Predicting health outcomes with intensive longitudinal data collected by mobile health devices: a functional principal component regression approach.

BACKGROUND: Intensive longitudinal data (ILD) collected in near real time by mobile health devices provide a new opportunity for monitoring chronic diseases, early disease risk prediction, and disease prevention in health research. Functional data analysis, specifically functional principal component analysis, has great potential to abstract trends in ILD but has not been used extensively in mobile health research. OBJECTIVE: To introduce functional principal component analysis (fPCA) and demonstrate its potential applicability in estimating trends in ILD collected by mobile heath devices, assessing longitudinal association between ILD and health outcomes, and predicting health outcomes. METHODS: fPCA and scalar-to-function regression models were reviewed. A case study was used to illustrate the process of abstracting trends in intensively self-measured blood glucose using functional principal component analysis and then predicting future HbA1c values in patients with type 2 diabetes using a scalar-to-function regression model. RESULTS: Based on the scalar-to-function regression model results, there was a slightly increasing trend between daily blood glucose measures and HbA1c. 61% of variation in HbA1c could be predicted by the three preceding months' blood glucose values measured before breakfast (P < 0.0001, [Formula: see text]). CONCLUSIONS: Functional data analysis, specifically fPCA, offers a unique tool to capture patterns in ILD collected by mobile health devices. It is particularly useful in assessing longitudinal dynamic association between repeated measures and outcomes, and can be easily integrated in prediction models to improve prediction precision.

HyperVein: A Hyperspectral Image Dataset for Human Vein Detection.

HyperSpectral Imaging (HSI) plays a pivotal role in various fields, including medical diagnostics, where precise human vein detection is crucial. HyperSpectral (HS) image data are very large and can cause computational complexities. Dimensionality reduction techniques are often employed to streamline HS image data processing. This paper presents a HS image dataset encompassing left- and right-hand images captured from 100 subjects with varying skin tones. The dataset was annotated using anatomical data to represent vein and non-vein areas within the images. This dataset is utilised to explore the effectiveness of dimensionality reduction techniques, namely: Principal Component Analysis (PCA), Folded PCA (FPCA), and Ward's Linkage Strategy using Mutual Information (WaLuMI) for vein detection. To generate experimental results, the HS image dataset was divided into train and test datasets. Optimum performing parameters for each of the dimensionality reduction techniques in conjunction with the Support Vector Machine (SVM) binary classification were determined using the Training dataset. The performance of the three dimensionality reduction-based vein detection methods was then assessed and compared using the test image dataset. Results show that the FPCA-based method outperforms the other two methods in terms of accuracy. For visualization purposes, the classification prediction image for each technique is post-processed using morphological operators, and results show the significant potential of HS imaging in vein detection.

Evaluating Prognostic Value of Dynamics of Circulating Lactate Dehydrogenase in Colorectal Cancer Using Modeling and Machine Learning.

Pretreatment serum lactate dehydrogenase (LDH) levels have been associated with poor prognosis in several types of cancer, including metastatic colorectal cancer (mCRC). However, very few models link survival to longitudinal LDH measured repeatedly over time during treatment. We investigated the prognostic value of on-treatment LDH dynamics in mCRC. Using data from two large phase III studies (2L and 3L+ mCRC settings, n = 824 and 210, respectively), we found that integrating longitudinal LDH data with baseline risk factors significantly improved survival prediction. Current LDH values performed best, enhancing discrimination ability (area under the receiver operating characteristic curve) by 4.5~15.4% and prediction accuracy (Brier score) by 3.9~15.0% compared with baseline variables. Combining all longitudinal LDH markers further improved predictive performance. After controlling for baseline covariates and other longitudinal LDH indicators, current LDH levels remained a significant risk factor in mCRC, increasing mortality risk by over 90% (P < 0.001) in 2L patients and 60-70% (P < 0.01) in 3L+ patients per unit increment in current log (LDH). Machine-learning techniques, like functional principal component analysis (FPCA), extracted informative features from longitudinal LDH data, capturing over 99% of variability and allowing prediction of survival. Unsupervised clustering based on the extracted FPCA features stratified patients into three groups with distinct LDH dynamics and survival outcomes. Hence, our approaches offer a valuable and cost-effective way for risk stratification and improves survival prediction in mCRC using LDH trajectories.

