Biomedical subjects

S Houle

Publications and source records attributed to S Houle.

At least 55 records · Page 3Linked to original sources

PubMed1999

Imaging of cAMP-specific phosphodiesterase-IV: comparison of [11C]rolipram and [11C]Ro 20-1724 in rats.

The phosphodiesterase type IV (PDEIV) family of enzymes contributes to the metabolism of cAMP formed by the stimulation of beta-adrenergic, A2-adenosine, and H2-histamine receptors in the brain. Disturbances in cAMP-mediated signaling have been implicated in several neuropsychiatric disorders, and there is evidence that increasing cAMP levels through PDEIV inhibition improves the symptoms of these disorders. In the present study, the selective PDEIV inhibitors rolipram and Ro 20-1724, labeled with C-11, were evaluated in vivo in rats, as potential radioligands for imaging PDEIV enzymes with positron emission tomography (PET). Biodistribution experiments revealed a greater than threefold increased regional brain retention of [11C]rolipram as compared to [11C]Ro 20-1724. [nC]Rolipram uptake was higher in rat brain areas (e.g., cortical regions and olfactory system) showing higher expression of PDEIV enzymes, as determined previously using [3H]rolipram autoradiography or molecular genetic techniques. Binding of [n1C]rolipram and [11C]Ro 20-1724 was specific, since coadministration of high doses of unlabeled rolipram (10 mg/Kg, i.v.) or Ro 20-1724 (30 mg/Kg with [11C]rolipram and 10 mg/Kg with [11C]Ro 20-1724, i.v.) reduced radioactivity uptake in brain regions. Pretreatment with high doses of the PDEI selective inhibitor vinpocetine (10 mg/Kg, i.p., 15 min prior), or the noradrenaline reuptake inhibitor desipramine (10 mg/Kg, i.p., 30 min prior), or coinjection with the adenylyl cyclase activator forskolin (6.5 or 15 mg/Kg, i.v.), did not inhibit [11C]rolipram uptake in brain areas, suggesting binding selectivity for PDEIV enzymes. We conclude that [11C]rolipram, but not [11C]Ro 20-1724, is a promising radioligand for imaging the PDEIV enzymes with PET.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1999

Dopamine D1 agonist R-[11C]SKF 82957: synthesis and in vivo characterization in rats.

The active enantiomer R-SKF 82957 was labeled with 11C by N-[11C]methylation of the full dopamine (D1) agonist R-SKF 81297, using [11C]methyl iodide in the presence of N-ethyldiisopropylamine, in high specific activity, radiochemical purity and yields. Compared with the D1 agonist R/S-[11C]SKF 82957, R-[11C]SKF 82957 showed higher binding in the D1 rich regions, such as striatum and olfactory tubercles (approximately 1.7 times), thereby improving the tissue contrast. R-[11C]SKF 82957 exhibited high in vivo binding selectivity for D1 receptors in rats, because only high doses of D1 competitors, but not D2 or serotonin (5-HT2) blockers, significantly reduced the radioactivity levels in all brain areas. No labeled metabolites were detected in rat brain. These results indicate that R-[11C]SKF 82957 will provide more sensitive measurements of D1 receptors in in vivo studies than the racemic mixture.

Animals↗

PubMed1999

Cloning and preliminary pharmacological characterization of the anaphylatoxin C5a receptor in the rabbit.

1 The rabbit receptor for C5a was cloned from a genomic library and found to be 79.5% identical to the human homologue, the highest degree of similarity found so far in nonprimate laboratory animals. 2 The rabbit C5a receptor stably expressed in RBL cells binds human 125I-C5a (2 nM). Unlabelled C5a and the C-terminal analogue N-acetyl-Tyr-Ser-Phe-Lys-Pro-Met-Pro-Leu-D-Ala-Arg (Ac-YSFKPMPLaR) were found to be competitors of that binding, the peptide analogue retaining approximately 0.1% of the affinity of human C5a. 3 The order of potency human C5a>Ac-YSFKPMPLaR was conserved in bioassays based on rabbits (relaxation of the isolated portal vein and pulmonary artery; acute in vivo neutropenia), but with a decreasing potency gap between the two compounds, a likely consequence of the resistance to peptidases of the analogue. 4 The molecular definition of the rabbit C5a receptor evidenced a high preservation degree of sequence and pharmacologic properties relative to the human ortholog receptor, thus defining a set of molecular tools for the investigation of the role of C5a in physiologic and pathologic models based on the rabbit (e.g. atherosclerosis, inflammation).

