Positron Emission Tomography Neuroimaging Research Articles

Simultaneous assessment of rodent behavior and neurochemistry using a miniature positron emission tomograph

Positron emission tomography (PET) neuroimaging and behavioral assays in rodents are widely used in neuroscience. PET gives insights into the molecular processes of neuronal communication, and behavioral methods analyze the actions that are associated with such processes. These methods have not been directly integrated, because PET studies in animals have until now required general anesthesia to immobilize the subject, which precludes behavioral studies. We present a method for imaging awake, behaving rats with PET that allows the simultaneous study of behavior. Key components include the 'rat conscious animal PET' or RatCAP, a miniature portable PET scanner that is mounted on the rat's head, a mobility system that allows considerable freedom of movement, radiotracer administration techniques and methods for quantifying behavior and correlating the two data sets. The simultaneity of the PET and behavioral data provides a multidimensional tool for studying the functions of different brain regions and their molecular constituents.

소동물 [F-18]FDG 양전자단층촬영 기법을 이용한 청각신경에서의 소리크기에 대한 적응효과 연구

Although sound intensity is considered as one of important factors in auditory processing, its neural mechanism in auditory neurons with limited dynamic range of firing rates is still unclear. In this study, we examined the effect of sound intensity adaptation on the change of glucose metabolism in a rat brain using [F-18] micro positron emission tomography (PET) neuroimaging technique. In the experiment, broadband white noise sound was given for 30 minutes after the [F-18]FDG injection in order to explore the functional adaptation of rat brain into the sound intensity levels. Nine rats were scanned with four different sound intensity levels: 40 dB, 60 dB, 80 dB, 100 dB sound pressure level (SPL) for four weeks. When glucose uptake during the adaptation of a high intensity sound level (100 dB SPL) was compared with that during adaptation to a low intensity level (40 dB SPL) in the experiment, the former induced a greater uptake at bilateral cochlear nucleus, superior olivary complexes and inferior colliculi in the auditory pathway. Expectedly, the metabolic activity in those areas linearly increased as the sound intensity level increased. In contrast, significant decrease interestingly occurred in the bilateral auditory cortices: The activities of auditory cortex proportionally decreased with higher sound intensities. It may reflect that the auditory cortex actively down-regulates neural activities when the sound gets louder.

Nonhuman Primate Positron Emission Tomography Neuroimaging in Drug Abuse Research

Positron emission tomography (PET) neuroimaging in nonhuman primates has led to significant advances in our current understanding of the neurobiology and treatment of stimulant addiction in humans. PET neuroimaging has defined the in vivo biodistribution and pharmacokinetics of abused drugs and related these findings to the time course of behavioral effects associated with their addictive properties. With novel radiotracers and enhanced resolution, PET neuroimaging techniques have also characterized in vivo drug interactions with specific protein targets in the brain, including neurotransmitter receptors and transporters. In vivo determinations of cerebral blood flow and metabolism have localized brain circuits implicated in the effects of abused drugs and drug-associated stimuli. Moreover, determinations of the predisposing factors to chronic drug use and long-term neurobiological consequences of chronic drug use, such as potential neurotoxicity, have led to novel insights regarding the pathology and treatment of drug addiction. However, similar approaches clearly need to be extended to drug classes other than stimulants. Although dopaminergic systems have been extensively studied, other neurotransmitter systems known to play a critical role in the pharmacological effects of abused drugs have been largely ignored in nonhuman primate PET neuroimaging. Finally, the study of brain activation with PET neuroimaging has been replaced in humans mostly by functional magnetic resonance imaging (fMRI). There has been some success in implementing pharmacological fMRI in awake nonhuman primates. Nevertheless, the unique versatility of PET imaging will continue to complement the systems-level strengths of fMRI, especially in the context of nonhuman primate drug abuse research.

