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Biomedical subjects

Tom G Bolwig

Publications and source records attributed to Tom G Bolwig.

At least 19 recordsLinked to original sources
PubMed2006

Effects of maternal separation on neuropeptide Y and calcitonin gene-related peptide in "depressed" Flinders Sensitive Line rats: a study of gene-environment interactions.

Interactions between genetic vulnerability to stress/depression and early life experience may play a crucial role in the pathogenesis of mood disorders. Here we explore this hypothesis by superimposing early life trauma in the form of maternal deprivation for 180 min per day from postnatal day 2 to 14 onto a genetic model of depression/susceptibility to depression, Flinders Sensitive Line (FSL) and their controls, Flinders Resistant Line (FRL) rats. We investigate effects on neuropeptide Y (NPY) and calcitonin gene-related peptide (CGRP) like immunoreactivity (LI) in 10 brain regions as these neuropeptides are affected by antidepressants and are altered in cerebrospinal fluid of depressed patients. NPY-LI was reduced while CGRP-LI was elevated in hippocampus and frontal cortex of "genetically depressed" FSL rats. The two peptides displayed a significant negative correlation in these regions that was strongest in the FSL strain. Maternal deprivation exacerbated the strain difference in hippocampal CGRP-LI, while it was without effect on NPY-LI. FSL rats had higher tissue concentration of both neuropeptides in periaqueductal grey and higher NPY-LI in caudate/putamen. Maternal deprivation selectively raised CGRP-LI in amygdala of the FRL control stain. Thus, in two brain regions implicated in the neurobiology of depression, hippocampus and frontal cortex, changes in CGRP-LI and NPY-LI were in opposite direction, and CGRP-LI appears to be more responsive to adverse experience. Our findings thus support the hypothesis that genetic disposition and developmental stress may contribute to the susceptibility to depression by exerting selective neuropeptide- and brain region-specific effects on adult neurobiology.

Analysis of Variance↗
PubMed2006

Cerebral 5-HT2A receptor binding is increased in patients with Tourette's syndrome.

Experimental and clinical data have suggested that abnormalities in the serotonergic neurotransmissions in frontal-subcortical circuits are involved in Tourette's syndrome. To test the hypothesis that the brain's 5-HT2A receptor binding is increased in patients with Tourette's syndrome, PET imaging was performed. Twenty adults with Tourette's syndrome and 20 healthy control subjects were investigated with PET-[18F]altanserin using a bolus-infusion protocol. Regions of interest were delineated automatically on co-registered MRI images, and partial volume-corrected binding parameters were extracted from the PET images. Comparison between control subjects and Tourette's syndrome patients showed increased specific [18F]altanserin binding, not only in the a-priori selected brain regions hypothesized to be involved in Tourette's syndrome, but also post-hoc analysis showed a global up-regulation when testing for a overall difference with a randomization test (p<0.03). Increased 5-HT2A receptor binding was found not only in regions closely related to subcortical regions in patients with Tourette's syndrome, but also in most other brain regions. Our data suggest that the serotonergic transmitter system is pathophysiologically involved in Tourette's syndrome and that a clinical trial with 5-HT2A receptor antagonists may be justified.

Adolescent↗
PubMed2006

Differential regulation of c-Fos and FosB in the rat brain after amygdala kindling.

Members of the inducible transcription factor Fos family, that are part of the AP-1 complex that binds to the corresponding promoter site, are implicated in the regulation of gene transcription after acute and chronic seizures. However, little is known about the temporal expression of the AP-1 transcription factors and if individual proteins composing this complex have distinct roles in development and maintenance of permanent epilepsy. In this study, the AP-1 binding capacity, its content of different Fos proteins, and the anatomical specificity, were analyzed 2 or 18 h after achieving full kindling in rats. The same analysis was performed in fully kindled animal receiving a new stimulus after a 3-week pause to determine the extent of stability of the AP-1 transcription factors. While both c-Fos and FosB were induced in all cortical areas after a single stimulus, only FosB-immunoreactivity remained after 18 h. A single stimulation to kindled animals left undisturbed for 3 weeks induced a long-lasting upregulation of AP-1 binding in the frontal cortex, but not in the hippocampus suggesting a permanent exposure of AP-1 heterocomplexes in the frontal cortex. Supershift assays showed that FosB is the dominant component of the long-term AP-1 complex. It is concluded that the AP-1 binding complex in fully kindled rats is composed of different proteins, and that FosB-containing AP-1 complexes mediate long-term effects in the frontal cortex.

