Schizophrenia Research Series: Neurodevelopment and PathophysiologyThe regulation of forebrain dopamine transmission: relevance to the pathophysiology and psychopathology of schizophrenia
Introduction
For the past 25 years, the predominant hypothesis regarding the pathophysiology of schizophrenia has been that excessive dopamine (DA) neurotransmission in the forebrain contributes significantly to psychosis Seeman 1987, Snyder 1976. This was based on several pieces of compelling evidence, including the psychotomimetic effects of indirect DA agonists such as amphetamine (for reviews see Angrist 1994) and the effective treatment of psychosis by drugs with high affinity for DA receptors of the D2 family (Seeman 1987, Snyder 1976; see also Arnt and Skarsfeldt 1998, Meltzer et al 1995). In addition, the possibility of excessive DA transmission in schizophrenia has been supported by functional imaging studies showing that schizophrenia patients display greater amphetamine-induced increases in synaptic DA in the striatum (as indicated by displacement of radiolabeled DA D2 receptor antagonists; Breier et al 1997b, Breier et al 1998, Laruelle et al 1996, Laruelle et al 1997a). Moreover, this increase in striatal DA release is associated with the emergence or worsening of psychotic symptoms (Laruelle et al 1996). Therefore, on first approximation, it would appear that overactivity of forebrain dopamine systems underlies at least the psychotic symptoms of schizophrenia.
The intensive study of schizophrenia in the past decade has revealed a multitude of abnormalities in the brains of schizophrenia patients, and it is now evident that forebrain DA neurons or receptors are not likely to be primary sites of neuropathology in this disease. For example, while the evidence for increases in DA turnover or receptors in the brains of schizophrenia patients is equivocal Bachus and Kleinman 1996, Breier et al 1997b, Laruelle et al 1996, Sedvall et al 1995, Tamminga et al 1992, numerous studies have reported structural and metabolic abnormalities in the anterior medial temporal lobe and prefrontal cortex Arnold and Trojanowski 1996, Frith 1996, Weinberger and Berman 1996. One explanation which links these findings with the evidence for abnormal DA transmission, is that DA transmission is not altered in schizophrenia as a result of a primary defect in the DA neurons, but as a result of abnormalities in the their regulation by prefrontal and limbic cortical regions Grace 1991, Weinberger and Lipska 1995.
In this review, we will first summarize the multiple mechanisms by which forebrain DA transmission can be regulated. We will then provide evidence that, in schizophrenia, a dysfunction within limbic-related cortical structures results in dysregulation of forebrain dopamine systems. The collective dysfunction of these systems leads to profound abnormalities in the function of cortical–basal ganglia–thalamic circuits and the behaviors mediated by these circuits.
Section snippets
Characteristics of DA neurons that support phasic and tonic DA release
It has been proposed that DA transmission in the striatum occurs in two different temporal modes, tonic and phasic Grace 1991, Grace 1993. Phasic release consists of DA released from the axonal varicosity during an action potential; it is defined as being transient and selectively affecting receptors that are within or near the synapse. The level of phasic DA, which is estimated to reach intrasynaptic concentrations in the low millimolar range (e.g., 1.6 mmol/L in nucleus accumbens; Garris et
The regulation of phasic dopamine transmission by inputs to the midbrain dopamine cells
Phasic DA release binds rapidly to receptors located very close to the site of the release and is then rapidly inactivated by uptake or diffusion. This release is likely to occur at about 40% of the release sites along DA axons, also occurring at a significant number of sites which are not apposed to any post-synaptic structure (Descarries et al 1996). It was recently demonstrated, in midbrain DA neurons in culture, that DA varicosities release discrete quanta estimated to contain 1000 to 3500
Regulation of tonic dopamine levels by glutamatergic systems
As proposed in the tonic/phasic model of dopamine (DA) transmission and as outlined previously, cortical GLUergic output functions as a homeostatic regulator of both phasic and tonic DA release Grace 1993, O’Donnell 1998b. Whereas phasic DA stimulation is a transient event contained in the synaptic cleft and eliminated primarily by DA reuptake and terminal autoreceptors, tonic DA levels in the extracellular space are relatively constant and tightly regulated Grace 1991, Grace 1993. This is
The role of nitric oxide in the regulation of tonic DA levels
In concert with direct presynaptic influences, corticostriatal afferents may regulate tonic DA levels via a secondary activation of striatal nitric oxide (NO)-containing interneurons. NO is a soluble gaseous neuromodulator generated by nitric oxide synthase (NOS) activation. In neurons, NOS activity is stimulated via an increase in intracellular calcium following EAA receptor activation (Garthwaite et al 1988). Striatal interneurons histochemically stained for NOS markers have been shown to
The role of reuptake in regulation of phasic and tonic DA levels
Aside from regulation of release, reuptake of DA by the DA transporter is the major determinant of extracellular DA levels in the striatum, and, thus, potently regulates both phasic and tonic pools of DA. In the striatum, DA transporters are positioned to regulate both phasic and tonic DA (Sesack et al 1998). The transporters located near the DA synapses or appositions limit the effective amount and duration of phasic DA release and may regulate the stimulation of DA autoreceptors by phasic DA
Regulation of synaptic transmission and plasticity in corticostriatal circuits by phasic and tonic DA transmission
There is considerable evidence that the frontal and limbic cortical regions are activated during learning and are necessary for normal appetitive conditioning. Activation of other limbic regions, such as the amygdala, is also necessary for specific components of appetitive conditioning (Everitt et al 1989) and aversive conditioning (Ledoux and Muller 1997). Moreover, projections from these regions can control both phasic (Figure 1) and tonic (Figure 2) DA release in regions where these
Interactions between corticostriatal circuits and DA in mediating the cognitive processes and behaviors affected in schizophrenia
The prefrontal and limbic corticostriatopallidal circuits mediate several psychomotor and cognitive processes that are altered in schizophrenia, including working memory (Goldman-Rakic 1996), selective attention (Carter and Barch 1999), contextual learning (e.g., Robbins et al 1989, Silva et al 1998), and in the formation of specific associations between stimuli or between stimuli and responses during appetitive or aversive conditioning Ledoux and Muller 1997, Robbins et al 1989. Dopamine
Acknowledgements
This work was supported by the National Institutes of Health (NIMH RO1 MH57440 to AAG; Postdoctoral NRSAs to HM and ARW), the National Alliance for Research on Schizophrenia and Depression (Distinguished Investigator Award to AAG and Young Investigator Award to HM), and the Stanley Foundation (HM and AAG).
The authors thank Amiel Rosenkranz, Christopher L. Todd, and Antonieta Lavin, PhD (University of Pittsburgh) for communication of unpublished data and insightful discussions, and James G.
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