The use of PET imaging in studying cognition, genetics and pharmacotherapeutic interventions in schizophrenia

Positron emission tomography (PET) offers a strategic imaging platform to provide a map of functional neural correlates associated with the underlying cognitive deficits in schizophrenia. It enables regional cerebral glucose metabolism and dopaminergic and serotonergic receptor function to be studied. PET neuroimaging can therefore be used in drug development and to study putative treatments. Recent PET studies of the first-generation antipsychotics flupentixol and haloperidol, and of the second-generation antipsychotics risperidone, aripiprazole, quetiapine, sertindole, ziprasidone, paliperidone and olanzapine, have been carried out; modulation of limbic circuitry has been found to be a predictor of treatment response. PET can also be used to predict and monitor likely extrapyramidal side effects from antipsychotic treatment. PET and neuropsychological testing can together also allow the study of putative molecular genetic changes associated with schizophrenia. Advances in the imaging, cognition and molecular genetics are likely to lead to the development of future diagnostics, treatments and novel pharmacological agents.

Anti-NMDA receptor encephalitis presenting with imaging findings and clinical features mimicking Rasmussen syndrome

Background Antibody mediated anti-N-methyl- d-aspartate (NMDA) receptor encephalitis is a recently reported diagnosis of clinical importance. Recognition of the syndrome, especially in pediatric populations, is difficult and often undiagnosed and/or confused with neurological disorders with similar clinical features. Results We report a case of an 11 year old female with explosive-onset epilepsy and predominantly unilateral frontal lobe abnormalities on magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) neuroimaging. A diagnosis of Rasmussen syndrome (RS) was considered. Cerebrospinal fluid analysis revealed strong positivity for NMDA receptor antibodies. Screening for occult ovarian teratoma with computed tomography (CT) and MRI initially did not demonstrate associated tumor. Treatment with steroids and plasma exchange improved her clinical course and subsequent MRI showed resolution. Conclusion NMDA receptor encephalitis has variable neuroimaging manifestations, and can mimic other entities. We emphasize the clinical syndrome of NMDA receptor encephalitis and consideration of the diagnosis in evaluating a child with explosive-onset epilepsy, unilateral imaging abnormalities, and neurocognitive decline.

Advocating neuroimaging studies of transmitter release in human physical exercise challenges studies

This perspective attempts to outline the emerging role of positron emission tomography (PET) ligand activation studies in human exercise research. By focusing on the endorphinergic system and its acclaimed role for exercise-induced antinociception and mood enhancement, we like to emphasize the unique potential of ligand PET applied to human athletes for uncovering the neurochemistry of exercise-induced psychophysiological phenomena. Compared with conventional approaches, in particular quantification of plasma beta-endorphin levels under exercise challenges, which are reviewed in this article, studying opioidergic effects directly in the central nervous system (CNS) with PET and relating opioidergic binding changes to neuropsychological assessments, provides a more refined and promising experimental strategy. Although a vast literature dating back to the 1980s of the last century has been able to reproducibly demonstrate peripheral increases of beta-endorphin levels after various exercise challenges, so far, these studies have failed to establish robust links between peripheral beta-endorphin levels and centrally mediated behavioral effects, ie, modulation of mood and/or pain perception. As the quantitative relation between endorphins in the peripheral blood and the CNS remains unknown, the question arises, to what extent conventional blood-based methods can inform researchers about central neurotransmitter effects. As previous studies using receptor blocking approaches have also revealed equivocal results regarding exercise effects on pain and mood processing, it is expected that PET and other functional neuroimaging applications in athletes may in future help uncover some of the hitherto unknown links between neurotransmission and psychophysiological effects related to physical exercise.

