Region-specific reductions in brain apparent diffusion coefficient in cytomegalovirus-infected fetuses.

OBJECTIVE: To evaluate the effects of cytomegalovirus (CMV) infection on apparent diffusion coefficient (ADC) values of the fetal brain in utero. METHODS: In this retrospective analysis we compared 58 fetal head magnetic resonance imaging (fhMRI) scans of PCR-verified CMV-infected fetuses, obtained in 2008-2012, with those of a normal control group of 36 gestational age (GA)-matched uninfected fetuses scanned between 2006 and 2012. Estimated GA at infection ranged from 1 to 32 weeks, and fhMRI was performed at 24 to 38 weeks. The frontal, parietal, temporal and occipital lobes (mainly white matter), basal ganglia, thalamus, pons and cerebellum were analyzed by assessing ADC values. Two pregnancies were terminated and postmortem confirmation was available in these cases. RESULTS: ADC values of CMV-infected fetuses correlated significantly and negatively with GA in all brain regions except the basal ganglia. The cerebellum had the greatest reduction (r = -0.52, P < 0.0001). Maternal age correlated positively with ADC in the frontal lobe (P < 0.05). GA at infection and overt pathological changes did not affect ADC significantly. Compared with non-infected fetuses, ADC values of affected fetuses were significantly reduced in the frontal (P < 0.0001), parietal (P < 0.0001), occipital (P = 0.0005) and temporal (P = 0.001) lobes and thalamus (P = 0.006). CONCLUSION: CMV infection of the fetal brain results in a highly significant, region-dependent reduction of ADC values in the frontal, parietal, occipital and temporal lobes and thalamus, probably reflecting hypercellularity and inclusion bodies in damaged areas. Further studies are needed to determine if reduction in ADC values may serve as a prognostic factor in CMV-infected fetuses. Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.

Sex differences in serotonin 1 receptor binding in rat brain.

Male and female rats exhibit sex differences in binding by serotonin 1 receptors in discrete areas of the brain, some of which have been implicated in the control of ovulation and of gonadotropin release. The sex-specific changes in binding, which occur in response to the same hormonal (estrogenic) stimulus, are due to changes in the number of binding sites. Castration alone also affects the number of binding sites in certain areas. The results lead to the conclusion that peripheral hormones modulate binding by serotonin 1 receptors. The status of the serotonin receptor system may affect the reproductive capacity of an organism and may be related to sex-linked emotional disturbances in humans.

A permanently charged tamoxifen derivative displays anticancer activity and improved tissue selectivity in rodents.

A quaternized form of tamoxifen (TAM), tamoxifen methiodide (TMI), was shown to demonstrate very low brain uptake compared to TAM and, unexpectedly, was considerably less estrogenic than TAM in the uterus. The agonist activity of TMI in the bone was similar to that of TAM. TMI manifested significant dose-dependent tumoricidal activity with a rapid onset of action against MCF-7 human breast cancer implants in nude mice and a mean reduction in tumor size of 60% over six weeks.

Autoradiographic analysis of tritiated imipramine binding in the human brain post mortem: effects of suicide.

In vitro quantitative autoradiography of high-affinity tritiated imipramine binding sites was performed on brains of 12 suicide victims and 12 matched controls. Region-specific differences in imipramine binding were found between the two groups. Thus, the pyramidal and molecular layers of the cornu ammoni hippocampal fields and the hilus of the dentate gyrus exhibited 80%, 60%, and 90% increases in binding in the suicide group, respectively. The postcentral cortical gyrus, insular cortex, and claustrum had 45%, 28%, and 75% decreases in binding in the suicide group, respectively. No difference in imipramine binding was observed in prefrontal cortical regions, in the basal ganglia, and in mesencephalic nuclei. No sex and postmortem delay effects on imipramine binding were found. Imipramine binding was positively correlated with age, the effect of age being most pronounced in portions of the basal ganglia and temporal cortex.

Autoradiographic analysis of alpha 1-noradrenergic receptors in the human brain postmortem. Effect of suicide.

