An investigation into aripiprazole's partial D(2) agonist effects within the dorsolateral prefrontal cortex during working memory in healthy volunteers

Rationale: Working memory impairments in schizophrenia have been attributed to dysfunction of the dorsolateral prefrontal cortex (DLPFC) which in turn may be due to low DLPFC dopamine innervation. Conventional antipsychotic drugs block DLPFC D2 receptors, and this may lead to further dysfunction and working memory impairments. Aripiprazole is a D2 receptor partial agonist hypothesised to enhance PFC dopamine functioning, possibly improving working memory. Objectives: We probed the implications of the partial D2 receptor agonist actions of aripiprazole within the DLPFC during working memory. Investigations were carried out in healthy volunteers to eliminate confounds of illness or medication status. Aripiprazole’s prefrontal actions were compared with the D2/5-HT2A blocker risperidone to separate aripiprazole’s unique prefrontal D2 agonist actions from its serotinergic and striatal D2 actions that it shares with risperidone. Method: A double-blind, placebo-controlled, parallel design was implemented. Participants received a single dose of either 5 mg aripiprazole, 1 mg risperidone or placebo before performing the n-back task whilst undergoing fMRI scanning. Results: Compared with placebo, the aripiprazole group demonstrated enhanced DLPFC activation associated with a trend for improved discriminability (d’) and speeded reaction times. In contrast to aripiprazole’s neural effects, the risperidone group demonstrated a trend for reduced DLPFC recruitment. Unexpectedly, the risperidone group demonstrated similar effects to aripiprazole on d’ and additionally had reduced errors of commission compared with placebo. Conclusion: Aripiprazole has unique DLPFC actions attributed to its prefrontal D2 agonist action. Risperidone’s serotinergic action that results in prefrontal dopamine release may have protected against any impairing effects of its prefrontal D2 blockade

Molecular imaging in schizophrenia spectrum disorders

In this chapter, we aim to shed light on the schizophrenia spectrum disorders using molecular imaging. Schizophrenia spectrum disorders consist primarily of the disorders with full-blown psychosis in their course and are grouped in the DSM-V category of schizophrenia and other psychotic disorders. The treatment of psychosis has been very successful in the era of psychopharmacology, starting with the discovery of the "neuroleptic" drug chlorpromazine (Largactil). The notion that the so-called typical antipsychotics bind to dopamine D2 and D3 receptors is one of the cornerstones of the dopamine hypothesis of schizophrenia (Davis et al., Am J Psychiatry 148:1474-1486, 1991). For more than a decade, this hypothesis has been the most influential hypothesis in schizophrenia research. It postulates that schizophrenia is a manifestation of a "hyperdopaminergic" state in some regions of the brain. The binding of antipsychotics to D2/D3 receptors can be directly visualized and quantified with dopamine receptor PET and SPECT ligands, such as [11C]-raclopride or [123I]-IBZM, respectively (Laruelle, Q J Nucl Med 42:211-221, 1998). Typical antipsychotics bind to D2/D3 receptors and displace these radiotracers from the postsynaptic receptors in the dopamine projection areas, such as the striatum, providing a unique way to quantify occupancy of these compounds to the D2/D3 receptors. In one of the first human studies with [11C]-raclopride, described that an occupancy of 70-80% of the D2/D3 receptors was sufficient for its antipsychotic effects while parkinsonistic effects were associated with much higher occupancies. The anti-dopaminergic effects in the striatum explain the major side effect of typical antipsychotics, i.e., parkinsonism. Very efficacious second-line or "atypical" antipsychotics appear to be less dependent on D2 blockade for clinical effect. The major example of this line of drugs is clozapine. Clozapine acts partly by its affinity for the postsynaptic 5HT2A receptor but has "pleiotropic" effects by affecting many other neurotransmitter receptors, hormone receptors, and inflammatory mediators. However, it was found that the newer "atypical" antipsychotics marketed after clozapine still bind for a large proportion to dopamine D2/D3 receptors, which contributes significantly to their antipsychotic efficacy. Despite the enormous progress in the development of antipsychotics, and growth of choice for the clinician to treat schizophrenia, the effect remains limited to a suppressive effect on the positive psychotic symptoms, like delusions and hallucinations. Antipsychotics do not cure the disease and have major metabolic side effects, like weight gain, increasing the risk for diabetes enormously. Therefore, more knowledge on the working mechanism and the discovery of alternative molecular pathways of treatment are needed. It is the aim of this chapter to translate molecular imaging in experimental models of schizophrenia and patients to better understand the etiopathogenesis of the clinical syndrome of schizophrenia. The ultimate aim is to design better prevention, care, and cure for schizophrenia by pinpointing to the molecular focus of the disease process.</p

