Per Allard

Age-correlated loss of dopamine uptake sites labeled with [3H]GBR-12935 in human putamen

The effects of age (19-100 years) upon dopamine uptake sites labeled with [3H]GBR-12935 in human postmortem putamen from 20 individuals were studied. There was a 70% decrease in binding density (Bmax) over the adult age range. No significant changes in binding affinity (Kd) were detected, the mean Kd being 1.0 +/- 0.2 nM (mean +/- S.E.M.). Nor were there any changes in binding related to the postmortem delay. Based on the findings that [3H]GBR-12935 labels the uptake site for dopamine, it is suggested that the age-related loss of [3H]GBR-12935 binding in human putamen reflects a degeneration of dopamine neurites.

Unaltered [3H]GBR-12935 binding after chronic treatment with dopamine active drugs.

Rats were injected intraperitoneally with haloperidol 0.5 mg/kg, raclopride 1 mg/kg, bromocriptine 2.5 mg/kg,d-amphetamine 2.5 mg/kg, or cocaine 10 mg/kg twice daily for 21 days. The animals were sacrificed 72 h after last injection. Control rats were injected with saline, following the same schedule. The radioligand [3H]GBR-12935 was used as a presynaptic marker for dopamine neurites. There were no significant differences in [3H]GBR-12935 binding to striatum between drug-treated rats and controls.

Loss of Dopamine Uptake Sites Labeled with [3H]GBR-12935 in Alzheimer’s Disease

The binding of the dopamine uptake inhibitor [3H]GBR-12935 to postmortem putamen from a control group and patients with Alzheimers disease/senile dementia of Alzheimer type (AD/SDAT) or vascular dementia (VD) was studied. The binding density (Bmax) in AD/SDAT was significantly reduced to 50% of control. A reduction of Bmax in VD was also noted, but it did not reach statistical significance. No differences in apparent binding affinity (Kd) between controls and dementia groups were obtained. The concentrations of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT) and homovanillic acid were also determined. The concentrations of DA and DOPAC were reduced by 30-40% in AD/SDAT and VD, but the reductions did not reach statistical significance. The concentration of 3-MT was reduced by 40% in AD/SDAT and by 30% in VD. The [3H]GBR-12935-binding densities correlated significantly with corresponding concentrations of DA in control brains. It is suggested that the loss of [3H]GBR-12935-binding sites in human putamen in AD/SDAT reflects a degeneration of dopamine neurites.

Influence of menstrual cycle on platelet serotonin uptake site and serotonin2A receptor binding

Depression and anxiety are common health problems affecting women, particularly during the reproductive years. Major depression is two to three times as common in women than in men. Neuroendocrine factors are likely to contribute to this overall increased risk for developing mood disorders in women, and the neuroendocrine influence is most obviously seen in women with premenstrual dysphoric disorder (PMDD) as these women experience depressed mood and anxiety premenstrually only during ovulatory cycles. Moreover, dysfunction of serotonergic transmission has been regarded as an important mechanism in several psychiatric disorders and ovarian steroids have been shown to profoundly influence the activity of the serotonergic system. Given these facts, the purpose of this study was to examine whether binding of [3H]paroxetine to the platelet serotonin transporter or binding of [3H]lysergic acid diethylamide ([3H]LSD) to the platelet 5-HT2A receptor are influenced by the cyclical changes in circulating estradiol and progesterone that occur during the menstrual cycle. We examined 28 healthy women, without oral contraceptives and with regular menstrual cycles. In the late follicular phase, Bmax for [3H]paroxetine binding was significantly higher than in the ovulatory (p<0.01), early luteal phase (p<0.05) and mid-luteal phase (p<0.01). Bmax for [3H]LSD binding was significantly higher in the early follicular phase and the early luteal phase compared to the mid-luteal phase (p<0.001 and p<0.05, respectively). In the early follicular phase and the ovulatory phase, significant correlations between estradiol serum concentrations and Kd for [3H]paroxetine were obtained (p<0.001, respectively). In the luteal phase, significant inverse correlations between progesterone as well as estradiol serum concentrations and Kd for [3H]LSD binding were found (p<0.05, respectively).

Gender differences in depression among the very old.

OBJECTIVES The aim of this study was to investigate factors associated with depression among men and women aged 85 and over. METHOD A population-based study was undertaken in northern Sweden. Out of 527 eligible participants, aged 85, 90 or > or = 95, 363 were evaluated for depression. Data were collected from structured interviews, assessments and medical charts and from relatives and caregivers. Depression was screened for using the Geriatric Depression Scale-15 and further assessed using the Montgomerysberg Depression Rating Scale (MADRS). RESULTS A higher proportion of women were diagnosed with depression (33% vs. 18.6%, p = 0.006). In both men and women experienced loneliness (OR 3.4 vs. 7.0) and not going outside independently (OR 2.6 vs. 26.0) were associated with depression in the final regression model. Depression among men was also independently associated with loss of a child/children during the preceeding ten years (OR 30.0). CONCLUSION Depression was more common among women than among men. Experienced loneliness and not going outside independently seem to be closely related to depression in both men and women. Loss of a child seems to be the most important factor among men.