Amino Acid Sequence↗

PubMed1999

Effect of endogenous kinins, prostanoids, and NO on kinin B1 and B2 receptor expression in the rabbit.

To determine whether kinin receptor expression is regulated by kinins, prostaglandins, and/or nitric oxide (NO), rabbits were treated with a B(1) receptor (B(1)R) antagonist, a B2 receptor (B2R) antagonist, a prostacyclin mimetic, or inhibitors of NO synthase, cyclooxygenase, or angiotensin-converting enzyme. The mRNA concentrations for B1R and B2R (multiplex RT-PCR) were measured in several organs. The B2R mRNA expression was not significantly upregulated by any of the treatments; it was notably downregulated by angiotensin-converting enzyme or cyclooxygenase blockade or B2R antagonism in the heart and duodenum. A treatment with bacterial lipopolysaccharide (LPS), known to induce B1R expression, has also been applied and was the most consistent in upregulating the expression of B1R mRNA (kidney, duodenum, and striated muscle). The contractile responses mediated by kinin receptors in blood vessels isolated from the treated rabbits also indicated that LPS was the only B1R inducer (aorta). Icatibant, a nonequilibrium antagonist of the rabbit B2R, was the sole tested drug to alter the contractions mediated by the B2R in the jugular vein or the intensity of the immunohistochemical B2R staining in several organs (inhibition in both cases). B2R mRNA expression was downregulated in some organs by several of the applied treatments, but the data did not support generally applicable feedback for the regulation of B2R expression involving endogenous kinins, prostanoids, or NO. There was no indication of compensatory or reciprocal regulation of B1Rs, relative to B2Rs, inasmuch as B1R expression was restricted to LPS-treated animals.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1999

Serotonin 5-HT2 receptors in schizophrenia: a PET study using [18F]setoperone in neuroleptic-naive patients and normal subjects.

OBJECTIVE: Several postmortem studies have reported a decreased density of serotonin 5-HT2 receptors in the prefrontal cortex in schizophrenia. The purpose of this study was to investigate this in patients with schizophrenia by means of [18F]setoperone and positron emission tomography (PET) imaging. METHOD: Thirteen neuroleptic-free patients with schizophrenia, 10 of whom were also neuroleptic-naive, were compared with a group of 26 normal subjects in the same age range. The density of 5-HT2 receptors was assessed with the use of [18F]setoperone and PET in standardized cortical regions of interest. RESULTS: Increasing age was associated with similar declines in 5-HT2 receptors in all cortical regions in the patient group and in the normal comparison group. After control for the effect of age, there was no statistically significant difference between the patients and the comparison subjects in 5-HT2 receptor density in any of the cortical regions. CONCLUSIONS: This study failed to find the decrease in 5-HT2 receptors reported in postmortem studies of schizophrenia. The study had the power to detect a decrease of 25% or more in 5-HT2 receptors, which was anticipated on the basis of the previous postmortem studies. Thus, a primary serotonergic abnormality in schizophrenia, if one exists, is either small or unlikely to be at the level of the 5-HT2 receptors. This finding does not rule out a therapeutic role for 5-HT2 antagonists in schizophrenia, but it does suggest that the therapeutic contribution is likely to be an indirect one.

Antipsychotic Agents↗

PubMed1999

Prefrontal cortex 5-HT2 receptors in depression: an [18F]setoperone PET imaging study.

OBJECTIVE: Widespread disturbances of serotonin (5-HT) are implicated in the pathophysiology of depression. Of 5-HT receptor abnormalities reported, the most replicated finding is increased 5-HT2 receptor binding in the postmortem prefrontal cortex of depressed suicide victims. The extent to which these findings exist in depressed persons without recent suicide attempts is uncertain. The objective of this study was to evaluate 5-HT2 receptors in depressed patients who were medication-free and who had not made recent suicide attempts. METHOD: With the use of [18F]setoperone and positron emission tomography (PET), 5-HT2 receptor binding potential was assessed in 14 depressed and 19 healthy subjects. Exclusion criteria for depressed patients included use of antidepressant medication within the past 6 months, a history of suicide attempts within the past 5 years, other current axis I disorders including bipolar disorder, and the presence of psychotic symptoms. The 5-HT2 (setoperone) binding potential in the two groups of subjects was compared by analysis of covariance with age as the covariate. RESULTS: Age had a significant effect on 5-HT2 binding potential, but depression did not. The interaction of age and depression was not significant. CONCLUSIONS: The 5-HT2 binding potential is not increased in untreated depressed subjects who have not made recent suicide attempts. This negative finding does not rule out the possibility that there is a role for 5-HT2 receptors in treatment or that 5-HT2 receptors are increased in highly suicidal states.

