The Relationship Between Frontostriatal Connectivity and Striatal Dopamine Function in Schizophrenia: An 18F-DOPA PET and Diffusion Tensor Imaging Study in Treatment Responsive and Resistant Patients

Objective Striatal dopamine dysfunction caused by cortical abnormalities is a leading hypothesis of schizophrenia. Although prefrontal cortical pathology is negatively correlated with striatal dopamine synthesis, the relationship between structural frontostriatal connectivity and striatal dopamine synthesis has not been proved in patients with schizophrenia with different treatment response. We therefore investigated the relationship between frontostriatal connectivity and striatal dopamine synthesis in treatment-responsive schizophrenia (non-TRS) and compared them to treatment-resistant schizophrenia (TRS) and healthy controls (HC). Methods Twenty-four patients with schizophrenia and twelve HC underwent [¹⁸F] DOPA PET scans to measure dopamine synthesis capacity (the influx rate constant Kicer) and diffusion 3T MRI to measure structural connectivity (fractional anisotropy, FA). Connectivity was assessed in 2 major frontostriatal tracts. Associations between Kicer and FA in each group were evaluated using Spearman’s rho correlation coefficients. Results Non-TRS showed a negative correlation (r=-0.629, p=0.028) between connectivity of dorsolateral prefrontal cortex-associative striatum (DLPFC-AST) and dopamine synthesis capacity of associative striatum but this was not evident in TRS (r=-0.07, p=0.829) and HC (r=-0.277, p=0.384). Conclusion Our findings are consistent with the hypothesis of dysregulation of the striatal dopaminergic system being related to prefrontal cortex pathology localized to connectivity of DLPFC-AST in non-TRS, and also extend the hypothesis to suggest that different mechanisms underlie the pathophysiology of non-TRS and TRS.     

Selective relationship between prefrontal N-acetylaspartate measures and negative symptoms in schizophrenia

OBJECTIVE: Certain cognitive, behavioral, and emotional deficits (so-called negative symptoms) in patients with schizophrenia have often been attributed to prefrontal cortical pathology, but direct evidence for a relationship between prefrontal neuronal pathology and negative symptoms has been lacking. The authors hypothesized that an in vivo measure of prefrontal neuronal pathology (N:-acetylaspartate [NAA] levels) in patients with schizophrenia would predict negative symptoms. METHOD: Proton magnetic resonance spectroscopic imaging ((1)H-MRSI) and rating scales for negative and positive symptoms were used to study 36 patients with schizophrenia. Magnetic resonance spectra were analyzed as metabolite ratios, and parametric correlations were performed. RESULTS: A regionally selective negative correlation was found between prefrontal NAA-creatine ratio and negative symptom ratings in this group of patients with schizophrenia. CONCLUSIONS: Lower prefrontal NAA-and by inference greater neuronal pathology-predicted more severe negative symptoms in patients with schizophrenia. These data demonstrate a relationship between an intraneuronal measure of dorsolateral prefrontal cortex integrity and negative symptoms in vivo and represent further evidence for the involvement of the dorsolateral prefrontal cortex in negative symptoms associated with schizophrenia.     

Specific relationship between prefrontal neuronal N-acetylaspartate and activation of the working memory cortical network in schizophrenia

OBJECTIVE: Abnormal activation of the dorsolateral prefrontal cortex and a related cortical network during working memory tasks has been demonstrated in patients with schizophrenia, but the responsible mechanism has not been identified. The present study was performed to determine whether neuronal pathology of the dorsolateral prefrontal cortex is linked to the activation of the working memory cortical network in patients with schizophrenia. METHOD: The brains of 13 patients with schizophrenia and 13 comparison subjects were studied with proton magnetic resonance spectroscopic ((1)H-MRS) imaging (to measure N-acetylaspartate as a marker of neuronal pathology) and with [(15)O]water positron emission tomography (PET) during performance of the Wisconsin Card Sorting Test (to measure activation of the working memory cortical network). An independent cohort of patients (N=7) was also studied in a post hoc experiment with (1)H-MRS imaging and with the same PET technique during performance of another working memory task (the "N-back" task). RESULTS: Measures of N-acetylaspartate in the dorsolateral prefrontal cortex strongly correlated with activation of the distributed working memory network, including the dorsolateral prefrontal, temporal, and inferior parietal cortices, during both working memory tasks in the two independent groups of patients with schizophrenia. In contrast, N-acetylaspartate in other cortical regions and in comparison subjects did not show these relationships. CONCLUSIONS: These findings directly implicate a population of dorsolateral prefrontal cortex neurons as selectively accounting for the activity of the distributed working memory cortical network in schizophrenia and complement other evidence that dorsolateral prefrontal cortex connectivity is fundamental to the pathophysiology of the disorder.     

