Biomedical subjects

R W Horton

Publications and source records attributed to R W Horton.

At least 19 recordsLinked to original sources

PubMed2000

Altered brain protein kinase C in depression: a post-mortem study.

[(3)H]Phorbol 12,13-dibutyrate (PDBu) binding was measured in soluble and particulate fractions of frontal cortex and hippocampus from suicides, with a firm retrospective diagnosis of depression, and individually matched controls. Suicides were divided into those who had been free of antidepressant drugs for at least 3 months and those in whom prescription of antidepressants was clearly documented. In frontal cortex, there was a significantly higher number (by 75%) of [(3)H]PDBu binding sites in the soluble fraction in antidepressant-free suicides compared to controls; significant differences were also seen in the proportion of sites in the soluble and particulate fractions. Higher numbers of [(3)H]PDBu binding sites in the particulate fraction of hippocampus in antidepressant-free suicides was restricted to those who died by violent means. No significant differences in the number of [(3)H]PDBu binding sites were found in antidepressant-treated suicides compared to controls. This study provides evidence for the involvement of protein kinase C in the pathophysiology of depression.

Antidepressive Agents↗

PubMed1999

The influence of gender and age on neonatal rat hypothalamic 5-HT1A and 5-HT2A receptors.

1. Rat hypothalamic 5-hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) concentrations are transiently sexually differentiated in the second week postpartum (pp), with higher levels in the female. In this report we investigate the possibility that 5-HT receptors may also exhibit sexual dimorphism in the neonatal period. 2. 5-HT1A and 5-HT2A receptors were quantitated by radioligand binding of [3H]ketanserin and [3H]8-OH DPAT, respectively, in hypothalamus and amygdala from male and female rats at days 8-16 pp. 3. There was no sexual dimorphism or change in the density of 5-HT2A binding in hypothalamus or amygdala over days 8-16 pp. There was also no sexual dimorphism of 5-HT1A receptors. 4. There was an increase in 5-HT1A receptor density in both the hypothalamus and the amygdala. In the hypothalamus, but not the amygdala, this increase was interrupted on day 14 by a decrease in 5-HT1A receptors, which we suggest may be of physiological significance in modifying the eventual pattern of adult agonistic activity. 5. The results suggest that the sexual dimorphism in 5-HT turnover is predominantly presynaptic, relating to altered synthesis and/or release, and is not of sufficient magnitude or duration to produce adaptive responses in postsynaptic 5-HT1A or 5-HT2A receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1998

[3H] imipramine binding in brain samples from depressed suicides and controls: 5-HT uptake sites compared with sites defined by desmethylimipramine.

Using desmethylimipramine (DMI) defined and Na+ dependent [3H]imipramine binding, we have examined both 5-HT uptake sites and sites unrelated to 5-HT uptake, in frontal cortex, putamen and substantia nigra of suicides with a firm retrospective diagnosis of depression and matched controls. No differences were seen between antidepressant-free suicides and controls, although [3H]imipramine binding sites were significantly lower in putamen of the subgroup of non-violent suicides. The number of DMI defined [3H]imipramine binding sites was also significantly lower in putamen of antidepressant-treated suicides.

Adolescent↗

PubMed1997

Reduced dopamine turnover in the basal ganglia of depressed suicides.

We have measured the concentrations of dopamine, and the dopamine metabolites homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC), in five brain regions from suicide victims with a firm retrospective diagnosis of depression, and matched controls. The suicides were divided into those free of antidepressant drugs and those in whom prescription of antidepressant drugs was clearly documented. DOPAC concentrations were significantly lower in caudate, putamen and nucleus accumbens of antidepressant-free suicides compared to controls. In antidepressant-treated suicides, lower concentrations of DOPAC were observed in the basal ganglia, reaching statistical significance in caudate. Lower DOPAC concentrations were largely restricted to those suicides who died by non-violent methods. There were no significant differences in dopamine and HVA concentrations in either suicide group compared to controls, although there was a trend for HVA concentrations to be lower in suicides. This study provides evidence for reduced dopamine turnover, as judged from reduced DOPAC levels, in depressed suicides, although we cannot exclude the possibility that this may be due to ingestion of toxic agents.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1997

Brain [3H]cAMP binding sites are unaltered in depressed suicides, but decreased by antidepressants.