[Fucoidan-Modified Phase-Transitional Contrast Agent for Ultrasound Imaging and Targeting of Hepatoma Cells].

Objective: To prepare a fucoidan-modified phase-transitional contrast agent (FPCA) and to evaluate its in vitro capabilities for ultrasound imaging and targeting of hepatoma cells. Methods: Nano-liposomes encapsulated with perfluoropentane were prepared using thin-film hydration and ultrasonic emulsification methods. Then, FPCA nanoparticles were prepared through chemical grafting of fucoidan and the characterization of their physical and chemical properties was performed. After applying external stimuli of heating with hot water bath and microwave irradiation, the phase-transition status of FPCA was observed with microscope. The imaging abilities of phase-transited FPCA on two-dimensional ultrasound and contrast-enhanced ultrasound were observed with ultrasonic diagnostic instrument. The ability of FPCA to target at hepatoma cells was evaluated and verified with fluorescence confocal observation and flow cytometry analysis. Results: The FPCA prepared in the study had an average diameter of (222.1±32.5) nm, displaying spherical appearance, good dispersion, good stability, and good biocompatibility. The phase-transition of FPCA was induced by both heating with hot water bath and microwave irradiation. For phase transition, the optimal temperature was found to be 50 ℃ and the preferred microwave power was 1.5 W/cm 2. Moreover, after phase transition, FPCA showed significant imaging enhancement on both two-dimensional ultrasonography and contrast-enhanced ultrasonography. Through fluorescein isothiocyanate (FITC) labeling, FPCA could specifically bind with hepatoma cells at a high binding rate of (96.19±1.62)%, while it rarely bound with normal liver cells, showing a binding rate of less than 10%. Conclusion: A new type of phase-transitional ultrasound contrast agent with good stability and biocompatibility was successfully prepared. It not only could enhance ultrasound imaging through phase transition, but also had specific active hepatoma cell-targeting properties.

Orphan Receptor GPR88 as an Emerging Neurotherapeutic Target.

Although G protein-coupled receptors (GPCRs) are recognized as pivotal drug targets involved in multiple physiological and pathological processes, the majority of GPCRs including orphan GPCRs (oGPCRs) are unexploited. GPR88, a brain-specific oGPCR with particularly robust expression in the striatum, regulates diverse brain and behavioral functions, including cognition, mood, movement control, and reward-based learning, and is thus emerging as a novel drug target for central nervous system disorders including schizophrenia, Parkinson's disease, anxiety, and addiction. Nevertheless, no effective GPR88 synthetic ligands have yet entered into clinical trials, and GPR88 endogenous ligands remain unknown. Despite the recent discovery and early stage study of several GPR88 agonists, such as 2-PCCA, RTI-13951-33, and phenylglycinol derivatives, further research into GPR88 pharmacology, medicinal chemistry, and chemical biology is urgently needed to yield structurally diversified GPR88-specific ligands. Drug-like pharmacological tool function and relevant signaling elucidation will also accelerate the evaluation of this receptor as a viable neurotherapeutic target.

Development and validation of a high-throughput calcium mobilization assay for the orphan receptor GPR88.