Acetylcholine–Dopamine Interactions in the Pathophysiology and Treatment of CNS Disorders

Dopaminergic neurons in the substantia nigra pars compacta and ventral tegmental area of the midbrain form the nigrostriatal and mesocorticolimbic dopaminergic pathways that, respectively, project to dorsal and ventral striatum (including prefrontal cortex). These midbrain dopaminergic nuclei and their respective forebrain and cortical target areas are well established as serving a critical role in mediating voluntary motor control, as evidenced in Parkinson's disease, and incentive‐motivated behaviors and cognitive functions, as exhibited in drug addiction and schizophrenia, respectively. Although it cannot be disputed that excitatory and inhibitory amino acid‐based neurotransmitters, such as glutamate and GABA, play a vital role in modulating activity of midbrain dopaminergic neurons, recent evidence suggests that acetylcholine may be as important in regulating dopaminergic transmission. Midbrain dopaminergic cell tonic and phasic activity is closely dependent upon projections from hindbrain pedunculopontine and the laterodorsal tegmental nuclei, which comprises the only known cholinergic inputs to these neurons. In close coordination with glutamatergic and GABAergic activity, these excitatory cholinergic projections activate nicotinic and muscarinic acetylcholine receptors within the substantia nigra and ventral tegmental area to modulate dopamine transmission in the dorsal/ventral striatum and prefrontal cortex. Additionally, acetylcholine‐containing interneurons in the striatum also constitute an important neural substrate to provide further cholinergic modulation of forebrain striatal dopaminergic transmission. In this review, we examine neurological and psychopathological conditions associated with dysfunctions in the interaction of acetylcholine and dopamine and conventional and new pharmacological approaches to treat these disorders.     

Neurobiological correlates of delusion: beyond the salience attribution hypothesis

Dopamine dysfunction is a mainstay of theories aimed to explain the neurobiological correlates of schizophrenia symptoms, particularly positive symptoms such as delusions and passivity phenomena. Based on studies revealing dopamine dysfunction in addiction research, it has been suggested that phasic or chaotic firing of dopaminergic neurons projecting to the (ventral) striatum attribute salience to otherwise irrelevant stimuli and thus contribute to delusional mood and delusion formation. Indeed, several neuroimaging studies revealed that neuronal encoding of usually irrelevant versus relevant stimuli is blunted in unmedicated schizophrenia patients, suggesting that some stimuli that are irrelevant for healthy controls acquire increased salience for psychotic patients. However, salience attribution per se may not suffice to explain anxieties and feelings of threat that often accompany paranoid ideation. Here, we suggest that beyond ventral striatal dysfunction, dopaminergic dysregulation in limbic areas such as the amygdala in interaction with prefrontal and temporal cortex may contribute to the formation of delusions and negative symptoms. Neuroleptic medication, on the other hand, appears to interfere with anticipation of reward in the ventral striatum and can thus contribute to secondary negative symptoms such as apathy and avolition.     

Dorsolateral prefrontal N-acetyl-aspartate concentration in male patients with chronic schizophrenia and with chronic bipolar disorder

OBJECTIVES: A study of N-acetyl-aspartate (NAA) can provide data of interest about cortical alterations in psychotic illnesses. Although a decreased NAA level in the cerebral cortex is a replicated finding in chronic schizophrenia, the data are less consistent for bipolar disease. On the other hand, it is likely that NAA values in schizophrenia may differ in men and women. METHODS: We used proton magnetic resonance spectroscopy ((1)H MRS) to examine NAA levels in the prefrontal cortex in two groups of male patients, one with schizophrenia (n=11) and the other with bipolar disorder (n=13) of similar duration, and compared them to a sample of healthy control males (n=10). Additionally, we compared the degree of structural deviations from normal volumes of gray matter (GM) and cerebrospinal fluid (CSF) in the dorsolateral prefrontal cortex. RESULTS: Compared to controls, schizophrenia and bipolar patients presented decreased NAA to creatine ratios, while only the schizophrenia group showed an increase in CSF in the dorsolateral prefrontal region. There were no differences in choline to creatine ratios among the groups. CONCLUSIONS: These data suggest that the decrease in NAA in the prefrontal region may be similar in schizophrenia and bipolar disorder, at least in the chronic state. However, cortical CSF may be markedly increased in schizophrenia patients.     