Saturation binding of [3H]cAMP to the regulatory subunit of cAMP-dependent protein kinase (PKA) was measured in the soluble fraction of brain samples, obtained at post-mortem, from suicides with a firm retrospective diagnosis of depression and individually matched controls. Suicides were subdivided into those who had been free of antidepressant drugs for at least 3 months and those in whom prescription of antidepressants was clearly documented. In antidepressant-free suicides, we found no significant differences in the number or affinity of [3H]cAMP binding sites in the five regions studied. In antidepressant-treated suicides however, Bmax values were lower in all regions, reaching statistical significance in parietal cortex and amygdala. Kd values for antidepressant-treated suicides were significantly higher in parietal cortex, temporal cortex and amygdala. These results suggest the regulatory subunit of PKA is unaltered in depression, but is influenced by antidepressant drugs.

Adult↗

PubMed1997

Brain alpha-adrenoceptors in depressed suicides.

alpha1-Adrenoceptors and alpha2-adrenoceptors were measured by radioligand binding to homogenates of brain samples obtained at post-mortem from suicides with a retrospective diagnosis of depression, and age and gender-matched controls. Suicides were subdivided into those who had been free of antidepressant drugs for at least three months, and those in whom prescription of antidepressant drugs was clearly documented. The number of alpha1-adrenoceptors (or alpha1A + alpha1D-adrenoceptors) did not differ significantly between antidepressant-free or antidepressant-treated suicides and controls. In antidepressant-free suicides, the number of alpha2-adrenoceptors was significantly higher in temporal cortex (Ba 21/22). alpha2A-Adrenoceptors did not differ significantly from controls in this brain region, suggesting the involvement of other alpha2-adrenoceptor subtypes. In antidepressant-treated suicides, significantly lower numbers of alpha2-adrenoceptors were found in occipital cortex and hippocampus (and for alpha2A-adrenoceptors in caudate and amygdala) compared to controls.

Adolescent↗

PubMed1997

Dopamine D1 and D2 receptor binding sites in brain samples from depressed suicides and controls.

Dopamine D1 and D2 receptors were measured (by saturation binding of [3H]SCH23390 and [3H]raclopride) in caudate, putamen and nucleus accumbens, obtained at post-mortem from suicide victims with a firm retrospective diagnosis of depression, and matched controls. There were no differences in the number or affinity of D1 or D2 receptors between suicides who had been free of antidepressants for at least three months prior to death, and controls. Increased numbers and decreased affinity of D2 receptors were however found in each brain region of antidepressant-treated suicides. We argue that these increases are related to concurrent treatment with neuroleptics rather than a direct effect of antidepressants. Increased numbers of D1 receptors in antidepressant-treated suicides were seen only in nucleus accumbens. This increase could not be clearly attributed to neuroleptics and may be related to antidepressant treatment.

Adolescent↗

PubMed1997

Corticotropin-releasing factor binding sites in cortex of depressed suicides.

Corticotropin-releasing factor (CRF) receptors were measured by saturation binding in frontal and motor cortex of suicides with a firm retrospective diagnosis of depression, and matched controls. The suicides were divided into those who were free of antidepressant drugs, and those in whom prescription of antidepressant drugs was clearly documented. There were no differences in the number or affinity of CRF receptors between antidepressant-free or antidepressant-treated suicides and matched controls in either brain region. When suicides were divided according to violence of death, again there were no differences between violent or non-violent suicides and controls.

Adolescent↗

PubMed1997

5-HT1A receptor binding sites in post-mortem brain samples from depressed suicides and controls.

5-HT1A receptor binding sites were measured, by saturation binding with [3H]8-OH-DPAT, in frontal and occipital cortex, hippocampus and amygdala obtained at post-mortem examination from suicide victims with a firm retrospective diagnosis of depression, and matched controls. The number of 5-HT1A binding sites did not differ significantly between suicides and controls, either in the total sample or when the suicides were divided on the basis of violence of death or recent antidepressant treatment.

Adolescent↗

PubMed1997

Enhanced displacement of [3H]imipramine, but not [3H]paroxetine binding by plasma from depressed patients.

Plasma from healthy subjects inhibited the binding of [3H]imipramine competitively and [3H]paroxetine non-competitively to platelet membranes in a volume-dependent manner. Plasma from 40 depressed patients was more effective at inhibiting [3H]imipramine, but not [3H]paroxetine, binding compared to plasma from matched controls. This difference was not related to recent antidepressant treatment. The results suggest that the concentration of an endogenous modulator of [3H]imipramine binding is increased in depressive illness. The concentration of alpha 1-acid glycoprotein, a proposed endogenous modulator of [3H]imipramine binding, did not differ between depressed patients and controls. Our results suggest that factors other than alpha 1-acid glycoprotein may modulate [3H]imipramine binding.