BACKGROUND: GPR88 is an orphan G protein-coupled receptor highly expressed in the striatum and is implicated in basal ganglia-associated disorders. However, the receptor functions of GPR88 are still largely unknown due to the lack of potent and selective ligands appropriate for central nervous system investigation. Development of a high-throughput screening assay for GPR88 should facilitate the discovery of novel ligands to probe GPR88 functions. METHODS: In this paper, we describe the development of a CHO-Gαqi5-GPR88 cell-based calcium mobilization assay. The assay takes advantage of functional coupling of GPR88 with the promiscuous Gαqi5 protein and consequent mobilization of intracellular calcium, which can be measured in a 384-well format with a Fluorescent Imaging Plate Reader. RESULTS: The CHO-Gαqi5-GPR88 cell-based calcium mobilization assay was validated by the structure-activity relationship study of known GPR88 agonist (1R,2R)-2-PCCA analogues. The assay was automated and miniaturized to a 384-well format, and was deemed robust and reproducible with a Z'-factor of 0.72 and tolerated dimethyl sulfoxide to a final concentration of 2%. Screening a pilot neurotransmitter library consisting of 228 compounds yielded 10 hits, but none of the hits were confirmed as GPR88 agonists in follow-up assays. CONCLUSIONS: We have developed a high-throughput calcium mobilization assay for the orphan receptor GPR88. This calcium mobilization assay can be used to identify several different types of GPR88 ligands including agonists, competitive and noncompetitive antagonists, inverse agonists, and allosteric modulators. These ligands will serve as valuable tools to probe signaling mechanisms and in vivo functions of GPR88, and could expedite development of novel therapies for diseases potentially mediated by GPR88.

Effect of Substitution on the Aniline Moiety of the GPR88 Agonist 2-PCCA: Synthesis, Structure-Activity Relationships, and Molecular Modeling Studies.

GPR88, an orphan receptor richly expressed in the striatum, is implicated in a number of basal ganglia-associated disorders. In order to elucidate the functions of GPR88, an in vivo probe appropriate for CNS investigation is required. We previously reported that 2-PCCA was able to modulate GPR88-mediated cAMP production through a Gαi-coupled pathway. Early structure-activity relationship (SAR) studies suggested that the aniline moiety of 2-PCCA is a suitable site for diverse modifications. Aimed at elucidating structural requirements in this region, we have designed and synthesized a series of analogues bearing a variety of substituents at the phenyl ring of the aniline moiety. Several compounds (e.g., 5j, 5o) showed improved or comparable potency, but have lower lipophilicity than 2-PCCA (clogP 6.19). These compounds provide the basis for further optimization to probe GPR88 in vivo functions. Computational studies confirmed the SAR trends and supported the notion that 4'-substituents on the biphenyl ring exit through a largely hydrophobic binding site to the extracellular loop.

Synthesis, pharmacological characterization, and structure-activity relationship studies of small molecular agonists for the orphan GPR88 receptor.

GPR88 is an orphan G-protein-coupled receptor (GPCR) enriched in the striatum. Genetic deletion and gene expression studies have suggested that GPR88 plays an important role in the regulation of striatal functions and is implicated in psychiatric disorders. The signal transduction pathway and receptor functions of GPR88, however, are still largely unknown due to the lack of endogenous and synthetic ligands. In this paper, we report the synthesis of a GPR88 agonist 2-PCCA and its pure diastereomers, which were functionally characterized in both transiently and stably expressing GPR88 HEK293 cells. 2-PCCA inhibited isoproterenol-stimulated cAMP accumulation in a concentration-dependent manner in cells expressing GPR88 but not in the control cells, suggesting that the observed cAMP inhibition is mediated through GPR88 and that GPR88 is coupled to Gαi. 2-PCCA did not induce calcium mobilization in GPR88 cells, indicating no Gαq-mediated response. A structure-activity relationship (SAR) study of 2-PCCA was also conducted to explore the key structural features for GPR88 agonist activity.

The GPR88 receptor agonist 2-PCCA does not alter the behavioral effects of methamphetamine in rats.

