Agneta Ekman

Dopamine D3 receptor antisense influences dopamine synthesis in rat brain

Intracerebroventricular infusion of an all-phosphorothioate antisense oligodeoxynucleotide targeted at the rat dopamine D3 receptor mRNA (10 micrograms h-1, 5 days) resulted in a significant reduction (19%) of the binding of the [D2 + D3] ligand [3H]spiperone in the limbic forebrain, where D3 receptors are relatively abundant, but not in caudate-putamen, where D3 receptors are sparse. In nucleus accumbens antisense treatment also caused an increase in dopamine synthesis; in contrast, antisense administration did not counteract the effect of apomorphine on dopamine formation. No effect of antisense administration on dopamine synthesis was observed in caudate-putamen. The results support the usefulness of the antisense strategy for the study of D3 receptors and suggest that D3 receptors may influence dopamine synthesis.

Central administration of dopamine D3 receptor antisense to rat: effects on locomotion, dopamine release and [3H]spiperone binding

Abstract A 15-mer, all-phosphorothioate-modified antisense oligodeoxynucleotide (ASO) targeted against rat dopamine D3 receptor mRNA (4 µM, 5 days) significantly reduced (28%) the amount of binding sites labelled with [3H]spiperone in monolayer cultured Chinese hamster ovary (CHO) cells transfected with the complementary desoxyribonucleic acid (cDNA) for the rat D3 receptor. In contrast, D3-ASO treatment did not reduce the amount of bound [3H]spiperone in CHO cells transfected with D2 receptor cDNA. Intracerebroventricular infusion of D3-ASO (osmotic minipump, 10 µg/µl/h, 7 days) influenced dopamine receptor density in the limbic forebrain such that the upper part of the dopamine/[3H]spiperone displacement curve – tentatively representing the D3 receptor – was altered significantly. Spontaneous locomotor activity of non-habituated rats was increased significantly in D3-ASO-treated animals; in addition, in vivo microdialysis revealed a moderate increase in dopamine release in the nucleus accumbens in these animals. In all experiments, an oligodeoxynucleotide comprising the same nucleotides as the antisense sequence, but in random order, was used as control. It is concluded that the antisense strategy is useful for investigating the functional role of dopamine D3 receptors and that the dopamine D3 receptor is involved in rat locomotor behaviour.

Heart rate variability in premenstrual dysphoric disorder

Measuring heart rate variability (HRV) is a way to assess the autonomic regulation of the heart. Decreased HRV, indicating reduced parasympathetic tone, has previously been found in depression and anxiety disorders. The objective of this study was to assess HRV in women with premenstrual dysphoric disorder (PMDD). To this end, time domain variables and frequency domain variables were assessed in 28 women with PMDD and in 11 symptom-free controls during both the symptomatic luteal phase and the non-symptomatic follicular phase of the menstrual cycle. Two variables reflecting vagal activity in the time domain, the root mean square of differences of successive normal RR intervals (rMSSD) and standard deviation of normal RR intervals (SDNN) were lower in PMDD patients, but this difference was statistically significant in the follicular phase only. The most important vagal measure in the frequency domain, supine high frequency (HF), also appeared lower in PMDD subjects during the follicular phase. It is suggested that PMDD may be associated with reduced vagal tone compared to controls and that this difference is most apparent in the non-symptomatic follicular phase of the menstrual cycle.

Direct dopamine D2-receptor-mediated modulation of arachidonic acid release in transfected CHO cells without the concomitant administration of a Ca2+-mobilizing agent

In CHO cells transfected with the rat dopamine D2 receptor (long isoform), administration of dopamine per se elicited a concentration‐dependent increase in arachidonic acid (AA) release. The maximal effect was 197% of controls (EC50=25 nM). The partial D2 receptor agonist, (−)‐(3‐hydroxyphenyl)‐N‐n‐propylpiperidine [(−)‐3‐PPP], also induced AA release, but with somewhat lower efficacy (maximal effect: 165%; EC50=91 nM). The AA‐releasing effect of dopamine was counteracted by pertussis toxin, by the inhibitor of intracellular Ca2+ release, 8‐(N N‐diethylamino)octyl‐3,4,5‐trimethoxybenzoate (TMB‐8), by excluding calcium from the medium, by the phospholipase A2 (PLA2) inhibitor, quinacrine, and by long‐term pretreatment with the phorbol ester, 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA). In addition, it was antagonized by the D2 antagonists, raclopride and (−)‐sulpiride–but not by (+)‐sulpiride–and absent in sham‐transfected CHO cells devoid of D2 receptors. The results obtained contrast to the previous notion that dopamine and other D2 receptor agonists require the concomitant administration of calcium‐mobilizing agents such as ATP, ionophore A‐23187 (calcimycin), thrombin, and TRH, to influence AA release from various cell lines.