Adult↗

PubMed1997

Dopamine uptake sites, labelled with [3H]GBR12935, in brain samples from depressed suicides and controls.

We have quantitated dopamine uptake sites, labelled with [3H]GBR12935, in caudate, putamen and nucleus accumbens of suicides with a retrospective diagnosis of depression, and age and gender-matched controls. Suicides were subdivided into those who had been free of antidepressant drugs for at least three months, and those in whom prescription of antidepressant drugs was clearly documented. We found no significant differences between controls and suicides overall, or when the suicides were divided on the basis of antidepressant treatment or violence of death. A significant negative correlation between the number of dopamine uptake sites and age was found in each region studied. Our results suggest dopamine uptake sites are not critically involved in depression or antidepressant drug action.

Adolescent↗

PubMed1997

Species differences in brain adenosine A1 receptor pharmacology revealed by use of xanthine and pyrazolopyridine based antagonists.

1. The pharmacological profile of adenosine A1 receptors in human, guinea-pig, rat and mouse brain membranes was characterized in a radioligand binding assay by use of the receptor selective antagonist, [3H]-8-cyclopentyl-1,3-dipropylxanthine ([3H]-DPCPX). 2. The affinity of [3H]-DPCPX binding sites in rat cortical and hippocampal membranes was similar. Binding site affinity was higher in rat cortical membranes than in membranes prepared from guinea-pig cortex and hippocampus, mouse cortex and human cortex. pKD values (M) were 9.55, 9.44, 8.85, 8.94, 8.67, 9.39 and 8.67, respectively. The binding site density (Bmax) was lower in rat cortical membranes than in guinea-pig or human cortical membranes. 3. The rank order of potency of seven adenosine receptor agonists was identical in each species. With the exception of 5'-N-ethylcarboxamidoadenosine (NECA), agonist affinity was 3.5-26.2 fold higher in rat cortical membranes than in human and guinea-pig brain membranes; affinity in rat and mouse brain membranes was similar. While NECA exhibited 9.3 fold higher affinity in rat compared to human cortical membranes, affinity in other species was comparable. The stable GTP analogue, Gpp(NH)p (100 microM) reduced 2-chloro-N6-cyclopentyladenosine (CCPA) affinity 7-13.9 fold, whereas the affinity of DPCPX was unaffected. 4. The affinity of six xanthine-based adenosine receptor antagonists was 2.2-15.9 fold higher in rat cortical membranes compared with human or guinea-pig membranes. The rank order of potency was species-independent. In contrast, three pyrazolopyridine derivatives, (R)-1-[(E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl) acryloyl]-2-piperidine ethanol (FK453), (R)-1-[(E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl) acryloyl]-piperidin-2-yl acetic acid (FK352) and 6-oxo-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-1(6H)-pyridazinebutyric acid (FK838) exhibited similar affinity in human, guinea-pig, rat and mouse brain membranes. pKi values (M) for [3H]-DPCPX binding sites in human cortical membranes were 9.31, 7.52 and 7.92, respectively. 5. Drug affinity for adenosine A2A receptors was determined in a [3H]-2-[4-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamido ade nosine ([3H]-CGS 21680) binding assay in rat striatal membranes. The pyrazolopyridine derivatives, FK453, FK838 and FK352 exhibited pKi values (M) of 5.90, 5.92 and 4.31, respectively, compared with pKi values of 9.31, 8.18 and 7.57 determined in the [3H]-DPCPX binding assay in rat cortical membranes. These novel pyrazolopyridine derivatives therefore represent high affinity, adenosine A1 receptor selective drugs that, in contrast to xanthine based antagonists, exhibit similar affinity for [3H]-DPCPX binding sites in human, rat, mouse and guinea-pig brain membranes.

Adenosine↗

PubMed1997

5-HT1D and 5-HT1E/1F binding sites in depressed suicides: increased 5-HT1D binding in globus pallidus but not cortex.

5-HT1D and 5-HT1E/1F receptor binding sites were measured in brain samples obtained at postmortem from suicide victims with a firm retrospective diagnosis of depression, and matched controls. In antidepressant-free suicides a significantly higher number of 5-HT1D receptors was found in globus pallidus. This was largely restricted to those suicides who died by violent means. This effect was not observed in antidepressant-treated suicides. No differences or trends in 5-HT1D binding were found in putamen, parietal or frontal cortex, in antidepressant-free or antidepressant-treated suicides. There were no differences in the number of 5-HT1E/1F receptors in any of the regions studied.

Adolescent↗

PubMed1997

Beta-adrenoceptors in human pineal glands are unaltered in depressed suicides.