Effects of L-DOPA monotherapy on psychomotor speed and [11C] raclopride binding in high-risk older adults with depression

Background: A high-risk subgroup of older patients with depression has slowed processing and gait speeds. This study examined whether carbidopa/levodopa (L-DOPA) monotherapy increased dopamine availability, increased processing/gait speed, and relieved depressive symptoms. Methods: Adult outpatients with depression >59 years old underwent baseline [11C]raclopride positron emission tomography followed by open L-DOPA for 3 weeks (1 week each of 150 mg, 300 mg, and 450 mg). Generalized estimating equations tested the pre- and post-L-DOPA differences in processing and gait speed measures, depressive symptoms, and reported side effects. The decrease in binding potential between the pre- and posttreatment scans indexed enhanced synaptic dopamine availability induced by L-DOPA treatment. Results: Thirty-six subjects participated (age, 75.3 ± 7.5 years; 44.4% male). Significant, dose-dependent increases in processing and gait speed were observed with L-DOPA (450-mg dose: processing speed factor score effect size = 0.41, p = .001; dual-task gait speed effect size = 0.43, p = .002). [11C]raclopride decrease in binding potential was significantly different from 0 in sensorimotor (t24 = −4.85, p < .001) and associative striatum (t24 = −2.52, p = .019) but not in limbic striatum (t24 = 0.265, p = .793). Depressive symptoms decreased significantly on the Hamilton Rating Scale for Depression (effect size = −0.37, p = .002). Dropout rate was 8.3%, and nausea was the most frequently reported side effect. Conclusions: By enhancing availability of dopamine, L-DOPA improved processing and gait speed in older adults with depression and significantly decreased [11C]raclopride binding in selected striatal subregions

Neuroanatomical predictors of L-DOPA response in older adults with psychomotor slowing and depression: A pilot study

Background: Declining function in dopamine circuits is implicated in normal aging and late-life depression (LLD). Dopamine augmentation recently has shown therapeutic promise, but predictors of response are unknown. Methods: Depressed elders with slowed gait underwent baseline magnetic resonance imaging (MRI) and [11C]raclopride positron emission tomography (PET). Subjects then received open treatment with carbidopa/levodopa (L-DOPA) for three weeks. Linear regressions examined relationships between baseline MRI measures, [11C]raclopride binding, and behavioral outcomes. Results: Among N = 16 participants aged 72.5 ± 6.8 years, higher left superior temporal gyrus volume was associated with higher processing speed at baseline, while cortical thinning in a processing speed network was associated with greater improvement following L-DOPA. Greater volume and cortical thickness in brain regions associated with mobility were associated with higher baseline gait speed. Higher baseline white matter hyperintensity volume predicted less post-L-DOPA improvement on dual task gait speed and IDS-SR scores. Higher [11C]raclopride binding in the associative striatum was associated with cortical thickness in some, but not all, processing speed brain regions, while higher binding in sensorimotor striatum was significantly associated with left caudate volume. Limitations: Limiting the conclusions drawn from this pilot study are the small sample size and open administration of L-DOPA. Conclusions: Greater baseline brain volumes and cortical thickness in regions supporting cognition and gait were associated with higher behavioral performance, while lower structural integrity was associated with increased responsivity to L-DOPA. If substantiated in larger studies, these findings could facilitate the targeting of dopaminergic treatments to those LLD patients most likely to respond

No Differential Regulation of Dopamine Transporter (DAT) and Vesicular Monoamine Transporter 2 (VMAT2) Binding in a Primate Model of Parkinson Disease