Dopamine uptake sites in Parkinson's disease and in dementia of the Alzheimer type

The binding of [3H]GBR-12935 to dopamine (DA) uptake sites was studied in post-mortem putamen from a control group and from patients with Parkinsons disease (PD) or dementia of the Alzheimer type (DAT). The specific binding (Bmax) was almost completely abolished in the PD group and reduced by 65% in the DAT group. There were no significant differences in apparent binding affinity (Kd) between the DAT group and controls. The decreases in [3H]GBR-12935 binding to DA uptake sites in this study indicate a marked degeneration of DA neurites in the putamen in PD and also in DAT.

[3H]GBR-12935 binding to cytochrome P450 in the human brain.

Abstract: The presence of multiple [3H] GBR‐12935 binding sites in the human brain has been revealed in several recent studies. One site represents the dopamine uptake site. In rat brain it was demonstrated that [3H] GBR‐12935 also binds to nondopaminergic “piperazine acceptor sites.” One of these sites has been identified as cytochrome P450IID1 in canine brain. [3H] GBR‐12935 binding to the piperazine acceptor sites in the human brain was investigated in the present study. A pharmacological definition of the piperazine acceptor sites is presented: the [3H]‐ GBR‐12935 binding fraction that could be discriminated by 10 μM GBR‐12909 in the presence of 0.3 μM mazindol. This binding fraction was saturable, with binding affinity in the range of 3–8 nM. It was also demonstrated that the piperazine acceptor or cytochrome P450‐sensitive drugs cis‐flupentixol and proadifen (SKF 525 A) compete for the same binding sites, suggesting the cytochrome P450 nature of the binding. The findings presented support the proposal that at least part of this fraction represents cytochrome P450IID6, the human form of P450IID1. The distribution of [3H] GBR‐12935 binding to the suggested P450IID6‐site in 12 brain regions was examined, without significant differences in binding densities between the regions. The significance of the present findings on the cytochrome P450 system in brain is discussed.

Circannual variations in the binding of [3H]lysergic acid diethylamide to serotonin2A receptors and of [3H]paroxetine to serotonin uptake sites in platelets from healthy volunteers.

BACKGROUND Circannual variations occur in several serotonergic parameters, including platelet serotonin uptake and platelet [3H]imipramine binding. METHODS Binding of [3H]lysergic acid diethylamide ([3H]LSD) to platelet serotonin (5-HT)2A receptors and binding of [3H]paroxetine to platelet serotonin uptake sites were studied longitudinally for 1 year in 12 healthy volunteers. RESULTS For [3H]LSD, the number of binding sites (Bmax) showed no significant seasonal variation (two-way analysis of variance), although Bmax was significantly higher during the months October through February than during the months April through August (32.6 vs. 29.8 fmol/mg protein; p = .015). For [3H]paroxetine, Bmax showed a significant seasonal variation (p = .003) with maximum in August (1322 fmol/mg protein) and minimum in February (1168 fmol/mg protein). The affinity constant (Kd) showed a significant seasonal variation for [3H]LSD binding (p = .046), but not for [3H]paroxetine binding. The seasonal fluctuations in [3H]LSD binding and in paroxetine binding tended to be inversely correlated for Bmax (r = -.70; p = .08) and were significantly negatively correlated for Kd (r = -.88; p = .009). CONCLUSIONS The present study demonstrates a seasonal effect on platelet serotonin uptake site binding and indicates a possible seasonal effect on 5-HT2A receptor binding. The results imply that circannual fluctuations should be taken into account when these platelet serotonin markers are studied.

Depression in the oldest old in urban and rural municipalities

Introduction: The aim was to compare an urban and a rural old population regarding depression. Method: A population-based, cross-sectional study in five depopulated areas and one expanding urban city in northern Sweden. Participants aged 85 and above were evaluated for depression. Data were collected from structured interviews and assessments and from relatives, caregivers and medical charts. Depression was screened for using the Geriatric Depression Scale-15 (GDS-15) and evaluated by the Montgomery-Åsberg Depression Rating Scale (MADRS). Results: In total, 29% of the 363 participants were depressed (34% in the rural municipality and 27% in the urban municipality). Fifty-one percent versus 69% were receiving treatment with antidepressants. In the rural areas, those with depression were less frequently treated with selective serotonin reuptake inhibitor (SSRI) medications (36% versus 65%; p = 0.004), instead there were participants treated with Tri Cyclic Antidepressants (TCAs) (10%, versus 0%; p = 0.0018). A larger proportion of the participants in the urban sample had responded to treatment (59% versus 27%; p = 0.175). Conclusion: Depression in old age appears to be a common cause of emotional suffering among the oldest old. In the rural areas, depression was more often inadequately treated and it was also treated with inappropriate medications.

Caudate nucleus dopamine D(2) receptors in depressed suicide victims

Several lines of evidence indicate the involvement of the dopamine system in depressive states. In this post-mortem study, the binding of [3H]raclopride to dopamine D2 receptors in the caudate nucleus was investigated in 13 depressed suicide victims and 19 controls. There were no differences in Bmax or Kd between the two groups. A subgroup consisting of individuals with major depression, however, had significantly higher Kd values than controls. Previous findings regarding changes in dopamine metabolism in depression and antidepressant effects of dopamine agonists seem, according to the present study, not to be reflected by alterations in density or affinity of dopamine D2 receptors in depressed suicide victims.