We have measured beta-adrenoceptor binding in pineal glands obtained at post mortem from suicides with a firm retrospective diagnosis of depression, and from age and gender-matched controls. In both antidepressant-free and antidepressant-treated suicides there were no significant differences in the number or affinity of beta-adrenoceptors compared to controls. Within the total group of subjects we found no variation in beta-adrenoceptor binding in relation to time of death or season of death. There was a significant negative correlation between the number of beta-adrenoceptors and age in controls, but not in suicides. These results suggest that pineal beta-adrenoceptors are not altered either in depression or as a result of antidepressant treatment.

Adolescent↗

PubMed1997

Brain 5-hydroxytryptamine uptake sites labeled with [3H]paroxetine in antidepressant drug-treated depressed suicide victims and controls.

Saturation binding of [3H]paroxetine was performed in 10 brain regions from a group of suicide victims who had a firm, retrospective diagnosis of depression and who had been prescribed antidepressant drugs, as well as in a group of controls. The number of binding sites did not differ significantly between suicide victims and controls, apart from in putamen, where a lower number of sites was found in the suicide victims. Higher dissociation constant (Kd) values were found in suicide victims dying by antidepressant overdose and also in those dying by other means when compared with controls.

Adolescent↗

PubMed1996

Desipramine administration in the olfactory bulbectomized rat: changes in brain beta-adrenoceptor and 5-HT2A binding sites and their relationship to behaviour.

1. The effects of repeated administration of the tricyclic antidepressant drug, desipramine (DMI), on behaviour (locomotor activity and rearing) and the number and affinity of brain beta-adrenoceptor and 5-HT2A receptor binding sites were examined in olfactory bulbectomized (OB) and sham-operated control rats. 2. Locomotor activity and rearing were increased in OB rats compared to sham-operated controls. The effect of various doses of DMI (administered orally twice daily for 21 days) on these behavioural measures was examined. A dose of 7.5 mg kg-1 provided optimal reversal of hyperlocomotion and increased rearing in OB rats, without changing these measures in sham-operated controls. 3. The time course of DMI (7.5 mg kg-1) on behavioural and neurochemical measures was examined. locomotion and rearing in OB rats were not significantly altered after 7 days, were significantly attenuated after 14 days and were normalized after 21 days. 4. After 7 days of DMI administration the number of beta-adrenoceptors was lower in frontal and occipital cortex and hippocampus. This reduction was largely restricted to the beta 1-adrenoceptor subtype. Administration of DMI for 14 or 21 days did not further reduce the number of beta-adrenoceptors. The DMI induced reduction in beta-adrenoceptors did not differ in OB and sham-operated control rats. 5. DMI administration for up to 21 days produced a progressive reduction in the number of 5-HT2A receptors in frontal cortex, without significant alterations in occipital cortex. 6. The time course of the reduction in the number of 5-HT2A receptors was similar to that of the DMI-induced behavioural changes whereas that for the reduction in beta-adrenoceptors was clearly different. 7. The present results suggest that the action of DMI in this animal model is unlikely to be directly related to a reduction in beta-adrenoceptors but may be related to a reduction in frontal cortical 5-HT2A receptors.

Animals↗

PubMed1996

GTP gamma S and forskolin-stimulated adenylyl cyclase activity in post-mortem brain from depressed suicides and controls.

We have measured basal, guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) and forskolin-stimulated adenylyl cyclase activity in samples of frontal and parietal cortex obtained at post-mortem from suicides, with a firm retrospective diagnosis of depression. The suicides were divided into those free of antidepressants and those receiving antidepressants. Each suicide was individually compared to a gender and age-matched control. Although we found no significant differences in adenylyl cyclase activity between controls and either antidepressant-free or antidepressant-treated suicides, there was a trend for lower stimulated adenylyl cyclase activity in suicides.

Adenylyl Cyclases↗

PubMed1994

Brain 5-HT2 receptors in suicide victims: violence of death, depression and effects of antidepressant treatment.

5-HT2 binding sites were quantitated, by saturation binding with [3H]ketanserin, in six brain regions from 73 subjects who died by suicide and 70 sudden death controls. There were no significant differences in the number of 5-HT2 binding sites between suicides and controls in any brain region within the total suicide group or when suicides were divided on the basis of violence of death. Similar results were found when suicides were divided into those with a firm retrospective diagnosis of depression, whether they had been receiving antidepressants or not, and those who were heterogeneous in respect of psychiatric diagnosis and drug treatment. The present findings contrast with previous reports of higher cortical 5-HT2 binding sites in suicides; possible reasons for these differences are discussed.

Adolescent↗