Impact of early life stress on the reinforcing and behavioral-stimulant effects of psychostimulants in rhesus monkeys

Early life stress has effects on behavior and stress reactivity, which are linked to enhanced sensitivity to stimulants in rodents. This study investigated whether rhesus monkeys that experienced early life stress would show altered sensitivity to the reinforcing effects of stimulants as compared with controls. Control (n=5) and maternally separated (n=4) monkeys were trained to self-administer cocaine (0.1 mg/kg/injection) under a second-order schedule of intravenous drug delivery. The rate of acquisition and subsequent dose-effect determinations for cocaine (0.01-1.0 mg/kg/injection) and amphetamine (0.003-0.3 mg/kg/injection) provided complementary measures of reinforcing effectiveness. In addition, stimulant-induced increases in home cage activity and dopamine D2 receptor binding potential were quantified with positron emission tomography neuroimaging. Compared with controls, maternally separated monkeys showed lower responding during the acquisition of self-administration and in the dose-response curves for both stimulants, and significantly lower response rates during maintenance of cocaine self-administration. Maternally separated monkeys also failed to exhibit stimulant-induced increases in motor activity. Groups did not differ in dopamine D2 receptor binding potential in the caudate nucleus or the putamen. Taken together, the results of this study do not provide support for early life stress leading to enhanced vulnerability to stimulant use in the nonhuman primate model employed.

18F]F15599, a novel 5-HT1A receptor agonist, as a radioligand for PET neuroimaging

The serotonin-1A (5-HT(1A)) receptor is implicated in the pathophysiology of major neuropsychiatric disorders. Thus, the functional imaging of 5-HT(1A) receptors by positron emission tomography (PET) may contribute to the understanding of its role in those pathologies and their therapeutics. These receptors exist in high- and low-affinity states and it is proposed that agonists bind preferentially to the high-affinity state of the receptor and therefore could provide a measure of the functional 5-HT(1A) receptors. Since all clinical PET 5-HT(1A) radiopharmaceuticals are antagonists, it is of great interest to develop a( 18)F labelled agonist. F15599 (3-chloro-4-fluorophenyl-(4-fluoro-4{[(5-methyl-pyrimidin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl)-methanone) is a novel ligand with high affinity and selectivity for 5-HT(1A) receptors and is currently tested as an antidepressant. In pharmacological tests in rat, it exhibits preferential agonist activity at post-synaptic 5-HT(1A) receptors in cortical brain regions. Here, its nitro-precursor was synthesised and radiolabelled via a fluoronucleophilic substitution. Radiopharmacological evaluations included in vitro and ex vivo autoradiography in rat brain and PET scans on rats and cats. Results were compared with simultaneous studies using [(18)F]MPPF, a validated 5-HT(1A) antagonist radiopharmaceutical. The chemical and radiochemical purities of [(18)F]F15599 were >98%. In vitro [(18)F]F15599 binding was consistent with the known 5-HT(1A) receptors distribution (hippocampus, dorsal raphe nucleus, and notably cortical areas) and addition of Gpp(NH)p inhibited [(18)F]F15599 binding, consistent with a specific binding to G protein-coupled receptors. In vitro binding of [(18)F]F15599 was blocked by WAY100635 and 8-OH-DPAT, respectively, prototypical 5-HT(1A) antagonist and agonist. The ex vivo and in vivo studies demonstrated that the radiotracer readily entered the rat and the cat brain and generated few brain radioactive metabolites. Remarkably, in microPET studies, [(18)F]F15599 notably displayed a pattern of brain labelling that did not correlate with in vitro observations. Thus, in cat, the highest binding was observed in dorsal raphe and cingulate cortex with little binding in other cortical regions and none in hippocampus. In vivo binding was abolished by WAY100635, indicating specific labelling of 5-HT(1A) receptors. [(18)F]F15599 is a radiofluorinated agonist presenting interesting characteristics for probing in vitro and in vivo the high-affinity states of the 5-HT(1A) receptors. Its differential labelling of 5-HT(1A) receptors in vitro and in vivo may result from its reported preferential interaction with receptors coupled to specific G-protein subtypes.