Adolescent↗

PubMed1998

Functional network differences in schizophrenia: a rCBF study of semantic processing.

Studies of regional cerebral blood flow in patients with schizophrenia have led to the idea that dysfunctional neurocircuitry may play a role in patients' cognitive deficits. The present PET study was designed to explore this idea by comparing the functional neural networks associated with semantic processing for patients and normal controls through structural equation modeling (path analysis). The patients showed significantly different neural interactions among frontal regions, between the frontal and temporal cortices, and between the frontal lobe and anterior cingulate than controls. These discrepancies were especially striking given there were minimal group differences in task performance. Results suggest that schizophrenia involves a neural abnormality that is evident in functional networks during cognitive performance.

Adult↗

PubMed1998

Task-independent effect of time on rCBF.

Positron emission tomography was used to identify brain regions that showed general increase or decrease in regional cerebral blood flow (rCBF) across time that was task-independent. Twelve male subjects were scanned eight times: the first and last scans were taken while subjects performed a baseline fixation task and the middle six scans were taken while subjects performed a visuomotor activation task. To determine whether there was a consistency across different studies in the regions that showed this time-related change in rCBF two additional datasets were analyzed. There were similarities across all three studies in the regions that showed a monotonic task-independent change in activity. In all three studies there was a general bilateral decrease in rCBF of occipital and temporal areas across scans that might be related to habituation in the visual domain. Increases in rCBF were found in anterior cingulate, postcentral gyrus, and precentral gyrus across studies. It is likely that these changes reflect motor learning and motor program retrieval. This implies that, unless the experimenter controls for time-dependent changes in brain activity, the interpretation of task-related changes in rCBF may be confounded by these monotonic changes in rCBF. We present analytic strategies to identify experimental effects that are independent of nonspecific time effects, which can be used when it is not possible to control these effects through counterbalancing the experimental design. Nonspecific confounds are particularly relevant in functional MRI studies in which the number of scans acquired per study is much larger.

Adult↗

PubMed1998

Altered frequency of a promoter polymorphic allele of the kinin B1 receptor gene in inflammatory bowel disease.

BACKGROUND & AIMS: Evidence of kinin-mediated inflammation in the gastrointestinal tract is accumulating. The genes and some polymorphic sites have been characterized for both kinin B1 and B2 receptors. These candidate genes were studied for their possible association with inflammatory bowel disease (IBD). METHODS: In a retrospective study, the prevalence of allele pairs for four polymorphic sites of the two kinin receptor genes was determined in 53 patients with IBD and in 110 healthy volunteers similar in age, body weight, and gender proportions, using polymerase chain reaction and other techniques. RESULTS: Only the B1 receptor promoter polymorphism (G-699-->C) exhibited a significantly different allele frequency between the two groups (prevalence of the C allele of 5.7% in patients with IBD compared with 33.6% in controls; P = 0.0002) or between the controls and either etiologic subgroup (ulcerative colitis and Crohn's disease). Allelic polymorphisms affecting exon 3 of the B1 receptor gene (A1098-->G) or exon 2 (C181-->T) or 1 (a 9-base pair deletion) of the B2 receptor gene were found to be neutral. CONCLUSIONS: The gene corresponding to the B1 receptor for kinins may be a nonetiologic marker of symptomatic IBD, as suggested by the altered prevalence of a polymorphism presumably affecting its regulation.

Adult↗

PubMed1998

Networks of domain-specific and general regions involved in episodic memory for spatial location and object identity.