GPR88 is a novel orphan G protein-coupled receptor that is primarily located at the striatum. Genetic knockout studies reveal phenotypes of increased dopamine D(2) receptor sensitivity in mice, suggesting that GPR88 receptors may be involved in the modulation of dopaminergic system. However, there is no study that examines the pharmacological effects of GPR88 receptor ligands in in vivo preparations. This study examined the effects of a GPR88 receptor agonist, (1R, 2R)-2-pyridin-2-yl-cyclopropane carboxylic acid ((2S, 3S)-2-amino-3-methyl-pentyl)-(4'-propylbiphenyl-4-yl)-amide (2-PCCA), on the motor activity in rats and on methamphetamine-induced hyperactivity and discriminative stimulus effects. 2-PCCA (0.1-3.2mg/kg) dose-dependently decreased the locomotor activity in rats and, when studied in combination with 1.0mg/kg methamphetamine, also dose-dependently decreased methamphetamine-induced hyperactivity. However, the dose of 2-PCCA that significantly attenuated methamphetamine-induced hyperactivity was also the dose that by itself markedly decreased the baseline locomotor activity. In rats discriminating 0.32mg/kg methamphetamine, 2-PCCA (1-3.2mg/kg) itself did not produce methamphetamine-like discriminative stimulus effects and, when studied in combination, did not alter the discriminative stimulus effects of methamphetamine. Together, these data have provided the first line of evidence that activation of GPR88 receptors does not alter the behavioral effects of methamphetamine. The potential implications of these findings are also discussed.

Possible involvement of dopamine in the long-term serotonin depletion by p-chloroamphetamine and beta,beta-difluoro-p-chloroamphetamine in rats.

The role of dopamine in the long-term depletion of serotonin in rat brain by p-chloroamphetamine (PCA) and related compounds was investigated by comparing effects of beta,beta-difluoro-p-chloroamphetamine (beta,beta-difluoro-PCA) and 4-methyl-alpha-ethyl-meta-tyramine (H75/12), reported to cause only short-term serotonin depletion, with those of PCA. A single dose of beta,beta-difluoro-PCA had no long-term effects on serotonin in whole rat brain, even after pretreatment with proadifen which decreased the rate at which beta,beta-difluoro-PCA disappeared from brain. The possibility that proadifen might antagonize serotonin depletion was ruled out; proadifen did not prevent long-term serotonin depletion by PCA. Long-term depletion of brain serotonin was found after repeated injections of beta,beta-difluoro-PCA (five injections 4 hr apart) and was prevented by fluoxetine pretreatment. beta,beta-Difluoro-PCA given after the monoamine oxidase inhibitor pargyline or after carbidopa/L-dopa also caused long-term serotonin depletion, although H75/12 did not. At early times after single doses producing the same initial depletion of serotonin, PCA caused a large increase in dopamine and a large decrease in the metabolite 3,4-dihydroxyphenylacetic acid in whole brain, thereby increasing the ratio dopamine/3,4-dihydroxyphenylacetic, and the other two drugs caused smaller effects. Extracellular dopamine was increased markedly by PCA, less by beta,beta-difluoro-PCA, and not at all by H75/12. These results suggest an association between dopamine release and long-term depletion of serotonin and add to evidence that dopamine release by PCA may be essential to its neurotoxic actions on brain serotonin neurons.

[3H]monoamine releasing and uptake inhibition properties of 3,4-methylenedioxymethamphetamine and p-chloroamphetamine analogues.