Prefrontal cortical dopamine systems and the elaboration of functional corticostriatal circuits: implications for schizophrenia and Parkinson's disease

Summary The dopaminergic innervation of the prefrontal cortex is able to transsynaptically regulate the activity of subcortical dopamine innervations. Disruption of the prefrontal cortical DA innervation results in the enhanced biochemical responsiveness of the dopamine innervation of the nucleus accumbens. We present recent data indicating that distinct prefrontal cortical dopamine innervations can be functionally dissociated on the basis of responsiveness to stress. The ventral striatal projection target (nucleus accumbens shell) of the prefrontal cortical region that is stress sensitive is also responsive to stress. In this manner interconnected cortico-striato-pallido-mesencephalic loops can be defined on the basis of the biochemical responsive of local dopamine systems to stress and on the basis of responsiveness to antipsychotic drugs. These data suggest the functional derangement of a distinct corticofugal loops in schizophrenia and in certain aspects of Parkinson's disease.     

Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: implications for schizophrenia.

BACKGROUND: Recent brain imaging studies have indicated that schizophrenia is associated with increased amphetamine-induced dopamine release in the striatum. It has long been hypothesized that dysregulation of subcortical dopamine systems in schizophrenia might result from a failure of the prefrontal cortex (PFC) to adequately control subcortical dopaminergic function. The activity of midbrain dopaminergic neurons is regulated, in part, by glutamatergic projections from the PFC acting via glutamatergic N-methyl-D-aspartate (NMDA) receptors. The goal of this study was to test the hypothesis that a pharmacologically induced disruption of NMDA transmission leads to an increase in amphetamine-induced dopamine release in humans. METHODS: In eight healthy volunteers, we compared striatal amphetamine-induced (0.25 mg/kg) dopamine release under control conditions and under sustained disruption of NMDA transmission induced by infusion of the noncompetitive NMDA antagonist ketamine (0.2 mg/kg intravenous bolus followed by 0.4 mg/kg/hour intravenous infusion for 4 hours). Amphetamine-induced dopamine release was determined with single photon emission computed tomography, as the reduction in the binding potential (BP) of the radiolabeled D(2) receptor antagonist [(123)I]IBZM. RESULTS: Ketamine significantly enhanced the amphetamine-induced decrease in [(123)I]IBZM BP, from -5.5% +/- 3.5% under control conditions to -12. 8% +/- 8.8% under ketamine pretreatment (repeated-measures analysis of variance, p =.023). CONCLUSIONS: The increase in amphetamine-induced dopamine release induced by ketamine (greater than twofold) was comparable in magnitude to the exaggerated response seen in patients with schizophrenia. These data are consistent with the hypothesis that the alteration of dopamine release revealed by amphetamine challenge in schizophrenia results from a disruption of glutamatergic neuronal systems regulating dopaminergic cell activity.     

Dopamine and the diseased brain

Dysfunction of central dopaminergic neurotransmission has been implicated in a series of neuropsychiatric disorders, including Tourette's syndrome, schizophrenia, and drug and alcohol dependence. The behavioral and psychopathological manifestations of central dopaminergic dysfunction differ depending on the site of their neurobiological correlate. These sites may be found in the dorsal or ventral striatum, but also in cortical regions such as the limbic and prefrontal cortex, among other locations. A low basic dopamine turnover and an increase in the availability of dopamine D2 receptors in the caudate body have been associated with the severity of motor tics in Tourette's syndrome. In the ventral striatum and particularly in the nucleus accumbens, different drugs of abuse stimulate dopamine release and thus reinforce drug consumption. The downregulation of dopamine D2 receptors in this area of the brain has been associated with alcohol craving and an increase in the processing of alcohol-related stimuli in the medial prefrontal cortex. Brain imaging studies in which intrasynaptic dopamine release is manipulated in vivo have shown that increased subcortical dopamine release is associated with the pathogenesis of positive symptoms in schizophrenia. This review discusses a broad range of brain imaging and neuroendocrinological studies on dopaminergic dysfunction in neuropsychiatric disorders, including relevant findings on the basis of primate studies. In addition, the hypothesis is examined that phasic dopamine release is associated with salience attribution to external stimuli, insofar as it mediates reward anticipation in the ventral striatum and limbic cortex, habit formation in the dorsal striatum, and working memory function in the prefrontal cortex.     