Amygdala↗
PubMed2005

Differential suppression of seizures via Y2 and Y5 neuropeptide Y receptors.

Neuropeptide Y (NPY) prominently inhibits epileptic seizures in different animal models. The NPY receptors mediating this effect remain controversial partially due to lack of highly selective agonists and antagonists. To circumvent this problem, we used various NPY receptor knockout mice with the same genetic background and explored anti-epileptic action of NPY in vitro and in vivo. In Y2 (Y2-/-) and Y5 (Y5-/-) receptor knockouts, NPY partially inhibited 0 Mg2+-induced epileptiform activity in hippocampal slices. In contrast, in double knockouts (Y2Y5-/-), NPY had no effect, suggesting that in the hippocampus in vitro both receptors mediate anti-epileptiform action of NPY in an additive manner. Systemic kainate induced more severe seizures in Y5-/- and Y2Y5-/-, but not in Y2-/- mice, as compared to wild-type mice. Moreover, kainate seizures were aggravated by administration of the Y5 antagonist L-152,804 in wild-type mice. In Y5-/- mice, hippocampal kindling progressed faster, and afterdischarge durations were longer in amygdala, but not in hippocampus, as compared to wild-type controls. Taken together, these data suggest that, in mice, both Y2 and Y5 receptors regulate hippocampal seizures in vitro, while activation of Y5 receptors in extra-hippocampal regions reduces generalized seizures in vivo.

Animals↗
PubMed2005

Patients with obsessive-compulsive disorder have increased 5-HT2A receptor binding in the caudate nuclei.

The pharmacological efficacy of serotonergic-acting drugs suggest that patients with obsessive-compulsive disorder (OCD) may have alterations in their cerebral serotonergic (5-HT) receptor system, and previous neuroimaging studies of OCD patients have shown abnormalities in several fronto-subcortical regions. In this study we investigated cerebral 5-HT(2A) receptor binding in 15 untreated OCD patients and in 15 age- and gender-matched healthy volunteers by magnetic resonance imaging and [(18)F]altanserin positron emission tomography (PET). Eleven of the patients were rescanned with PET after receiving treatment with a selective serotonin reuptake inhibitor (SSRI). The distribution volumes of specific tracer binding (DV(3)') were calculated for 12 brain regions, and comparisons were made between: (1) healthy volunteers vs. untreated OCD patients, (2) healthy volunteers vs. treated OCD patients, and (3) OCD patients before and during treatment. When comparing the distribution volume for specific fronto-subcortical brain regions, significantly higher values were recorded in the caudate nuclei in OCD patients (DV(3)': 0.24+/-0.14) compared to the healthy control group (DV(3)': 0.15+/-0.13) (p<0.05, Wilcoxon matched-pairs test). This difference between groups was not present after treatment with SSRIs. There was no correlation between the severity of OCD symptoms and 5-HT(2A )receptor binding. An increase in 5-HT(2A) receptor binding is found in the caudate nuclei of untreated patients with OCD. The up-regulation in 5-HT(2A) receptors might be compensatory for a lack of serotonin in the feedback loop between the thalamus and orbito-frontal cortex, the caudate nuclei, and the globus pallidus.

Adolescent↗
PubMed2005

Cholecystokinin tetrapeptide effects on HPA axis function and elevated plus maze behaviour in maternally separated and handled rats.