Positron emission tomography (PET) was used to investigate human episodic memory for spatial location and object identity. We measured regional cerebral bloodflow (rCBF) while subjects engaged in perceptual matching of the location or the identity of line drawings of objects. Perceptual matching also involved incidental encoding of the presented information. Subsequently, rCBF was measured when subjects retrieved the location or the identity of these objects from memory. Using the multivariate partial least squares image analysis, we identified three patterns of activity across the brain that allowed us to distinguish structures that are differentially involved in processing spatial location and object identity from structures that are differentially involved in encoding and retrieval but operate across both domains. Domain-specificity was evident by increased rCBF during the processing of spatial location in the right middle occipital gyrus, supramarginal gyrus, and superior temporal sulcus, and by increased rCBF during the processing of object identity in portions of bilateral lingual and fusiform gyri. There was a nearly complete overlap between domain-specific dorsal and ventral extrastriate cortex activations during perceptual matching and memory retrieval. Evidence of domain-specificity was also found in the prefrontal cortex and the left hippocampus, but the effect interacted with encoding and retrieval. Domain-general structures included bilateral superior temporal cortex regions, which were preferentially activated during encoding, and portions of bilateral middle and inferior frontal gyri, which were preferentially activated during retrieval. Together, our data suggest that encoding and retrieval in episodic memory depend on the interplay between domain-specific structures, most of which are involved in memory as well as perception, and domain-general structures, some of which operate more at encoding and others more at retrieval.

Adult↗

PubMed1998

Derivatives of WAY 100635 as potential imaging agents for 5-HT1A receptors: syntheses, radiosyntheses, and in vitro and in vivo evaluation.

Analogues of the potent and selective 5-HT1A ligand, WAY 100635, were synthesized and examined as potential candidates for imaging 5-HT1A receptors by positron emission tomography (PET). Several of the analogues displayed nanomolar affinity for the 5-HT1A receptor, comparable to WAY 100635. Three of these were examined in a model of human liver metabolism vis-à-vis WAY 100635. All showed a markedly lower propensity for amide hydrolysis than WAY 100635. Radiolabelling of these three potential PET radiotracers with carbon-11 was readily achieved from [11C]-iodomethane, and the newly synthesized radioligands were tested in vivo in rats for binding to 5-HT1A receptors. Whereas two of the ligands failed to bind to 5-HT1A receptors in vivo, one was successful. The latter, [11C]-7 [4-(2'-methoxyphenyl)-1-[2'-[N-(2'-pyridinyl)-2-bicyclo[2.2.2]octanec arboxamido]ethyl]-piperazine], showed good brain penetration, hippocampal:cerebellar ratios of 10:1 at 45 min postinjection. Blocking studies with a variety of drugs demonstrated that the binding of [11C]-7 in vivo was selective for 5-HT1A receptors. [11C]-7 is a promising candidate as a ligand for imaging 5-HT1A receptors by PET.

Animals↗

PubMed1998

Neuroanatomical correlates of human reasoning.

One of the important questions cognitive theories of reasoning must address is whether logical reasoning is inherently sentential or spatial. A sentential model would exploit nonspatial (linguistic) properties of representations whereas a spatial model would exploit spatial properties of representations. In general terms, the linguistic hypothesis predicts that the language processing regions underwrite human reasoning processes, and the spatial hypothesis suggests that the neural structures for perception and motor control contribute the basic representational building blocks used for high-level logical and linguistic reasoning. We carried out a [(15)O] H(2)O PET imaging study to address this issue. Twelve normal volunteers performed three types of deductive reasoning tasks (categorical syllogisms, three-term spatial relational items, and three-term nonspatial relational items) while their regional cerebral blood flow pattern was recorded using [(15)O] H(2)O PET imaging. In the control condition subjects semantically comprehended sets of three sentences. In the deductive reasoning conditions subjects determined whether the third sentence was entailed by the first two sentences. The areas of activation in each reasoning condition were confined to the left hemisphere and were similar to each other and to activation reported in previous studies. They included the left inferior frontal gyrus (Brodmann area 45, 47), a portion of the left middle frontal gyrus (Brodmann area 46), the left middle temporal gyrus (Brodmann areas 21, 22), a region of the left lateral inferior temporal gyrus and superior temporal gyrus (Brodmann areas 22, 37), and a portion of the left cingulate gyrus (Brodmann areas 32, 24). There was no significant right-hemisphere or parietal activation. These results are consistent with previous neuroimaging studies and raise questions about the level of involvement of classic spatial regions in reasoning about linguistically presented spatial relations.