In vitro quantitative autoradiography of alpha 1-noradrenergic receptors, using tritiated prazosin as a ligand, was performed on 24 human brains postmortem. Twelve brains were obtained from suicide victims and 12 from matched controls. We found significant lower binding to alpha 1 receptors in several brain regions of the suicide group as compared with matched controls. This decrease in receptor density was evident in portions of the prefrontal cortex, as well as the temporal cortex and in the caudate nucleus. Age, sex, presence of alcohol, and time of death to autopsy did not affect prazosin binding, in our sample, as measured by autoradiography.

Improved brain delivery and in vitro activity of zidovudine through the use of a redox chemical delivery system.

OBJECTIVE: Improved therapy for AIDS dementia and related encephalopathies may be achieved through enhanced delivery of effective antiretroviral agents to the central nervous system (CNS). DESIGN: A novel chemical delivery system (CDS) was used, which utilized redox trapping of drugs in the brain. This study was aimed at defining the pharmacokinetics of a zidovudine (ZDV)-CDS as well as establishing its in vitro antiviral efficacy against HIV in both lymphocytes and in a neural cell line. RESULTS: ZDV-CDS administered parenterally to rats produced significantly higher brain levels of ZDV [area under the curve (AUC), 425 micrograms x min/g] than equimolar ZDV (AUC, 13.5 micrograms x min/g). Native ZDV uptake was minimal after 1 h when analyzed in CEM lymphocytes and in SKNMC neuroblastoma cell line. By contrast, marked uptake of ZDV-CDS was followed by biochemical conversion of ZDV-CDS to its main metabolites (ZDV-CDS quaternary salt, ZDV-Q+, and native ZDV). These improved uptake profiles were associated with greater in vitro virucidal effect. ZDV-CDS at 0.5 microM was 80% more effective than ZDV in suppressing p24 production in a lymphocyte culture infected with 6000 median tissue culture infective doses (TCID50) of the HIV N1T strain and 50% more effective at 0.05 microM. Furthermore, syncytia formation was completely suppressed at a ZDV-CDS dose of 0.5 microM (600 TCID50) but native ZDV at the same dose was ineffective. Finally, while ZDV (at 0.5 microM) is not active in reducing viral replication in an SKNMC neural cell line, the ZDV-CDS complex significantly suppressed p24 synthesis. CONCLUSION: The ZDV-CDS complex is capable of delivering higher ZDV doses to lymphocytes and neural cells, with improved antiretroviral activity.

The suicide brain: a review of postmortem receptor/transporter binding studies.

The present review summarizes the last 15 years of research involving postmortem receptor/transporter binding studies on brains of suicide victims. It is our working hypothesis, on the basis of psychological, behavioral and epidemiological studies, that suicidal behavior is an independent unique behavioral entity with specific neurochemical characteristics. This review tries to test this hypothesis at the level of neurotransmitter receptors by using a different approach to data analysis. We suggest that this statistical approach, involving multivariate analyses, can contribute to the formulation of new hypotheses at the level of molecular biology and genetics. Such studies if undertaken in the future, would help define suicidal behavior as a psycho-neuro-pathological entity.

Lactation elevates vasoactive intestinal peptide messenger ribonucleic acid in rat suprachiasmatic nucleus.

Vasoactive intestinal peptide (VIP) has been suggested to play a role in lactation; indeed several studies implied that VIP induces the release of PRL in the pituitary. Quantitative RNA studies from our laboratory show an increase in the VIP messenger RNA (mRNA) content in the hypothalamus of lactating rats. The purpose of this investigation is to determine which hypothalamic neurons are increasing the expression of VIP. A sensitive in situ hybridization assay employing synthetic oligodeoxynucleotide probes corresponding to specific exons of the VIP gene was used to study VIP gene expression at the neuronal level. We were able to detect VIP-encoding transcripts in various brain regions including the ventrolateral thalamus, neocortex, pyriform cortex, and hypothalamus with a particularly high concentration in the suprachiasmatic nucleus. When lactating animals were compared to non-lactating animals, a 2-fold increase was observed in VIP transcripts in the suprachiasmatic nucleus. Since the suprachiasmatic nucleus is not directly associated with the physiology of lactation, the response of the VIP gene to lactation may be, in part, indirect. Taken together, our results suggest that lactation and the expression of the VIP gene are interrelated.

