficit in schizophrenia was developed at the time when delusions and hallucinations were central to the diagnosis of schizophrenia and negative symptoms, affective symptoms, and

cognitive dysfunction were relegated to a secondary role. These latter aspects of schizophrenia have never been associated with excessive DA activity. As mentioned earlier in this chapter, researchers have proposed that decreased DA activity may lead to cognitive impairment and possibly depression. There is little evidence that blockade of D2 or D4 receptors induces depression or cognitive impairment. Recent studies in primates have implicated the D1 receptor family in the control of working memory, a cognitive function that is impaired in schizophrenia. Postmortem studies of patients with schizophrenia have not found consistent abnormalities in the density of any of the five DA receptors or changes in their affinities for DA, with the possible exception of the D3 receptor, which may have an abnormal form. Several research groups have also reported a link between D3 polymorphisms and schizophrenia. There is no reliable evidence, from either postmortem studies or positron emission tomography (PET) studies, for an increase in the density of D2 receptors in schizophrenia. Recent PET studies of the release of DA in the striatum of patients with schizophrenia have suggested that the extracellular concentration of DA in this region is increased compared to normal subjects. Plasma and cerebrospinal fluid (CSF) levels of homovanillic acid, the major metabolite of DA, are not elevated in patients who have schizophrenia. Some researchers have suggested that DA receptor sensitization occurs in schizophrenia, but only indirect evidence supports this hypothesis. Serotonin Hypothesis Serotonin (5-HT) neurons originate in the midbrain dorsal and median raphe nuclei, which project to the cortex, striatum, hippocampus, and other limbic regions. There are at least 15 types of 5-HT receptors; of these, the most relevant to schizophrenia are the 5-HT1, 5-HT1D, 5-HT2, 5-HT3, 5-HT6, and 5-HT7 receptors. Somatodendritic autoreceptors (of the 5-HT1A type) are present on the cell bodies of 5-HT raphe neurons and inhibit firing of serotonergic neurons. Terminal autoreceptors (5-HT1D in humans) regulate the synthesis and release of 5-HT. 5-HT3 receptors stimulate DA release. Postsynaptic 5-HT2A receptors are localized on pyramidal neurons in mesocortical areas. The complex interaction between 5-HT and DA varies by brain region and by types of 5-HT and DA receptors. An early theory of the etiology of schizophrenia was that it was due to an excess of brain serotonergic activity. This theory was based on the belief that the psychotomimetic properties of lysergic acid diethylamide (LSD), an indole compound, were due to its 5-HT agonist properties. This led to a search for endogenous indole hallucinogens in the brain, blood, and urine of schizophrenic patients. The enzymes that synthesize and catabolize indoles, of which 5-HT is the most important, were also studied in detail; however, none of the putative abnormalities was confirmed by subsequent careful study.

The notion that the effects of LSD and other indole hallucinogens, such as psilocybin and N,N-dimethyltryptamine, provide an adequate model of schizophrenia was also rejected because the primary effect of these drugs is to cause visual hallucinations. The potency of these agents as hallucinogens is highly correlated with their 5-HT2A-receptor antagonist affinity. The thought disorder, auditory hallucinations, and bizarre behavior usually present in schizophrenia are generally absent in normal individuals who are given these agents. However, ingestion of these agents can cause an exacerbation of positive symptoms in schizophrenic patients. Neuroleptic drugs are not particularly useful in decreasing the effects of the indole hallucinogens. Newer antipsychotic drugs such as clozapine, olanzapine, risperidone, quetiapine, and sertindole are potent antagonists of the 5-HT2A receptor. Some of the advantages of these drugs may result from their greater potency as 5-HT2A-receptor antagonists, relative to D2receptor blockade. The most likely advantages of these drugs, related to their higher affinity to 5-HT2A versus DA receptors, are their low D2-induced EPS profile and their ability to improve negative symptoms. Increased stimulation of 5-HT2A receptors may be important in the etiology of negative symptoms and EPS. Although this concept of the role of 5-HT in schizophrenia is no longer considered viable, alternative theories of the role of 5-HT are of interest and are discussed in subsequent sections. Glutamate Hypothesis Clinical and experimental evidence has supported a complex role for glutamate in the etiology of schizophrenia. Evidence indicates that decreased glutamatergic activity is the result of decreased levels of glutamate receptors of the N-methyl-Daspartate (NMDA) subtype. Decreased levels of glutamate in the CSF of patients with schizophrenia have also been reported. Consistent with the role of glutamate in schizophrenia, three noncompetitive antagonists of NMDA receptors (phencyclidine [PCP], ketamine, and MK-801), and three competitive antagonists cerebral perfusion pressure (CPP), CPP-ene, and CGS 19755), can produce a range of positive and negative symptoms and cognitive dysfunction in normal control subjects and in schizophrenic patients. Neuroleptics can block some of the clinical effects of PCP. The ability of the 5-HT2A- and D2-receptor antagonists, such as clozapine and olanzapine, to block the clinical effects of these NMDAreceptor antagonists is unknown. However, the preclinical effects of PCP, such as disruption of sensory gatings, can be blocked by selective 5-HT2A-receptor antagonists, such as MDL100907, and by clozapine. Glycine, which can enhance the ability of glutamate to stimulate the glutamate receptor, has been reported to decrease negative but not positive symptoms in patients with schizophrenia when administered in conjunction with typical neuroleptic drugs. It has also been suggested that increased levels of glutamate can have neurotoxic effects on various neurons; however, there is no conclusive evidence for neurodegenerative changes in schizophrenia. A recent report shows that mice expressing 5% of normal N-methyl-D-aspartate-receptor (NMDARI) levels exhibit schizophrenia-

like behavioral abnormalities when they reach adulthood supporting a hypoglutamatergic hypothesis of schizophrenia. Neurodevelopmental Hypothesis According to the neurodevelopmental hypothesis, the etiology of schizophrenia may involve pathologic processes that begin before the brain approaches its adult anatomical state in adolescence. These neurodevelopmental abnormalities, developing in utero for some and thereafter for others, have been suggested to lead to the activation of pathologic neural circuits during adolescence or young adulthood (sometimes owing to severe stress), which leads to the emergence of positive or negative symptoms, or both. Earlier neuropathologic work indicated that some cases of schizophrenia result from embryologic maldevelopment. E. Slater also referred to maldevelopmental similarities between temporal lobe epilepsy and schizophrenia and stressed their possible neuropathologic basis. The emergence of evidence for cortical maldevelopment in schizophrenia and the development of several plausible animal models of schizophrenia, which are based on neonatal lesions that produce behavioral abnormalities or altered sensitivity to dopaminergic drugs only in adolescent or adult animals, have strengthened the link between maldevelopment and schizophrenia. The concept of schizophrenia as a neurodevelopmental disorder is also consistent with other epidemiologic and clinical lines of evidence, discussed in the following sections.