Adult↗

PubMed1998

5-HT2 and D2 receptor occupancy of olanzapine in schizophrenia: a PET investigation.

OBJECTIVE: Olanzapine is a new atypical antipsychotic recently introduced for the treatment of schizophrenia. The purpose of this study was to investigate olanzapine's binding to the serotonin 5-HT2 and dopamine D2 receptors in schizophrenic patients being treated with clinically relevant doses. METHOD: Twelve patients with schizophrenia were randomly assigned to 5, 10, 15, or 20 mg/day of olanzapine in a prospective fashion. Three other subjects taking 30-40 mg/day were also included. Once steady-state plasma levels were achieved, dopamine D2 and serotonin 5-HT2 receptors were assessed by using [11C]raclopride and [18F]setoperone positron emission tomography imaging, respectively. Ratings of clinical status, extrapyramidal side effects, and prolactin levels were also obtained. RESULTS: Olanzapine induced near saturation of the 5-HT2 receptors, even at 5 mg/day. Its D2 occupancy increased with dose: patients taking 5-20 mg/day showed 43%-80% D2 occupancy, while patients taking 30-40 mg/day showed 83%-88%. CONCLUSIONS: Olanzapine is a potent 5-HT2 blocker and shows a higher 5-HT2 than D2 occupancy at all doses. However, its D2 occupancy is higher than that of clozapine and similar to that of risperidone. In the usual clinical dose range of 10-20 mg/day, its occupancy varies from 71% to 80%, and this restricted range may explain its freedom from extrapyramidal side effects and prolactin elevation. However, doses of 30 mg/day and higher are associated with more than 80% D2 occupancy and may have a higher likelihood of prolactin elevation and extrapyramidal side effects.

Adult↗

PubMed1998

A study of vestibular schwannomas using positron emission tomography and monoclonal antibody Ki-67.

OBJECTIVE: This study aimed to evaluate the role of positron emission tomography (PET) as an in vivo determinant of tumor aggressiveness and growth. STUDY DESIGN: The study design was a prospective pilot study. SETTING: Positron emission tomography was performed at the Clarke Institute of Psychiatry. All patients were treated at the Sunnybrook Health Science Centre. Both institutions are affiliated with the University of Toronto, Toronto, Canada. PATIENTS: The study consisted of five consecutive patients with vestibular schwannomas with tumor size of 1 cm or larger within the cerebellopontine angle. One was a recurrent tumor and four were primary tumors. INTERVENTIONS: Preoperative PET studies were conducted using 18-fluorodeoxyglucose (FDG) as a radionuclide tracer to measure glucose metabolism within tumors. Tumors were processed and immunostained against Ki-67 nuclear antigen; their proliferative potentials were quantified based on immunoreactivity of tumor cells. MAIN OUTCOME MEASURES: Tumor metabolic activity on PET was compared with that of contralateral cerebellum to arrive at an FDG index. This number was compared with clinical parameters and Ki-67 reactivity. RESULTS: On PET, all tumors showed less metabolic activity than the cerebellum. The FDG uptake varied greatly between tumors independent of clinical parameters. All the tumors had a low proliferative index (<5%) with immunohistochemistry; there were quite a bit of intralesional variations in proliferative activities. CONCLUSION: Large tumor size and recurrent disease did not correlate well with increased FDG uptake on PET. Similarly, they did not show increased cellular activities as expressed by Ki-67 immunostaining.

Adult↗

PubMed1997

The seats of reason? An imaging study of deductive and inductive reasoning.

We carried out a neuroimaging study to test the neurophysiological predictions made by different cognitive models of reasoning. Ten normal volunteers performed deductive and inductive reasoning tasks while their regional cerebral blood flow pattern was recorded using [15O]H2O PET imaging. In the control condition subjects semantically comprehended sets of three sentences. In the deductive reasoning condition subjects determined whether the third sentence was entailed by the first two sentences. In the inductive reasoning condition subjects reported whether the third sentence was plausible given the first two sentences. The deduction condition resulted in activation of the left inferior frontal gyrus (Brodmann areas 45, 47). The induction condition resulted in activation of a large area comprised of the left medial frontal gyrus, the left cingulate gyrus, and the left superior frontal gyrus (Brodmann areas 8, 9, 24, 32). Induction was distinguished from deduction by the involvement of the medial aspect of the left superior frontal gyrus (Brodmann areas 8, 9). These results are consistent with cognitive models of reasoning that postulate different mechanisms for inductive and deductive reasoning and view deduction as a formal rule-based process.