Quantitative histochemistry of brain acetylcholinesterase and learning rate in the aged rat.

Using a newly developed method for quantitative acetylcholinesterase (AChE) histochemistry we find a substantial decrease in AChE content in aged rats compared to young controls in the cholinergic cell body regions (the ventral pallidum and the medial septal nuclei) and, to a smaller extent in the projection areas (the cortex and hippocampus). In the same group of aged rats we find a severe deficit in the acquisition of a water maze task. Quantitative histochemistry is a potent method for detecting localized changes in AChE content in otherwise intact, learning-impaired aged rats.

Aging and brain cholinergic muscarinic receptor subtypes: an autoradiographic study in the rat.

Cholinergic M1 and M2 muscarinic receptors in aged and young rat brains were studied by quantitative autoradiography of tritiated QNB in the presence of pirenzepine or carbachol. A selective pattern of decreased binding density was observed in the aged rat. A large number of regions showed no effect of aging; these include subdivisions of the hippocampal formation and most thalamic and hypothalamic nuclei. M1 and M2 receptors showed small but significant decreases in cortical regions and in the striatum. The largest effects were seen in M2 receptors of the ventral forebrain cholinergic nuclei where binding was reduced by up to 40%. No similar reductions were seen in the M1 receptor population in these regions. The results suggest that both muscarinic receptor subtypes show an anatomically selective pattern of decrease with age, with the M2 receptor subtype in the basal forebrain nuclei being specially vulnerable to the effects of aging.

Human corpus callosum in aging and Alzheimer's disease: a magnetic resonance imaging study.

The involvement of the corpus callosum in aging and Alzheimer's disease (AD) is not clear. We measured cross sectional areas of the entire corpus callosum (CC), as well as the front 20% (genu), middle 60% (body), and posterior 20% (splenium) of the structure from a midsagittal MRI slice in AD patients (N = 20), and young (N = 16) and old (N = 13) control subjects. We found that mean CC area in young controls was 570 +/- 107 mm2. Aging did not significantly affect the mean area of the CC (562 +/- 98 mm2). A small, significant reduction was seen in AD in comparison to the young control group (480 +/- 133 mm2). However, AD is accompanied by a large and statistically significant reduction in the genu area in comparison to both young and old control subjects. A trend toward an age-dependent reduction in the body area is also accentuated in AD patients who showed significantly smaller callosal bodies than young controls. We conclude that selective changes within corpus callosum accompany aging and AD pathology.

Decreased cerebral response to inhibitory neurotransmission in alcoholics.

OBJECTIVE: Changes in gamma-aminobutyric acid (GABA)-benzodiazepine receptor function have been implicated in alcohol tolerance, withdrawal, and dependence. The purpose of this study was to investigate whether recently detoxified alcoholic subjects had abnormalities in brain GABA-benzodiazepine receptor function. METHOD: The effect of 30 micrograms/kg of lorazepam on regional brain glucose metabolism was studied in 12 normal subjects and 10 alcoholic subjects with the use of positron emission tomography and [18F]fluorodeoxyglucose. RESULTS: Lorazepam decreased whole brain glucose metabolism in both the normal subjects (13% change) and the alcoholic subjects (10% change), and the response was correlated with the concentration of lorazepam in plasma. Whereas the normal and alcoholic subjects showed similar responses to lorazepam in occipital and cerebellar metabolism, the alcoholic subjects showed significantly less of a response than the comparison subjects in the thalamus, basal ganglia, and orbitofrontal cortex. The rate of response in the orbitofrontal cortex was significantly correlated with cerebellar metabolism at baseline. CONCLUSIONS: The alcoholic subjects had a blunted response to lorazepam that was specific to certain brain regions. The association between cerebellar metabolism and response to lorazepam suggests that the cerebellum may contribute to the decreased sensitivity to lorazepam which was seen in the alcoholic subjects.