11C]Mirtazapine binding in depressed antidepressant nonresponders studied by PET neuroimaging

Lack of benefit from antidepressant drug therapy is a major source of human suffering, affecting at least 25% of people with major depressive disorder. We want to know whether nonresponse to antidepressants can be linked to aberrant neuroreceptor binding. This study aims to assess the antidepressant binding in brain regions of depressed nonresponders compared with healthy controls. Healthy volunteers and depressed subjects who had failed to benefit from at least 2 antidepressant treatments were recruited by newspaper advertisements. All subjects had received no antidepressant medication for at least 2 months before positron emission tomography (PET) that was carried out with [11C]mirtazapine. Kinetic parameters of [11C]mirtazapine were determined from PET data in selected brain regions by the simplified reference tissue model. Binding potentials of [11C]mirtazapine in cerebral cortical regions were lower in depressed nonresponders than in healthy controls. Removal rates of [11C]mirtazapine were higher in diencephalic regions of depressed nonresponders than in healthy controls. PET neuroimaging with [11C]mirtazapine showed aberrant neuroreceptor binding in brain regions of depressed subjects who had failed to benefit from treatment with antidepressant drugs.

Changes in Relative Glucose Metabolic Rate Following Cortisol Administration in Aging Veterans with Posttraumatic Stress Disorder: An FDG-PET Neuroimaging Study

Changes in Relative Glucose Metabolic Rate Following Cortisol Administration in Aging Veterans with Posttraumatic Stress Disorder: An FDG-PET Neuroimaging Study

Changes in Relative Glucose Metabolic Rate Following Cortisol Administration in Aging Veterans with Posttraumatic Stress Disorder: An FDG-PET Neuroimaging Study

The authors aimed to examine central glucocorticoids effects by measuring relative glucose metabolic rate (rGMR) in the hippocampus, amygdala, and anterior cingulate cortex (ACC) and the relationship between amygdala and ACC activity. The participants were male combat veterans with and without PTSD, 52 to 81 years old. The authors utilized randomized, double-blind, placebo-controlled examinations of the rGMR response to 17.5 mg hydrocortisone (HCORT) using 2-Deoxy-2-[(18)F]fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) neuroimaging. Group differences in hemispheric laterality of rGMR were observed following placebo administration, reflecting lower rGMR in the right hippocampus and ventral amygdala, and higher rGMR in the left ventral amygdala in the PTSD+ group compared to the PTSD- group. HCORT reduced these group differences in laterality. The net effect of HCORT was to restore a normal inverse association between the ACC and amygdala in the PTSD+ group, but disrupt this neural network in the PTSD- group. The magnitude of improvement in working memory correlated with greater hemispheric laterality in the dorsal amygdala following HCORT in both groups. The restorative effects of HCORT on metabolism and working memory provide a rationale for examining the therapeutic benefits of glucocorticoid manipulation in aging PTSD patients.

Neuroimaging of mirtazapine enantiomers in humans

Mirtazapine is a racemic antidepressant with a multireceptor profile. Previous studies have shown that the enantiomers of mirtazapine have different pharmacologic effects in the brain of laboratory animals. In the present study, we used positron emission tomography (PET) and autoradiography to study effects of (R)- and (S)-[(11)C]mirtazapine in the human brain. Detailed brain imaging by PET using three methods of kinetic data analysis showed no reliable differences between regional binding potentials of (R)- and (S)-[(11)C]mirtazapine in healthy subjects. Autoradiographic studies carried out in whole hemispheres of human brain tissue showed, however, that (R)- and (S)-mirtazapine differ markedly as inhibitors of [(3)H]clonidine binding at alpha(2)-adrenoceptors. The multireceptor binding profiles of mirtazapine enantiomers, along with individual differences between subjects, may preclude PET neuroimaging from demonstrating reliable differences between the regional distribution and binding of (R)- and (S)-[(11)C]mirtazapine in the living human brain.