The ability of several 3,4-methylenedioxymethamphetamine (MDMA) analogues to inhibit the uptake of [3H]serotonin (5-HT), dopamine (DA) and norepinephrine (NE) into synaptosomes was examined. In addition, the ability of the compounds to inhibit the uptake of [3H]5-HT and DA into synaptosomes from rats pretreated with reserpine (5 mg/kg i.p., 16 h pretreatment) was compared to control experiments. All of the test compounds were found to be potent releasers of non-vesicular 5-HT (the reserpine IC50 was significantly smaller than the control IC50). The range of 5-HT inhibitory activity corresponds well to the small range of ED50 values of the test compounds to substitute in drug discrimination experiments with animals trained to discriminate MDMA or S-(+)-N-methyl-1-(1,3-benzodioxol-5-yl)-2-aminobutane (S-MBDB) from saline. In contrast, there was a wide range of potency for the inhibition of NE and DA uptake. In addition, several of the analogues appeared to be pure uptake inhibitors of DA while others were found to be releasers of non-vesicular DA. Several of the compounds were very selective for 5-HT over DA or NE uptake inhibition, including 3-methoxy-4-methylamphetamine (MMA) and 5-methoxy-6-methyl-2-aminoindan (MMAI). A correlation was noted between the 5-HT neurotoxic potential of some of the test compounds and their relative ability to induce a release of non-vesicular DA. The potential catechol metabolites of the methylenedioxy-substituted compounds also showed potent monoamine releasing properties, suggesting that metabolism may play a role in the neurotoxic actions of some of these drugs. The present data support the hypothesis that drug-stimulated non-vesicular 5-HT release is primarily responsible for the discriminative cue of MDMA.

Analysis of p-chloroamphetamine and a side-chain monofluorinated analogue in rat brain.

p-Chloro-alpha-fluoromethylphenylethylamine (fluoro-p-chloroamphetamine) (FpCA) has been shown in acute studies to be a less potent depletor of the neurotransmitter amine 5-hydroxytryptamine (5-HT) in brain than is p-chloroamphetamine (pCA). Gas chromatographic assay procedures for FpCA and PCA have been developed in our laboratories and applied to preliminary measurements in brain tissue from rats injected intraperitoneally with pCA or FpCA. Groups of male Sprague-Dawley rats were injected with pCA (0.03 mmol/kg) or FpCA (0.05 or 0.1 mmol/kg) and killed 1, 2, or 4 hr later. The brains were analyzed for the halogenated amphetamines by gas chromatography with electron-capture detection (GC-ECD) following derivatization with pentafluorobenzenesulfonyl chloride (for pCA) or trichloroacetic anhydride (for FpCA). At the 0.05-mmol/kg dose, FpCA attained lower brain concentrations at 1, 2, and 4 hr after injection than did pCA at a considerably lower dose (0.03 mmol/kg). Even at the higher dose of FpCA used (0.10 mmol/kg), where concentrations of FpCA were higher than those of pCA initially, concentrations of FpCA had dropped below those of pCA by 4-hr. These preliminary results indicate that FpCA attains lower brain concentrations and is eliminated from the brain more rapidly than is the parent drug, pCA. However, differences in potency between FpCA and pCA on 5-HT depletion cannot be explained fully on the basis of obtained brain levels of the drug as even at time intervals where FpCA levels were higher than or equal to those of pCA, there was less depletion of 5-HT by the former drug.

Inhibition of monoamine oxidase by two substrate-analogues, with different preferences for 5-hydroxytryptamine neurons.

Various intraperitoneal doses of 5-fluoro-alpha-methyltryptamine (5-FMT), given to mice, dose-dependently inhibited only MAOA activity, with similar degrees of inhibition in the striatum, hypothalamus and the rest of the forebrain. The activity inhibited in these regions, completely recovered to control levels within 24 hr after the injection. In contrast, p-chloro-beta-methylphenethylamine (p-CMP), selectively inhibited MAOB activity, with complete recovery within 45 min after the injection. Regardless of the differences in time interval and degree of inhibition of MAOA by 5-FMT or MAOB by p-CMP, both kinds of inhibition were competitive, with respect to oxidation of the respective substrate. 5-Fluoro-alpha-methyltryptamine markedly protected only MAOA against inhibition by phenelzine, without protecting MAOB. Also, 5-FMT greatly increased one kind of animal behaviour, the head-twitch and this behaviour was greatly reduced by treatment with fluoxetine, but increased by reserpine. The results indicate that p-CMP is a short-acting, probably reversible, MAOB-selective inhibitor and 5-FMT has the same characteristics of selectivity for MAOA in central serotonergic neurons.