Dexanabinol (HU-211) effect on experimental autoimmune encephalomyelitis: implications for the treatment of acute relapses of multiple sclerosis.

Dexanabinol (HU-211) is a synthetic non-psychotropic cannabinoid which suppresses TNF-alpha production in the brain and peripheral blood. The effects of dexanabinol in rat experimental autoimmune encephalomyelitis (EAE) were studied using different doses, modes of administration and time regimes. Dexanabinol, 5 mg/kg i.v. given once after disease onset (day 10), significantly reduced maximal EAE score. Increasing the dose or treatment duration resulted in further suppression of EAE. Drug administration at earlier phases during disease induction was not effective. Histological studies supported the clinical findings demonstrating reduction in the inflammatory response in the brain and spinal cord in animals treated with dexanabinol. The results suggest that dexanabinol may provide an alternative mode of treatment for acute exacerbations of multiple sclerosis (MS).

Iodine-123-5-iodo-6-nitroquipazine: SPECT radiotracer to image the serotonin transporter.

UNLABELLED: Because serotonergic function has been implicated in the pathophysiology of a number of diseases of the nervous system, efforts to image this system in vivo have received considerable recent attention. Promising preliminary results with the tracer 5-iodo-6-nitroquipazine (INQUIP) have prompted us to perform further studies designed to validate the use of the tracer as an in vivo ligand for the serotonin transporter. METHODS: We studied six adult macaca mulatta in eight experiments which involved SPECT imaging at 17 to 24 hr post-tracer injection, including three experiments with coinjection of the 123I-and 125I-radiolabeled tracer for direct comparison of autoradiography and SPECT, and three experiments in which animals were lesioned with the serotonergic neurotoxin (+/-)3,4-methyl-enedioxymethamphetamine (MDMA). In addition, we evaluated the metabolism of the tracer in the brain and periphery. RESULTS: SPECT images obtained at 17 and 24 hr reflected the known pattern of distribution of serotonin transporters and also showed close correspondence to the autoradiograms. Ratios of binding in the brain-stem to binding in the cerebellum were close to 3 at 17 hr. autoradiograms from an MDMA-treated animal showed up to 95% reductions of binding, while the SPECT data showed smaller reductions. Virtually all of the tracer in the brain stem was in the form of unmetabolized parent compound, but plasma showed rapid peripheral metabolism of the tracer. CONCLUSION: These results demonstrate that INQUIP SPECT images are sensitive measures of in vivo binding to the serotonin transporter, and support the further development of the tracer as a method for the in vivo study of serotonergic neurons in humans.

Age-related changes in serotonin 5HT2 receptors on human blood platelets.

Serotonin receptors of the 5HT2 type were labeled on platelet membranes using tritiated ketanserin. Blood was collected from the umbilical cord of newborns and venous samples were collected from 6-year-old children as well as junior-high and high school students (ages 13 through 18) to determine age-related changes in receptor binding. Among the ages sampled, the highest levels of 5HT2 receptor binding were found in 6-year-olds. A sharp decline in receptor binding occurred during adolescence, with levels reduced by half between ages 13 and 17. This pattern is similar to the one we have observed in brain 5HT2 receptors postmortem. There were no significant sex differences in 5HT2 receptors on platelets in newborn and young children. A trend towards higher binding in girls appears around the onset of menstruation in teenage girls (age 14 and up). These results demonstrate that platelet 5HT2 receptors can serve as a model for age dependent changes in 5HT2 receptors in the brain.

The in vivo distribution of an antidepressant drug (DMI) in male and female rats.