Relationship between rate of drug uptake in brain and behavioral pharmacology of monoamine transporter inhibitors in rhesus monkeys

Although inhibition of dopamine transporters (DAT) and the subsequent increase in dopamine clearly play a role in the effects of psychomotor stimulants, the reinforcing effectiveness of DAT inhibitors varies. Previous studies suggest that pharmacokinetic and pharmacodynamic properties of these drugs account for this variability. The present studies compared the time course and behavioral effects of five phenyltropane analogs of cocaine with high affinity for DAT and varying time courses of action in rhesus monkeys. The rate of drug uptake in putamen was measured using positron emission tomography neuroimaging. The rank order of the time to peak drug uptake was cocaine < RTI-336 < RTI-150 < RTI-113 < RTI-177. Cocaine and all five analogs fully substituted for the cocaine cue in animals trained to discriminate cocaine from saline. All of the drugs were self-administered under a progressive-ratio schedule of drug self-administration and reinstated previously extinguished self-administration maintained under a second-order schedule. The time to peak drug uptake corresponded closely with the time to peak discriminative stimulus effects, and there was a trend for the time of peak drug uptake to correspond negatively with the peak number of drug infusions. Collectively, these results indicate that the rate of drug entry in brain can play an important role in the behavioral pharmacology of psychomotor stimulants.

Sensory Processing Disorder in a Primate Model: Evidence From a Longitudinal Study of Prenatal Alcohol and Prenatal Stress Effects

Disrupted sensory processing, characterized by over- or underresponsiveness to environmental stimuli, has been reported in children with a variety of developmental disabilities. This study examined the effects of prenatal stress and moderate-level prenatal alcohol exposure on tactile sensitivity and its relationship to striatal dopamine system function in thirty-eight 5- to 7-year-old rhesus monkeys. The monkeys were from four experimental conditions: (a) prenatal alcohol exposed, (b) prenatal stress, (c) prenatal alcohol exposed + prenatal stress, and (d) sucrose controls. Increased D(2) receptor binding in the striatum, evaluated using positron emission tomography neuroimaging, was related to increased withdrawal (aversion) responses to repetitive tactile stimuli and reduced habituation across trials. Moreover, prenatal stress significantly increased overall withdrawal responses to repetitive tactile stimulation compared to no prenatal stress.

PET neuroimaging of [ 11C]mirtazapine enantiomers in pigs

Previously, we used positron emission tomography (PET) for studying the pharmacokinetics of rac-[ 11C]mirtazapine in living brain. Our findings showed that rac-[ 11C]mirtazapine has suitable properties for PET neuroimaging. However, separate studies of enantiomers are typically required for characterizing the pharmacokinetics of a racemic drug. Therefore, we have determined the whole-body distribution and brain pharmacokinetics of S- and R-[ 11C]mirtazapine in pigs. The enantiomers of [ 11C]mirtazapine produced similar effective doses of radioactivity in most body organs, except for the brain, in which the dose was ∼ 40% higher after injection of S-[ 11C]mirtazapine than the antipode. Kinetic analyses of dynamic brain PET recordings showed that values for regional accumulation of compound ( k 3) were significantly higher for S-[ 11C]mirtazapine than for the antipode, while the values for clearance of compounds from tissue to circulation ( k 2) were consistently lower for S-[ 11C]mirtazapine than for the R-form. No reliable difference occurred in the rate of metabolism of S- and R-[ 11C]mirtazapine in the bloodstream of the pigs. The present findings indicate that enantioselective processes affect the cerebral pharmacokinetics of rac-mirtazapine.