Dopaminergic modulation of resting‐state functional connectivity in de novo patients with Parkinson's disease

Parkinson's disease (PD) is characterized by degenerative changes of nigral dopamine neurons, resulting in the dopaminergic denervation of the striatum. Resting state networks studies have demonstrated that dopamine modulates distinct network connectivity patterns in both a linear and a nonlinear fashion, but quantitative analyses of dopamine‐dependent functional connectivity secondary to PD pathology were less informative. In the present study, we performed a correlation analysis between striatal dopamine levels assessed quantitatively by FP‐CIT positron emission tomography imaging and resting‐state functional connectivity in 23 drug naïve de novo patients with PD to elucidate dopamine‐dependent functional networks. The major finding is that the patterns of dopamine‐dependent positive functional connectivity varied depending on the location of striatal seeds. Dopamine‐dependent functional connectivity with the caudate predominantly overlay pericentral cortical areas, whereas dopamine‐dependent structures functionally connected with the posterior putamen predominantly involved cerebellar areas. The dorsolateral frontal area overlapped as a dopamine‐dependent cortical region that was positively connected with the anterior and posterior putamen. On the other hand, cortical areas where functional connectivity from the posterior cingulate was negatively correlated with dopaminergic status in the posterior putamen were localized in the left anterior prefrontal area and the parietal area. Additionally, functional connectivity between the anterior putamen and mesiofrontal areas was negatively coupled with striatal dopamine levels. The present study demonstrated that dopamine‐dependent functional network connectivity secondary to PD pathology mainly exhibits a consistent pattern, albeit with some variation. These patterns may reflect the diverse effects of dopaminergic medication on parkinsonian‐related motor and cognitive performance. Hum Brain Mapp 35:5431–5441, 2014. © 2014 Wiley Periodicals, Inc .     

Cognitive impairment and in vivo metabolites in first-episode neuroleptic-naive and chronic medicated schizophrenic patients: a proton magnetic resonance spectroscopy study

Involvement of the prefrontal cortex in schizophrenia has been implicated by neuropsychological, as well as neuropathological and imaging studies. Reductions of N-acetylaspartate (NAA), an in vivo marker of neuronal integrity, have repeatedly been detected in the frontal lobes of patients with schizophrenia by proton magnetic resonance spectroscopy (1H-MRS). In chronic medicated patients, a positive correlation between NAA levels of the prefrontal cortex and cognitive functioning has been observed, but to date, there have been no studies in first-episode neuroleptic-naive patients. In this study, single-voxel 1H-MRS was used to investigate neuronal function of the dorsolateral prefrontal cortex in 15 first-episode and 20 chronic schizophrenic patients. Outcomes were compared to 20 age-matched healthy controls to assess the relationship between prefrontal metabolism and neuropsychological performance. Patients with chronic schizophrenia had significant reductions of NAA, glutamate/glutamine, and choline levels compared to first-episode patients and healthy controls. Furthermore, creatine and phosphocreatine were significantly reduced in both patient groups compared to healthy controls. In the neuropsychological tests, chronic schizophrenic patients performed significantly poorer in the Auditory Verbal Learning Task (AVLT) compared to first-episode patients. In both patient groups, NAA levels of the left frontal lobe significantly correlated with performances in verbal learning and memory. These results corroborate data from recent structural and spectroscopic imaging studies of the frontal lobes in schizophrenia, in which cortical gray matter reductions after onset of symptoms as well as reduced levels of NAA in chronic, but not in first-episode schizophrenic patients have been reported.     

Striatal dopamine receptors and transporters in monkeys with neonatal temporal limbic damage

Developmental cortical damage has been implicated in the basic neurobiology of schizophrenia. Adult rhesus monkeys with neonatal temporal limbic damage show a stimulus-dependent disinhibition of subcortical dopamine (DA) release. We measured dopamine D2 receptors and transporters in vivo in rhesus monkeys with neonatal and adult mesial temporal limbic lesions and control monkeys to explore further the effects of this developmental lesion on striatal DA function. All monkeys were studied with [I-123]IBZM SPECT to assess the availability of striatal dopamine D2 receptors and with [I-123]beta-CIT SPECT to measure the availability of dopamine transporters in the striatum. IBZM binding was significantly reduced in monkeys with neonatal limbic lesions. No group difference in beta-CIT binding was found. The reduction in IBZM binding was significantly correlated with subcortical dopamine release after monoaminergic prefrontal stimulation as determined with in vivo microdialysis. Our findings imply specific interactions between age at lesion and the availability of DA transporter and receptors in non-human primates, and suggest that stimulus-dependent DA activity affects the expression of DA receptors.     