Deficits in the function of the hypothalamic-pituitary-adrenal (HPA) axis have been suggested to predispose to the development of depression and anxiety disorders. This is mirrored in the animal model "Maternal Separation (MS)" where the stress of repeated separation of rat pups from the dam during early postnatal development results in long lasting alterations in HPA axis function. Cholecystokinin increases serum concentrations of stress axis hormones and might be involved in the dam-pup interaction in rats. Therefore, we hypothesized that adult animals, which had been separated daily (postnatal days (PND) 2-14) for 180 min (MS180) would differ in HPA axis responsiveness to an intravenous challenge dose of cholecystokinin tetrapeptide (CCK-4) compared to handled rats, separated for 15 min daily. The study explored the effects of intravenous CCK-4 on elevated plus maze behaviour and HPA axis hormones. MS180 animals displayed reduced general activity but unaltered levels of open arm activity in the elevated plus maze. CCK-4 administration elevated general activity in the handled rats, while leaving MS180 rats unaffected. MS180 rats had increased baseline CRF mRNA expression in the paraventricular nucleus of the hypothalamus. When CRF mRNA was assessed in chronically catheter implanted and single housed rats, lower levels were found in the paraventricular nucleus of MS180 animals compared to handled animals and this parameter was not affected by CCK-4 treatment. Adrenocorticotropin concentrations in serum were equal in MS180 and handled rats and unaffected by CCK-4. Corticosterone serum concentrations were lower in saline treated MS180 rats compared to saline treated handled rats. CCK-4 injection raised serum corticosterone in MS180 rats to levels equal to the handled rats, while leaving handled rats unaffected. We suggest that the lower levels of hypothalamic CRF mRNA and serum corticosterone concentrations in MS180 rats might be due to the experimental set-up with chronic venous catheter implants and single housing. In conclusion, this study supports the hypothesis of elevated CCK sensitivity in separated rats as measured by corticosterone changes thus adding to the existing literature reporting early life stress having long-term impact on HPA axis function.

Adrenocorticotropic Hormone↗
PubMed2005

Increased adult hippocampal brain-derived neurotrophic factor and normal levels of neurogenesis in maternal separation rats.

Repeated maternal separation of rat pups during the early postnatal period may affect brain-derived neurotrophic factor (BDNF) or neurons in brain areas that are compromised by chronic stress. In the present study, a highly significant increase in hippocampal BDNF protein concentration was found in adult rats that as neonates had been subjected to 180 min of daily separation compared with handled rats separated for 15 min daily. BDNF protein was unchanged in the frontal cortex and hypothalamus/paraventricular nucleus. Expression of BDNF mRNA in the CA1, CA3, or dentate gyrus of the hippocampus or in the paraventricular hypothalamic nucleus was not affected by maternal separation. All animals displayed similar behavioral patterns in a forced-swim paradigm, which did not affect BDNF protein concentration in the hippocampus or hypothalamus. Repeated administration of bromodeoxyuridine revealed equal numbers of surviving, newly generated granule cells in the dentate gyrus of adult rats from the 15 min or 180 min groups. The age-dependent decline in neurogenesis from 3 months to 7 months of age did not differ between the groups. Insofar as BDNF can stimulate neurogenesis and repair, we propose that the elevated hippocampal protein concentration found in maternally deprived rats might be a compensatory reaction to separation during the neonatal period, maintaining adult neurogenesis at levels equal to those of the handled rats.

Age Factors↗
PubMed2005

Cognitive deficits in obsessive-compulsive disorder on tests of frontal lobe functions.

Individuals with obsessive-compulsive disorder (OCD) display frontal lobe deficits, but there are inconsistencies between various tests of frontal lobe functions and between the results from different studies. The objective of this work was to characterize frontal lobe dysfunctions in OCD patients. Fifteen patients and 17 control subjects matched for age, sex and intelligence were tested on classic tests of frontal lobe functions [Wisconsin Card Sorting Test (WCST) and tests of fluency], a smell identification test and one computerized test: the Intra/Extra Dimension test. The Intra/Extra Dimension test showed a significant difference between the two groups in reversal of response. The test of Figural fluency showed a significant difference between the two groups in numbers of produced figures. There were no differences on the WCST, verbal fluency and the smell identification test.