Gender differences in a fenfluramine-activated FDG PET study of borderline personality disorder

Neuroimaging studies of impulsive–aggressive subjects with borderline personality disorder (BPD) demonstrate hypometabolism in areas of prefrontal and frontal cortex, and a blunted cortical metabolic response to challenge with serotonergic agonists. Neuroendocrine responses to serotonergic challenge are known to vary greatly by gender, and may be related to sex differences in expression of impulsive aggression. We conducted single-blind, placebo-controlled fenfluramine-activated positron emission tomography (PET) studies in impulsive male and female subjects with BPD to look for gender differences in cortical response. The sample comprised 22 BPD (15 female, 7 male) and 24 control subjects (10 female, 14 male) who received placebo on Day 1 and d, l-fenfluramine on Day 2 before PET neuroimaging. In response to placebo, female, but not male, controls had areas of increased uptake of fluorodeoxyglucose-F18 in prefrontal cortex compared with BPD subjects, with greatest uptake in the medial orbital frontal cortex, bilaterally. Male, but not female, BPD subjects, showed areas of increased glucose utilization compared with controls in large areas of parietal and occipital cortex, bilaterally. In response to fenfluramine (relative to placebo), significant decreases in glucose uptake were found in male, but not female, BPD subjects, centered in the left temporal lobe. Female, but not male, control subjects showed significantly decreased uptake in areas of right frontal and temporal cortex. Covarying for impulsive-aggression rendered nonsignificant the gender differences in responses to placebo or fenfluramine. Gender differences in serotonergic function may mediate differences in behavioral expression of impulsive aggression in subjects with BPD.

Effects of dopamine transporter inhibitors on cocaine self-administration in rhesus monkeys: relationship to transporter occupancy determined by positron emission tomography neuroimaging.

The dopamine transporter (DAT) is a critical recognition site for cocaine and contributes to its significant abuse liability. Accordingly, the development of compounds that target the DAT represents a logical approach in the pharmacological treatment of cocaine abuse. The present study characterized the effects of DAT inhibitors as pretreatments in rhesus monkeys trained to self-administer cocaine under a second-order schedule of i.v. drug delivery. The drugs also were substituted for cocaine to characterize their effectiveness in maintaining drug self-administration. Positron emission tomography neuroimaging with [(18)F]8-(2-[(18)F]fluoroethyl)-2beta-carbomethoxy-3beta-(4-chlorophenyl) nortropane established the DAT occupancy associated with behaviorally relevant doses of each drug. The drugs studied included a selective DAT inhibitor, [1-(2[bis(4-fluorophenyl-) methoxy]ethyl)-4-(3-phenylpropyl)piperazine] bimesylate hydrate (GBR 12909); an inhibitor with equal potency at dopamine and norepinephrine transporters, [3beta-(4-chlorophenyl)tropane-2beta-(3-phenylisoxazol-5-yl)] HCl (RTI-177); and a nonselective inhibitor of dopamine, norepinephrinem and serotonin transporters, [(-)-3beta-(3'-methyl-4-chlorophenyl)tropane-2beta-carboxylic acid methyl ester] tartrate (RTI-112). All drugs produced dose-related reductions in cocaine self-administration. Doses of GBR 12909 and RTI-177 that reduced responding by 50% (ED(50)) resulted in DAT occupancies of 67 +/- 5 and 73 +/- 5%, respectively. In contrast, DAT occupancy was below the limit of detection for the ED(50) dose of RTI-112. Both GBR 12909 and RTI-177 reliably maintained drug self-administration, and DAT occupancies at doses that maintained peak rates of responding were 57 +/- 1 and 92 +/- 7%, respectively. In contrast, RTI-112 failed to maintain robust drug self-administration in any subject. The results indicate that selective DAT inhibitors may require high DAT occupancy to reduce cocaine self-administration and maintain drug self-administration. Moreover, the behavioral profile of DAT inhibitors may be influenced by actions at other monoamine transporters.

Functional imaging and neurochemical correlates of stimulant self-administration in primates.