The accumulation of IP injected 3H-desipramine (DMI) in the brain and in the liver has been studied in both male and female rats. The total amount of DMI in the brains of females is 2 to 4 times that found in the brains of males. In females the amount of DMI is highest on the day of estrus and lowest on proestrus. This sex difference was not found following the injections of another psychoactive drug, 3H-chlorpromazine. In both males and females the level of DMI in the cortex and caudate is slightyl higher than in the hippocampus, septum and hypothalamus. The pharmaco-kinetics and dose dependence of the accumulation of DMI are also similar in males and females. Maximal levels are reached in the liver in less than 15 min, whereas in the brain it takes 30 min. The decline of radioactivity in the liver is faster than in brain. There is no saturation in the amount of DMI taken in brain. There is no saturation in the amount of DMI taken up in brain or liver in the dose range up to 40 mg/kg. The sex difference in the amount of 3H-DMI in brain, which may be the result of sex-dependent metabolism in liver microsomes, may explain the male-female differences in reaction to antidepressants.

Sex differences in behavioral and thermal responses to pargyline and tryptophan.

The effects of parenterally injected pargyline and tryptophan on rectal temperature and behavior have been studied in male and female rats. Pargyline alone (50 mg/kg) produced hypothermia in both sexes. Pargyline (50 mg/kg) followed by low doses (20--50 mg/kg) of tryptophan caused a behavioral syndrome consisting of tremor, hindlimb abduction, forepaw treading, and straub tail. In females, but not in males, hypothermia was potentiated. The same dose of pargyline followed by higher doses (60--150 mg/kg) of tryptophan produced a short hypothermia followed by a dose-dependent behavioral syndrome, hyperthermia, and mortality. On all of these measures, females responded following shorter latencies and lower doses of tryptophan. Both hypothermia and hyperthermia were observed in treated animals following pretreatment with a peripheral decarboxylase inhibitor. The results suggest a complex role for serotonin in thermoregulation. The sex differences observed suggest higher activity of serotonin in female rat brains following the drug treatment, which may be accounted for by a higher utilization rate of tryptophan.

Desmethylimipramine (DMI) counteracts learned helplessness in rats.

In a study of the mechanisms controlling the learned helplessness phenomenon, rats were exposed to either inescapable preshocks or control procedures, treated with one of three dosages of desmethylimipramine, and tested for later adaptive responding. This catecholamine modulator attenuated the deficits in escape responding that ordinarily follow prior exposure to inescapable preshocks, and it did so in a dose-dependent fashion. These findings support the position that the learned helplessness phenomenon is mediated by catecholamine changes.

Serotonin 5-HT2 receptor binding on blood platelets as a state dependent marker in major affective disorder.

Serotonin receptors of the 5-HT2 type were studied on platelet membranes from 15 patients suffering from major depression. Receptor binding and clinical state (assessed by the Hamilton and Beck rating scales) were examined in a drug free state upon admission and after 1 and 3 weeks of treatment with the antidepressant maprotiline (MPT). 5-HT2 receptor binding changed in correlation with changes in the clinical state of the patients as judged by the rating scales. Since most patients showed a clinical improvement, the patients as a group exhibited a significant decrease in binding concomitant with a drop in depression scores. However, in those patients in whom there was no clinical change or an increase in depression scores, 5-HT2 receptor binding did not change or increased, respectively, thus resulting in a significant correlation between clinical changes and changes in binding. These results support the use of 5-HT2 receptors on platelets in evaluating depression and its treatment.

Increased serotonin 5-HT2 receptor binding on blood platelets of suicidal men.

In search of a physiological marker of depression and suicidal behavior, serotonin receptors of the 5-HT2 type were studied on platelet membranes from 19 control and 22 suicidal subjects. All were young, drug- and medication free men (18-21-years-old). 5-HT2 receptor binding was assayed using tritiated ketanserin at two concentrations. Receptor binding in the suicidal subjects was significantly higher than controls at both concentrations, the mean difference being around 50%. A similar difference between patients with major depressive disorder and matched controls has been observed previously. These findings support the use of 5-HT2 receptors on platelets as a research and diagnostic tool in depression and suicide.