Cortical Regulation of Striatal Neuropeptide Y (NPY)-Containing Neurons in the Rat

This study examined the functional relationships established by nigral, cortical, and thalamic striatal afferent pathways with neuropeptide Y (NPY)-containing neurons in the rat rostral striatum by coupling selective deafferentation procedures and NPY immunohistochemistry. Previous experiments have shown that after unilateral 6-hydroxydopamine (6-OHDA)-induced degeneration of nigrostriatal dopaminergic neurons, the mean number of NPY-immunoreactive (Ir) neurons per frontal section was increased in the striatum ipsilateral to the lesion side and unaltered in the contralateral striatum. The present topographical analysis of the 6-OHDA lesion effects led us to state that the increase in NPY-Ir neuron density occurs in restricted ventral and medial zones of the ipsilateral striatum. Unilateral ablation of the frontoparietal cerebral cortex by thermocoagulation was moreover shown to elicit, 20 - 30 days later, a significant bilateral increase in the number of striatal NPY-Ir cells. The increase was more marked in the striatum ipsilateral to the hemidecortication where it was similar in amplitude to that induced by the 6-OHDA lesion. The topographical analysis of the cortical lesion effects also revealed an uneven striatal response, but, in contrast to that observed for the 6-OHDA lesion, changes were restricted to dorsolateral areas of the striatum in both brain sides, revealing an apparent complementarity of nigral dopaminergic and cortical influences over striatal NPY neuronal system. Combined unilateral nigral and cortical lesions surprisingly counteracted in a survival time dependent manner the effects of each lesion considered separately. In that condition topographical changes related to the 6-OHDA lesion totally disappeared and those related to the cortical lesion were attenuated but still present. These results suggest that expression of striatal dopamine - NPY interaction is dependent on corticostriatal transmission. Interestingly lesion of thalamic areas projecting to the striatum did not significantly modify the mean number of NPY-Ir neurons determined per section from the whole striatal surface, but selectively increased the NPY neuron density in the mediodorsal region of the striatum, suggesting that the striatal NPY-containing neuronal system is also influenced by thalamostriatal projections.     

3H]Dopamine release in striatum in response to cortical stimulation in a corticostriatal slice preparation

A new method has been developed to investigate corticostriatal glutamatergic influence on [3H]dopamine release in striatum in complex corticostriatal slice preparation in vitro. Horizontal slices containing the striatum and the adjacent prefrontal cortex of rat brain were cut in a plane that maintains corticostriatal connections. After incubation with [3H]dopamine, slices were submerged in a two-compartment bath so that the cortical region was contained entirely in one compartment, corpus callosum passed through a silicone greased slot, and the striatal region was contained in the other compartment. A cannula was placed just above the striatal part of the slice and effluent was collected with a peristaltic pump, released tritiated materials were counted with a liquid scintillation counter. Electric field stimulation of cortex increased the release of [3H]dopamine in the striatum. Bicuculline (1 mM) increased the basal and stimulated release of [3H]dopamine in the striatum in response to cortical stimulation of cortex indicating the GABAergic control on dopamine release. This method allows investigation of the effect of cortical stimulation on glutamate-dopamine-GABA interactions in the striatum in vitro that might help to understand better the neurochemical background of schizophrenia or Parkinson's disease.     

Understanding the neurotransmitter pathology of schizophrenia: selective deficits of subtypes of cortical GABAergic neurons

Summary. Research aimed at understanding the neurotransmitter pathology of schizophrenia has been underway for half a century, with much emphasis on the dopamine system. Although this approach has advanced our understanding of treatment mechanisms, identification of primary dopaminergic abnormalities in the disease has been elusive. The increasing emphasis on a neuronal pathology of schizophrenia has led to the identification of abnormalities in GABAergic and glutamatergic systems; and we have identified selective deficits in GABAergic interneurons containing the calcium binding proteins parvalbumin and calbindin. Here we report further evidence for a loss of parvalbumin-immunoreactive neurons in both dorsolateral prefrontal and medial temporal cortex, indicating that these deficits are consistent with a subtle neurodevelopmental pathogenesis and hypothesising that they may contribute to a further degenerative process in schizophrenia. Received December 17, 2001; accepted February 21, 2002     

Dopaminergic dysfunction in alcoholism and schizophrenia--psychopathological and behavioral correlates.