Radioligands for DAT and VMAT2 are widely used presynaptic markers for assessing dopamine (DA) nerve terminals in Parkinson disease (PD). Previous in vivo imaging and postmortem studies suggest that these transporter sites may be regulated as the numbers of nigrostriatal neurons change in pathologic conditions. To investigate this issue, we used in vitro quantitative autoradioradiography to measure striatal DAT and VMAT2 specific binding in postmortem brain from 14 monkeys after unilateral internal carotid artery infusion of 1-Methyl-4-Phenyl-1,2,3,6-tetrahydropyridine (MPTP) with doses varying from 0 to 0.31 mg/kg. Quantitative estimates of the number of tyrosine hydroxylase (TH)-immunoreactive (ir) neurons in substantia nigra (SN) were determined with unbiased stereology, and quantitative autoradiography was used to measure DAT and VMAT2 striatal specific binding. Striatal VMAT2 and DAT binding correlated with striatal DA (rs = 0.83, rs = 0.80, respectively, both with n = 14, p<0.001) but only with nigra TH-ir cells when nigral cell loss was 50% or less (r = 0.93, n = 8, p = 0.001 and r = 0.91, n = 8, p = 0.002 respectively). Reduction of VMAT2 and DAT striatal specific binding sites strongly correlated with each other (r = 0.93, n = 14, p<0.0005). These similar changes in DAT and VMAT2 binding sites in the striatal terminal fields of the surviving nigrostriatal neurons demonstrate that there is no differential regulation of these two sites at 2 months after MPTP infusion

Model-based parametric study of frontostriatal abnormalities in schizophrenia patients

<p>Abstract</p> <p>Background</p> <p>Several studies have suggested that the activity of the prefrontal cortex (PFC) and the dopamine (DA) release in the striatum has an inverse relationship. One would attribute this relationship primarily to the circuitry comprised of the glutamatergic projection from the PFC to the striatum and the GABAergic projection from the striatum to the midbrain DA nucleus. However, this circuitry has not characterized satisfactorily yet, so that no quantitative analysis has ever been made on the activities of the PFC and the striatum and also the DA release in the striatum.</p> <p>Methods</p> <p>In this study, a system dynamics model of the corticostriatal system with dopaminergic innervations is constructed to describe the relationships between the activities of the PFC and the striatum and the DA release in the striatum. By taking published receptor imaging data from schizophrenia patients and healthy subjects into this model, this article analyzes the effects of striatal D2 receptor activation on the balance of the activity and neurotransmission in the frontostriatal system of schizophrenic patients in comparison with healthy controls.</p> <p>Results</p> <p>The model predicts that the suppressive effect by D2 receptors at the terminals of the glutamatergic afferents to the striatum from the PFC enhances the hypofrontality-induced elevation of striatal DA release by at most 83%. The occupancy-based estimation of the 'optimum' D2 receptor occupancy by antipsychotic drugs is 52%. This study further predicts that patients with lower PFC activity tend to have greater improvement of positive symptoms following antipsychotic medication.</p> <p>Conclusion</p> <p>This model-based parametric study would be useful for system-level analysis of the brains with psychiatric diseases. It will be able to make reliable prediction of clinical outcome when sufficient data will be available.</p

rTMS of the Left Dorsolateral Prefrontal Cortex Modulates Dopamine Release in the Ipsilateral Anterior Cingulate Cortex and Orbitofrontal Cortex

Background: Brain dopamine is implicated in the regulation of movement, attention, reward and learning and plays an important role in Parkinson’s disease, schizophrenia and drug addiction. Animal experiments have demonstrated that brain stimulation is able to induce significant dopaminergic changes in extrastriatal areas. Given the up-growing interest of noninvasive brain stimulation as potential tool for treatment of neurological and psychiatric disorders, it would be critical to investigate dopaminergic functional interactions in the prefrontal cortex and more in particular the effect of dorsolateral prefrontal cortex (DLPFC) (areas 9/46) stimulation on prefrontal dopamine (DA). Methodology/Principal Findings: Healthy volunteers were studied with a high-affinity DA D2-receptor radioligand, [ 11 C]FLB 457-PET following 10 Hz repetitive transcranial magnetic stimulation (rTMS) of the left and right DLPFC. rTMS on the left DLPFC induced a significant reduction in [ 11 C]FLB 457 binding potential (BP) in the ipsilateral subgenual anterior cingulate cortex (ACC) (BA 25/12), pregenual ACC (BA 32) and medial orbitofrontal cortex (BA 11). There were no significant changes in [ 11 C]FLB 457 BP following right DLPFC rTMS. Conclusions/Significance: To our knowledge, this is the first study to provide evidence of extrastriatal DA modulation following acute rTMS of DLPFC with its effect limited to the specific areas of medial prefrontal cortex. [ 11 C]FLB 457-PET combined with rTMS may allow to explore the neurochemical functions of specific cortical neural networks and help t