Inverse agonism at dopamine D2 receptors : Haloperidol-induced prolactin release from GH4C1 cells transfected with the human D2 receptor is antagonized by R(-)-n-propylnorapomorphine, raclopride, and phenoxybenzamine

Our earlier observation that the antipsychotic drug haloperidol in the absence of dopamine increases cAMP formation and prolactin release in two prolactin-producing cell lines expressing rat dopamine D2 receptors (GH3, GH4ZR7), but not in similar cells devoid of D2 receptors (GH4C1), prompted us to suggest that haloperidol may act as an inverse (or negative) agonist, rather than as a neutral antagonist, at the D2 receptor (Nilsson and Eriksson 1993). In the present study it is shown that haloperidol elicits a dose-dependent increase in prolactin release also in prolactin-producing GH4C1 cells transfected with the human dopamine D2 receptor (short isoform) (GH4C1-hD2s); in addition, it is shown that another antipsychotic drug, flupenthixol, also causes prolactin release per se in this cell line. The effect of haloperidol on prolactin release in GH4C1-hD2s is calcium dependent and counteracted by pretreatment either with the D2 receptor agonist R(−)-n-propylnorapomorphine or with a D2 receptor antagonist that does not affect prolactin release per se (raclopride). In addition, pretreatment with the alkylating compound phenoxybenzamine at a concentration causing a marked reduction of D2 receptor density in GH4C1-hD2s cells significantly counteracted haloperidol-induced prolactin release.

The ser9gly SNP in the dopamine D3 receptor causes a shift from cAMP related to PGE2 related signal transduction mechanisms in transfected CHO cells

The dopamine D3 receptor is a member of the D2 family of dopamine receptors. Several investigators have suggested that D3 receptors are involved in the regulation of locomotion,1 in the pathophysiology of schizophrenia,2 and in drug abuse.3 Dopamine enhances basal and stimulus evoked release of arachidonic acid, as well as the production of one of its metabolites, prostaglandin E2 (PGE2), in CHO (Chinese hamster ovary) cells transfected with the D2 receptor.4–6 In contrast, dopamine does not influence basal arachidonic acid release7–9 but inhibits stimulus evoked release in cells transfected with the rat D3 receptor.10 On the other hand, with respect to cAMP production, the effect of dopamine is similar in CHO cells transfected with either D2 or D3 receptors, both receptor subtypes mediating a reduction in forskolin induced cAMP formation.11,12 A single nucleotide polymorphism (SNP) in the first exon of the dopamine D3 receptor gene, the ser9gly polymorphism, leads to a serine to glycine amino acid substitution in the N -terminal extracellular domain of the receptor protein.13 An association between this polymorphism and schizophrenia has been suggested, but also questioned,14,15 a meta-analysis suggesting the effect to be small but real in white subjects.16 Other investigators have suggested that the gly-9 allele may be associated with an increased risk of developing antipsychotic induced tardive dyskinesia rather than with schizophrenia per se17; this finding also gained support from a report containing both pooled analyses of original data and a meta-analysis,18 and also from a recent primate study19 (see also a recent report by Lohmueller and coworkers20). In addition, the ser9gly polymorphism has been reported to be associated with therapeutic response to atypical antipsychotic agents, …

Escitalopram Administered in the Luteal Phase Exerts a Marked and Dose-Dependent Effect in Premenstrual Dysphoric Disorder