Adult↗
PubMed2004

Maternal separation affects male rat copulatory behaviour and hypothalamic corticotropin releasing factor in concert.

Maternal separation (MS) is an animal model of early adverse experience, which is known to affect hypothalamic-pituitary-adrenal (HPA) axis function and various aspects of emotional behaviour. Sexual dysfunction is a prominent symptom in depression and in the present study we investigated the effects of maternal separation on copulatory behaviour and partner preference in adult male rats and paced mating in adult female rats. It has been suggested that corticotropin releasing factor (CRF) inhibits copulatory behaviour in male rats and we therefore examined if changes in male sexual behaviour were accompanied by changes in hypothalamic corticotropin releasing factor protein content. We found changed copulatory behaviour reflected in decreased mount latency, intromission latency, and post-ejaculatory interval in rats subjected to 180 min daily separation compared to handled rats, separated for 15 min daily on postnatal days (PNDs) 2-14. Ejaculation latency was not affected and there were no changes in partner preference in male rats. Paced mating behaviour of adult maternally separated female rats was unaffected. The concentration of corticotropin releasing factor-like immunoreactivity was lower in the hypothalamus of male rats separated for 180 min compared to male handled rats. We therefore suggest that 180 min of maternal separation generates a male phenotype with increased sexual motivation possibly due to inadequate levels of corticotropin releasing factor in the hypothalamus.

Animals↗
PubMed2004

Differential roles for neuropeptide Y Y1 and Y5 receptors in anxiety and sedation.

Central administration of neuropeptide Y (NPY) causes both anxiolysis and sedation. Previous studies suggest that both effects are mediated via NPY Y1 receptors. However, most of these studies were carried out before the advent of specific NPY receptor ligands. Therefore, a potential role for other NPY receptors in anxiety and sedation remains a possibility. In the present study, we addressed this issue by testing the effects of intracerebroventricular (i.c.v.) injection of NPY as well as specific receptor agonists for the Y1 receptor ([D-His(26)]NPY), Y2 receptor (C2-NPY), and Y5 receptor ([cPP(1-7),NPY(19-23),Ala(31),Aib(32),Gln(34)]hPP) in the elevated plus maze and open field tests. As with NPY, the Y1 agonist had a dose-dependent anxiolytic-like effect in both behavioral tests. In contrast to NPY, which caused significant sedation in the open field test, the Y1 agonist was without sedative effect. The Y2 agonist showed neither anxiolytic-like nor sedative effects. The Y5 agonist showed anxiolytic-like activity in both behavioral tests and caused sedation in the same dose range as NPY in the open field test. These results indicate that anxiolytic-like effects of i.c.v.-administered NPY in rats are mediated via both Y1 and Y5 receptors, whereas sedation is mediated via Y5 receptors.

Analysis of Variance↗
PubMed2004

Neuropeptide Y Y5 receptors suppress in vitro spontaneous epileptiform bursting in the rat hippocampus.

Neuropeptide Y (NPY) has been implicated in antiepileptic action in different in vivo and in vitro epilepsy models in rats and mice. Both Y2 and Y5 receptors could mediate the seizure-suppressant effect of NPY. However, lack of selective ligands precluded previous studies from conclusively evaluating the role of Y5 receptors in anti-epileptiform action of NPY. In the present study, using the new highly selective Y5 receptor antagonist, CGP71683A, and agonist, [cPP]hPP, we show that the Y5 receptor subtype is centrally involved in NPY-induced suppression of spontaneous epileptiform (interictaform) bursting in the CA3 area of rat hippocampal slices. This novel finding underscores the importance of Y5 receptors as a potential target for future antiepileptic therapy, particularly, for interictal components of temporal lobe epilepsy.

Action Potentials↗