Behavioral, biochemical and neurotoxicological actions of the alpha-ethyl homologue of p-chloroamphetamine.

The present set of experiments was designed to examine the effects of extension of the alpha-methyl of p-chloroamphetamine (PCA) to an alpha-ethyl. Therefore, the alpha-ethyl homologue of PCA, 1-(4-chlorophenyl)-2-aminobutane (CAB), was compared to PCA in a number of pharmacological assays. CAB was 2-fold less potent than PCA at inhibiting synaptosomal uptake of [3H]5-hydroxytryptamine ([3H]5-HT), and 5-fold less potent at inhibiting uptake of [3H]dopamine ([3H]DA). In drug discrimination assays, CAB was approximately 3-fold less potent than PCA in animals trained to discriminate 3,4-methylenedioxymethamphetamine (MDMA) or its alpha-ethyl homologue, S-(+)-N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (S-(+)-MBDB), from saline. Monitoring with in vivo microdialysis, 10 mg/kg of PCA caused a large increase in extracellular DA and a significant decrease in 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum. In contrast, 11 mg/kg CAB caused no increase and 22 mg/kg CAB caused only a slight increase in extracellular DA. Both doses of CAB caused a decrease in extracellular DOPAC. The potential 5-HT neurotoxicity of CAB was examined by measuring monoamine and metabolite levels and [3H]paroxetine binding at one week following acute doses. A 10 mg/kg dose of PCA caused an 80% decrease in cortical and hippocampal serotonergic markers, while an equimolar dose of CAB decreased only hippocampal 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels. However, 22 mg/kg of CAB produced a 20-40% decrease in all serotonergic markers. Thus, extension of the alpha-alkyl significantly decreases the dopaminergic effects of PCA. The similar decrease in relative 5-HT neurotoxicity and the decreased ability to alter dopaminergic systems in vivo and in vitro supports the involvement of DA in the neurotoxicity of PCA.

Studies on 5-fluoro-alpha-methyltryptamine and p-chloro-beta-methylphenethylamine: determination of the MAO-A or MAO-B selective inhibition in vitro.

To further clarify highly MAO-A- or -B-selective inhibitory properties of 5-fluoro-alpha-methyltryptamine (5-FMT) and p-chloro-beta-methylphenethylamine (p-CMPEA), we determined the types and K1 values of inhibition of rat brain MAO-A and -B activity in vitro. The kinetic data obtained showed that 5-FMT is a competitive MAO-A-selective inhibitor with about a 18,000-fold higher sensitivity than MAO-B. In contrast, p-CMPEA is a competitive MAO-B-selective inhibitor with about a 620-fold higher sensitivity. Based on the present findings of highly MAO-A- or -B-selective inhibition, these two compounds might prove to be of value in in vivo studies.

p-Chloroamphetamine formation responsible for long-term depletion of brain serotonin after N-cyclopropyl-p-chloroamphetamine injection in rats.

After the injection of N-cyclopropyl-p-chloroamphetamine (N-cyclopropyl-PCA) into rats, p-chloroamphetamine (PCA) was identified in brain by high performance liquid chromatography with UV detection and was quantitated by that method and by spectrofluorometric analysis involving reaction with fluorescamine. The identity of PCA in brains of rats treated with N-cyclopropyl-PCA was confirmed by mass spectrometry. The peak concentrations of PCA in brain occurred 4 hrs after N-cyclopropyl-PCA injection. Brain concentrations of PCA and of N-cyclopropyl-PCA were measured at 1 or 4 hrs, respectively, after the injection of various doses of PCA or of N-cyclopropyl-PCA into rats. The depletion of brain serotonin and 5-hydroxyindoleacetic acid (5-HIAA) was measured 1 week after injection of those same doses of PCA or N-cyclopropyl-PCA. Comparing peak concentrations of PCA with the degree of depletion of brain serotonin supported the interpretation that PCA formed metabolically accounted for the long-term depletion of brain 5-hydroxyindoles after injection of N-cyclopropyl-PCA in rats.