Dysfunction of central dopaminergic neurotransmission has been implicated in the pathogenesis of schizophrenia as well as drug and alcohol dependence. Different drugs of abuse stimulate dopamine release in the ventral striatum and thus reinforce drug consumption. Increased subcortical dopamine release has also been associated with the pathogenesis of positive symptoms in schizophrenia and may be driven by a prefrontal dopaminergic dysfunction. These seemingly heterogeneous findings may be explained by recent research in non-human primates. According to these studies, reward anticipation but not anticipated reward consumption is accompanied by a phasic dopamine release in the striatum and prefrontal cortex. In the striatum, phasic dopamine release primarily affects motivation, psychomotor activation and reward craving, while in the prefrontal cortex, dopaminergic stimulation is involved in the activation of working memory and reward anticipation. In alcoholism, previously neutral stimuli that have been associated with alcohol intake can become conditioned cues which activate phasic dopamine release and reward craving. In schizophrenia, stress-induced or chaotic activation of dopamine release may attribute incentive salience to otherwise irrelevant stimuli and thus be involved in the pathogenesis of delusional mood and other positive symptoms. Studies in humans and non-human primates emphasize the role of dopaminergic neurotransmission in reward anticipation and its dysfunction in different neuropsychiatric diseases.     

Theta burst stimulation‐induced inhibition of dorsolateral prefrontal cortex reveals hemispheric asymmetry in striatal dopamine release during a set‐shifting task – a TMS–[11C]raclopride PET study

The prefrontostriatal network is considered to play a key role in executive functions. Previous neuroimaging studies have shown that executive processes tested with card‐sorting tasks requiring planning and set‐shifting [e.g. Montreal‐card‐sorting‐task (MCST)] may engage the dorsolateral prefrontal cortex (DLPFC) while inducing dopamine release in the striatum. However, functional imaging studies can only provide neuronal correlates of cognitive performance and cannot establish a causal relation between observed brain activity and task performance. In order to investigate the contribution of the DLPFC during set‐shifting and its effect on the striatal dopaminergic system, we applied continuous theta burst stimulation (cTBS) to left and right DLPFC. Our aim was to transiently disrupt its function and to measure MCST performance and striatal dopamine release during [¹¹C]raclopride PET. A significant hemispheric asymmetry was observed. cTBS of the left DLPFC impaired MCST performance and dopamine release in the ipsilateral caudate–anterior putamen and contralateral caudate nucleus, as compared to cTBS of the vertex (control). These effects appeared to be limited only to left DLPFC stimulation while right DLPFC stimulation did not influence task performance or [¹¹C]raclopride binding potential in the striatum. This is the first study showing that cTBS, by disrupting left prefrontal function, may indirectly affect striatal dopamine neurotransmission during performance of executive tasks. This cTBS‐induced regional prefrontal effect and modulation of the frontostriatal network may be important for understanding the contribution of hemisphere laterality and its neural bases with regard to executive functions, as well as for revealing the neurochemical substrate underlying cognitive deficits.     

Up-regulation of the D1 dopamine receptor-interacting protein,calcyon, in patients with schizophrenia

BACKGROUND: The dopamine hypothesis remains a prominent influence on research into the pathogenesis of schizophrenia, yet the presence of consistent schizophrenia-linked abnormalities in the presynaptic components of the dopamine system or in dopamine receptors still remains a matter of debate. The present study focuses on a recently recognized group of dopamine receptor-interacting proteins as possible novel sites of dysfunction in schizophrenia. Specifically, we examined whether the D1 dopamine receptor-interacting protein calcyon and the D2 dopamine receptor-interacting proteins filamin-A and spinophilin are affected in the dorsolateral prefrontal cortex of patients with schizophrenia. METHODS: Slot blots of dorsolateral prefrontal cortical tissue were used to compare the levels of the 3 proteins of interest in control, schizophrenic, bipolar, and major depression groups (n = 15 per group). The nonschizophrenic psychiatric groups were included to determine the specificity of the detected abnormalities. RESULTS: The dorsolateral prefrontal cortex in schizophrenic patients displayed nearly twice the normal levels of calcyon, whereas filamin-A and spinophilin levels were unaltered. Patients with bipolar disorder or major depression showed no changes in all 3 proteins examined. CONCLUSION: Our findings provide the first evidence that abnormalities in the dopamine system of patients with schizophrenia may lie in altered levels of dopamine receptor-interacting proteins.