Recent advances in neuroimaging and in vivo neurochemistry have documented drug-induced functional changes in brain activity under physiologically relevant conditions. These approaches have significant strengths and important limitations that should be considered. The present review describes current in vivo approaches to characterize drug effects as they relate to behavior, and highlights key contributions derived from each approach in the context of stimulant self-administration in primates. Techniques relating in vitro neurochemistry to behavioral pharmacology are compared to several in vivo approaches, including microdialysis, positron emission tomography (PET) neuroimaging and functional magnetic resonance imaging (fMRI). In vitro neurochemical correlates of behavioral pharmacology established a significant relationship between dopamine and the reinforcing effects of abused stimulants. Subsequent in vivo microdialysis studies in behaving animals supported a critical role for nucleus accumbens dopamine in the reinforcing effects of stimulants. PET neuroimaging in monkeys and humans documented a close relationship between dopamine transporter (DAT) occupancy in vivo and the reinforcing effects of stimulants. The effectiveness of selective DAT inhibitors to reduce cocaine self-administration also was linked to DAT occupancy in vivo. Lastly, the measurement of cerebral blood flow and metabolism with PET and fMRI has begun to define the neuronal circuitry influenced by acute and chronic stimulant exposure. Collectively, in vivo neurochemistry and functional imaging have complemented in vitro approaches and have enhanced our current understanding of the neurobiology of abused stimulants.

11C]Mirtazapine for PET neuroimaging: radiosynthesis and initial evaluation in the living porcine brain

We radiolabelled mirtazapine, a tetracyclic, atypical, antidepressant drug, for positron emission tomography (PET) and evaluated its regional kinetics in the living porcine brain. We produced [ N-methyl- 11C]mirtazapine with a radiochemical-purity >98% in a 21% decay-corrected radiochemical yield by alkylation of N-desmethyl mirtazapine with [ 11C]methyl iodide, followed by HPLC purification and formulation. [ N-Methyl- 11C]mirtazapine entered the brain readily and, under baseline conditions, it had an apparent volume of distribution ( V e′) of 9–13 in the basal ganglia, thalamus, and frontal cortex. Reference region and graphical analyses based on a one-compartment model showed that the binding of [ N-methyl- 11C]mirtazapine was reversible, with an apparent binding potential of more than two in thalamus and frontal cortex. Infusion of unlabelled mirtazapine markedly displaced [ N-methyl- 11C]mirtazapine from binding sites in the basal ganglia, thalamus and frontal cortex, but not in reference regions (cerebellum and olfactory tubercle). Thus, [ N-methyl- 11C]mirtazapine showed rapid passage into the living brain, slow metabolism in blood, and reversible, competitive binding, which may make it useful for PET neuroimaging of neuroreceptors involved in antidepressant actions.

Cocaine-induced brain activation determined by positron emission tomography neuroimaging in conscious rhesus monkeys.

Cerebral blood flow can provide a useful dependent measure to characterize cocaine-induced changes in brain function. The acute effects of cocaine administration on cerebral blood flow may have direct relevance to the etiology of cocaine addiction. The present study used positron emission tomography (PET) neuroimaging techniques to characterize the acute effects of cocaine administration on cerebral blood flow in conscious rhesus monkeys. Functional changes in cerebral blood flow were determined in four drug-naive subjects with the positron-emitting tracer 15O water following acute i.v. administration of cocaine (0.3 and 1.0 mg/kg). Specific attention was devoted to the development of an effective and comfortable head restraint device to use in the imaging of conscious monkeys. Experimental sessions comprised eight consecutive i.v. injections of 15O water at 10-min intervals. PET scans of 90 s duration occurred 10 s after each injection. Repeated baseline determinations of cerebral blood flow prior to drug administration were reliable. Cocaine had significant, dose-related effects on cerebral blood flow at 5 min postinjection that diminished relative to control (saline) conditions by 15 min postinjection. Brain activation maps normalized to global flow showed prominent cocaine-induced activation of prefrontal cortex localized primarily to dorsolateral regions. Importantly, cocaine-induced brain activation was blocked by pretreatment with the selective serotonin uptake inhibitor, alaproclate (3.0 and 10.0 mg/kg). The results document a distinct pattern of cocaine-induced brain activation that is sensitive to pharmacological manipulation. The pattern of brain activation induced by acute administration of cocaine may provide a useful means to evaluate medication effectiveness for treating cocaine addiction.