Adult↗

PubMed1997

Age-related differences in neural activity during memory encoding and retrieval: a positron emission tomography study.

Positron emission tomography (PET) was used to compare regional cerebral blood flow (rCBF) in young (mean 26 years) and old (mean 70 years) subjects while they were encoding, recognizing, and recalling word pairs. A multivariate partial-least-squares (PLS) analysis of the data was used to identify age-related neural changes associated with (1) encoding versus retrieval and (2) recognition versus recall. Young subjects showed higher activation than old subjects (1) in left prefrontal and occipito-temporal regions during encoding and (2) in right prefrontal and parietal regions during retrieval. Old subjects showed relatively higher activation than young subjects in several regions, including insular regions during encoding, cuneus/precuneus regions during recognition, and left prefrontal regions during recall. Frontal activity in young subjects was left-lateralized during encoding and right-lateralized during recall [hemispheric encoding/retrieval asymmetry (HERA)], whereas old adults showed little frontal activity during encoding and a more bilateral pattern of frontal activation during retrieval. In young subjects, activation in recall was higher than that in recognition in cerebellar and cingulate regions, whereas recognition showed higher activity in right temporal and parietal regions. In old subjects, the differences in blood flow between recall and recognition were smaller in these regions, yet more pronounced in other regions. Taken together, the results indicate that advanced age is associated with neural changes in the brain systems underlying encoding, recognition, and recall. These changes take two forms: (1) age-related decreases in local regional activity, which may signal less efficient processing by the old, and (2) age-related increases in activity, which may signal functional compensation.

Adult↗

PubMed1997

Cognitive subtractions may not add up: the interaction between semantic processing and response mode.

Determining the areas of brain activity associated with cognitive processing has typically relied on the use of a subtraction paradigm, which is based on the premise that the neural processes underlying behavior are additive. If the additivity assumption is valid then brain regions associated with a semantic processing task should be the same regardless of how participants make a response. To investigate this proposition, participants underwent six PET scans, in which they made semantic or letter word judgments, responding "yes" or "no" in three different modes: mouse-clicking, spoken response, or silent thought. Analyses showed an increase in regional cerebral blood flow associated with semantic processing in the left inferior frontal cortex, anterior cingulate, and right cerebellum for all three response conditions. However, there was a significant interaction: the greatest increase was observed in the mouse-click condition and the weakest change seen with silent thought. Moreover, other areas of the brain were uniquely activated for each response mode. The results indicate that different areas of the brain were recruited for semantic processing depending on how participants had to organize their responses. Implications for the additivity assumption and methods of analysis to be used in conjunction with the subtraction technique are discussed.

Adult↗

PubMed1997

The relationship between D2 receptor occupancy and plasma levels on low dose oral haloperidol: a PET study.

The purpose of this study was to determine the relationship between dopamine D2 receptor occupancy and plasma haloperidol. Twelve patients treated with 1-5 mg/day of haloperidol had their D2 occupancy measured using [11C]-raclopride and positron emission tomography and haloperidol plasma levels measured using gas chromatograph mass spectrophotometer. The patients exhibited haloperidol plasma levels ranging from 0.5 to 5.8 ng/ml and D2 occupancy from 53 to 88%. The D2 occupancy was related to the plasma level as a saturating rectangular hyperbola relationship (r2 = 0.84) and it showed that, on average, 50% D2 occupancy was achieved with 0.51 ng/ml and 80% D2 occupancy with 2.0 ng/ml. Our findings demonstrate that 2-5 mg/day of haloperidol, which usually leads to plasma levels of 1-2 ng/ml, would be expected to induce 60-80% dopamine D2 receptor occupancy. If, as has been claimed, 70% D2 occupancy is adequate for typical neuroleptic response, then the conventional use of > 10 mg/day may have been too high, since 70% occupancy can be achieved in most patients by 2-5 mg/day. On the other hand, if as others have suggested, 8-12 ng/ml of haloperidol is the correct therapeutic window for plasma levels, then the required therapeutic D2 occupancy is closer to 90%, not 70%. The implications of the D2 occupancy findings for the optimal dosing of neuroleptics are discussed.

Administration, Oral↗