This is the first placebo-controlled trial evaluating the efficacy of the selective serotonin reuptake inhibitor (SSRI), escitalopram, in the treatment of premenstrual dysphoric disorder (PMDD). Women with PMDD (intention-to-treat population, n = 151) were treated intermittently for 3 months, during luteal phases only, with 10 mg/d escitalopram, 20 mg/d escitalopram, or placebo. Escitalopram was found to exert a marked and a dose-dependent symptom-reducing effect, 20 mg/d being clearly superior to 10 mg/d. Although the primary outcome parameter, that is, the sum of the symptoms irritability, depressed mood, tension, and affective lability, was decreased by 90% with 20 mg/d escitalopram, the effect of active treatment on breast tenderness, food craving, and lack of energy was more modest and not significantly different from that of placebo; this outcome supports our previous assumption that the former symptoms are more inclined to respond to intermittent administration of an SSRI than are the latter. Although the placebo response was high, the difference between the placebo group and the 20-mg/d escitalopram group with respect to the percentage of subjects displaying 80% or greater reduction in the rating of the cardinal symptom of PMDD, that is, irritability, was considerable: 30% versus 80%. Adverse events were those normally reported in SSRI trials, such as nausea and reduced libido, and were not more common in patients given 20 mg/d of escitalopram than in patients given the lower dose. This study supports the usefulness of escitalopram for the treatment of PMDD and sheds further light on how different components of this syndrome are differently influenced by intermittent administration of an SSRI.

Interleukin-6 Gene Polymorphism −174G/C Influences Plasma Lipid Levels in Women

Elevated levels of the pro‐inflammatory cytokine interleukin‐6 (IL‐6) have been associated with cardiovascular risk factors. The objective of this study was to investigate potential associations between the promoter polymorphism IL‐6 −174G/C and the following indices of metabolism: BMI, waist‐to‐hip ratio, and plasma levels of IL‐6, cholesterol, low‐density lipoprotein, triglycerides, high‐density lipoprotein, leptin, and C‐reactive protein in 252 42‐year‐old women and 245 51‐year‐old men. Subgroups were also studied 5 years later. The CC genotype of the IL‐6 polymorphism was associated with lower levels of cholesterol and low‐density lipoprotein (p < 0.001) in women. This finding was replicated in the follow‐up, when a significant association between the CC genotype and low triglycerides was also observed. The association between the C allele and lipid pattern found in women was not found in men, where on the contrary, C carriers tended to display elevated triglycerides. IL‐6 genotype was not associated with IL‐6 plasma levels in either sample. The results suggest different effects of the IL‐6 polymorphism on metabolic indices in women and men. None of the associations between IL‐6 genotype and lipid pattern seemed to result from an effect of the polymorphism on IL‐6 plasma levels.

Low IL-8 is associated with anxiety in suicidal patients: genetic variation and decreased protein levels.

Recent studies indicate that inflammation may play a role in the pathophysiology of suicidality. Interleukin‐8 (IL‐8) is a chemokine that in addition to its function in the immune system also exert neuroprotective properties. The involvement of this chemokine in neuropsychiatric conditions is incompletely known.

Association between serum levels of C-reactive protein and personality traits in women

BackgroundWhile low-grade inflammation has consistently been observed in subjects with depression, studies on the possible relationship between inflammation and other aspects of brain function are as yet sparse. In this study, we aimed to investigate the possible association between serum levels of the inflammation marker C-reactive protein (CRP) and personality traits.MethodsIn this study, serum levels of high-sensitivity CRP were determined by ELISA in a population of 270 42-year-old women recruited from the population registry who had been assessed using the Temperament and Character Inventory. Self-reported previous or ongoing depression was also recorded. Unpaired two-tailed t-tests were used for comparison between two groups and correlations were evaluated by the calculation of Pearsons r-coefficient.ResultsThe temperament trait harm avoidance was positively (r = 0.227, p < 0.05) and the character trait self-directedness was negatively (r = -0.261, p < 0.01) associated with serum levels of CRP (p-values corrected for multiple comparisons). The correlations between the personality traits and CRP were observed also after exclusion of subjects reporting ongoing depression (n = 26). Whereas women reporting ongoing depression showed significantly increased levels of CRP as compared to non-depressed women (n = 155), women reporting a history of depression displayed no significant difference in CRP levels as compared to women that reported that they had never been depressed.ConclusionSerum levels of CRP in women was found to be associated with the personality traits harm avoidance and self-directedness. In addition, moderately elevated levels may be a state dependent marker of depression.