Selective inhibition of monoamine oxidase A and B by two substrate-analogues, 5-fluoro-alpha-methyltryptamine and p-chloro-beta-methylphenethylamine.

In order to develop new and potent reversible MAO-B-selective inhibitors, we examined the inhibitory effects of two substrate-analogues, 5-fluoro-alpha-methyltryptamine (5-FMT) and p-chloro-beta-methylphenethylamine (p-CMP) on rat brain MAO-A and -B activity in vitro. Studies of the inhibitory effects of both analogues showed that 5-FMT was a highly MAO-A-selective inhibitor, whereas p-CMP was a highly MAO-B-selective inhibitor. The degree of inhibition by 5-FMT or p-CMP was not enhanced by extending the time of preincubation of the enzyme and either analogue. Dilution studies revealed the inhibition to be reversible in nature, indicating that both analogues are reversible MAO-A-selective (5-FMT) or -B-selective inhibitor (p-CMP) with high selectivity.

Failure to detect any transport of the irreversible monoamine oxidase inhibitor N-cyclopropyl-4-chloroamphetamine by the carrier of 5-hydroxytryptamine in the brain of the rat in vivo.

N-Cyclopropyl-4-chloroamphetamine (LY 93716) was examined for its potential preference for inhibiting the activity of monoamine oxidase (MAO) within serotonergic nerve terminals in the hypothalamus of the rat. Such an effect should support the hypothesis of Fuller and Perry (1977) (Neuropharmacology 16: 495-497) that this compound is transported by the uptake mechanism for 5-hydroxytryptamine (5-HT). By using a small (0.1 microM) substrate concentration of [14C]5-HT and a synaptosomal preparation incubated in the absence and presence of a selective inhibitor of the uptake of 5-HT (citalopram) it is possible to measure the activity of MAO in serotonergic nerve terminals. It was found that LY 93716 caused greater inhibition outside than inside the serotonergic nerve terminals when the activity of MAO was analysed 24 hr after the injection, but an inverted relationship was observed when analysed 72 hr after administration. Inhibition of uptake did not cause any change in the inhibition of MAO within the serotonergic nerve terminals at the former time but antagonized the inhibition observed 72 hr after the injection. It is concluded that the latter effect was due to antagonism of the neurotoxic action of LY 93716 and that no evidence was found that LY 93716 is transported by the uptake carrier for 5-HT.

P-chloroamphetamine and a side-chain fluorinated analog: effects on brain amine levels and behavior.

Reserpinized (1 mg/kg, IP-24 hr) and saline-pretreated male rats were subdivided into groups receiving p-chloroamphetamine (pCA, 5.2 mg/kg, IP), 1-fluoromethyl-2-p-chlorophenylethylamine (FpCA, 5.6 mg/kg, IP), or saline, 90 minutes before the testing of behavior in the open-field and 150 minutes before sacrifice for assay of brain levels of amines. FpCA and pCA produced identical investigative and social patterns of behavior in saline pretreated animals in spite of the fact that pCA reduced serotonin levels whereas FpCA did not. Both pCA and FpCA enhanced dopamine and noradrenaline levels compared to saline controls. The behavioral syndrome common to FpCA and pCA animals was one of increased sitting still, and decreased locomotion and self-grooming while alone, and decreased locomotion, and social behavior but increased sniffing of the environment while in the company of an untreated male rat. Reserpine pretreatment exacerbated this syndrome of inactivity in pCA more than in FpCA rats even though the reserpinized groups did not differ from each other in the concentrations of the three amines.