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Home » Biology Articles » Neurobiology » Neurobiology of Diseases & Aging » Recent Advances in the Neurobiology of Schizophrenia » The Neurotransmitter Hypothesis of Schizophrenia

The Neurotransmitter Hypothesis of Schizophrenia
- Recent Advances in the Neurobiology of Schizophrenia

There are a number of theories of schizophrenia, dominated for many years by neuropharmacology, that implicate aberrant neurotransmission systems—in particular, aberrant dopaminergic, serotoninergic, and glutamatergic systems. It is unclear, however, to what extent any neurochemical findings reflect primary rather than secondary pathology, compensatory mechanisms, or environmental influences.

The dopamine hypothesis

The classical "dopamine hypothesis of schizophrenia" postulates a hyperactivity of dopaminergic transmission at the dopamine D2 receptor in the mesencephalic projections to the limbic striatum (42, 43). This hypothesis remains the preeminent neurochemical theory, despite several limitations [for review, see (44) ]. The notion was initially supported by a tight correlation between the therapeutic doses of conventional antipsychotic drugs and their affinities for the D2 receptor (45, 46). In addition, indirect dopamine agonists (e.g., L -dopa, cocaine, and amphetamines) can induce psychosis in healthy subjects and, at very low doses, provoke psychotic symptoms in schizophrenics (43). The dopamine hypothesis has received support from postmortem and positron emission tomography (PET) indications of increased dopamine D2 receptor levels in the brains of schizophrenic patients (Table 2Go) (47). However, it has been suggested that upregulation of D2 receptor expression may be the result of adaptation to antipsychotic drug treatment rather than a biochemical abnormality intrinsic to schizophrenia. In fact, some PET studies show no significant difference in D2 receptors densities between neuroleptic-naive schizophrenics and healthy controls (48).

There is emerging evidence for a presynaptic dopaminergic abnormality in schizophrenia, implying dysfunction in presynaptic storage, vesicular transport, release, reuptake, and metabolic mechanisms in mesolimbic dopamine systems (49). It has been further hypothesized that dysregulation and hyper-responsiveness of presynaptic dopamine neurons could lead to lasting consequences through the induction of sensitization and/or oxidative stress (5, 50). On the contrary, the functional activity of dopamine may be decreased in the neocortex in schizophrenia, which could be, at least partially, associated with negative symptoms (e.g., emotional or cognitive impairment) (5). Whether a dopamine hyperfunction or hypofunction occurs under minimal stress remains an open question.

Considerable data suggest that heritable abnormalities of prefrontal dopamine function are prominent features of schizophrenia that may relate to a unique role for COMT in dopamine-mediated prefrontal information processing in working memory [for review, see (51) ]. COMT inhibitors can improve working memory in both rodents (52) and humans (53). Interestingly, studies of COMT-deficient mice have demonstrated that dopamine levels are increased in the prefrontal cortex but not in the striatum, and that memory performance is enhanced (54).

Recently, Egan and coworkers have demonstrated that a COMT polymorphism that results in a valine residue at a position alternatively possessed by a methionine residue occurs at higher rates in both schizophrenics and their unaffected siblings (23). Moreover, patients and siblings containing the valine allele, which results in a COMT enzyme that is fourfold more active than the methionine allele, performed relatively poorly on a neuropsychological test of working memory and manifested inefficient brain activation as assessed by functional magnetic resonance imaging (fMRI). These findings suggest that the (high-activity) COMT valine allele impairs prefrontal cognition and physiology, and by virtue of this effect, may increase risk for schizophrenia.

The serotoninnergic system

Recent attention has focused on the involvement of serotonin (5-HT) in the pathophysiology of schizophrenia [for review, see (55) ]. The "serotonin hypothesis of schizophrenia" is informed by several observations: a) serotonin receptors are involved in the psychotomimetic and psychotogenic properties of hallucinogens [e.g., lysergic acid diethylamide (LSD)]; b) the number of cortical 5-HT2A and 5-HT1A receptors is altered in schizophrenic brains (Table 2Go); c) 5-HT2A and 5-HT1A receptors play a role in the therapeutic and/or side-effect profiles of atypical antipsychotics (e.g., clozapine); d) certain polymorphisms of the 5-HT2A receptor gene are associated with schizophrenia; e) the trophic role of serotonin in neurodevelopment may be usurped in schizophrenia; f) 5-HT2A receptor–mediated activation of the prefrontal cortex may be impaired in some schizophrenics; and g) serotoninergic and dopaminergic systems are interdependent and may be simultaneously affected in schizophrenia (55, 56).

The glutamatergic system

Phencyclidine (PCP) and ketamine, both potent non-competitive antagonists of the NMDA subtype of glutamate receptor (NMDA-R), induce schizophrenia-like symptoms in healthy individuals and worsen some symptoms in schizophrenia (103, 108). Decreased NMDA-R function may thus be a predisposing or causative factor in schizophrenia (57, 59, 60). One of the features that distinguish NMDA-R antagonists from other psychotogenic drugs such as amphetamine and LSD is the degree to which they produce frontal cognitive deficits that mimic schizophrenia [for review, see (61) ]. Postmortem studies of schizophrenics additionally indicate abnormalities in pre- and postsynaptic glutamatergic indices (Table 2Go). NMDA-R hypofunction in the cortical association pathways could be responsible for a variety of cognitive and other negative symptoms (62) and, in mice, partial deletion of the NMDA-R1 (NR1) subunit causes the same behavioral abnormalities as PCP (63). In addition, the NR1 hypomorphic animals manifest reduced [14 C]-2-deoxygluose uptake in the medial prefrontal and anterior cingulate cortices, as is observed in chronic schizophrenic patients (64).

The existence of anatomical and functional interrelationships between dopamine and glutamate systems in the central nervous system suggests that inhibition of the NMDA-R would influence dopamine neurotransmission (46, 65, 66). For example, NMDA-R antagonists decrease corticofugal inhibition of subcortical dopamine neurons [for review, see (62) ] and thereby enhance the firing rate of dopamine neurons (67, 68). In humans, PET studies of dopamine receptor occupancy after acute administration of ketamine suggest that the NMDA-R antagonists increase dopamine release in the striatum (69–71). In contrast, chronic administration of NMDA-R antagonists elicits decreased dopamine release (69) or hypoactivity of dopamine in the prefrontal cortex (60). Kapur and Seeman (72) have recently shown that both PCP and ketamine have direct effects on D2 and 5-HT2 receptors. It has also been proposed that NMDA-R antagonists can cause an excess compensatory release of glutamate that can overactivate unoccupied non-NMDA glutamate receptors, including {alpha} -amino-3-hydroxy-5-methy-isoxazole-4-propionic acid (AMPA) and kainate receptors (73). The release of glutamate in response to NMDA-R antagonists might in part be responsible for their behavioral effects. Finally, NMDA-R hypofunction may also produce abnormalities in the neuroplasticity of neurons by altering synaptic connectivity, as discussed below.

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