Peter Fitzgerald

Prolactin and dopamine: What is the connection? A Review Article:

Dopamine (DA) holds a predominant role in the regulation of prolactin (PRL) secretion. Through a direct effect on anterior pituitary lactotrophs, DA inhibits the basally high-secretory tone of the cell. It accomplishes this by binding to D2 receptors expressed on the cell membrane of the lactotroph, activation of which results in a reduction of PRL exocytosis and gene expression by a variety of intracellular signalling mechanisms. The hypothalamic dopaminergic neurons, which provide DA to the anterior pituitary gland, are themselves regulated by feedback from PRL through a short-loop feedback mechanism . A variety of other modulators of prolactin secretion act at the hypothalamic level by either disinhibition of the dopaminergic tone (e.g. serotonin, GABA, oestrogens and opioids) or by reinforcing it (e.g. substance P). All typical antipsychotic medications are associated with sustained hyperprolactinaemia due to their high affinity for the D2 receptor and their slow dissociation from the receptor once bound, but atypicals differ quite dramatically in their propensity to cause prolonged high prolactin levels. Of those atypicals that are associated with prolactin elevation, the main causative factor appears to be a higher peripheral-to-central dopamine receptor potency of either the parent drug or its active metabolite (e.g. risperidone, 9-hydroxy-risperidone and amisulpride). Antipsychotics that easily cross the blood—brain barrier and exhibit fast dissociation from the dopamine receptor once bound do not result in sustained hyperprolactinaemia.

Tryptophan degradation in irritable bowel syndrome: evidence of indoleamine 2,3-dioxygenase activation in a male cohort

BackgroundIrritable bowel syndrome (IBS) is a common disorder that affects 10–15% of the population. Although characterised by a lack of reliable biological markers, the disease state is increasingly viewed as a disorder of the brain-gut axis. In particular, accumulating evidence points to the involvement of both the central and peripheral serotonergic systems in disease symptomatology. Furthermore, altered tryptophan metabolism and indoleamine 2,3-dioxygenase (IDO) activity are hallmarks of many stress-related disorders. The kynurenine pathway of tryptophan degradation may serve to link these findings to the low level immune activation recently described in IBS. In this study, we investigated tryptophan degradation in a male IBS cohort (n = 10) and control subjects (n = 26).MethodsPlasma samples were obtained from patients and healthy controls. Tryptophan and its metabolites were measured by high performance liquid chromatography (HPLC) and neopterin, a sensitive marker of immune activation, was measured using a commercially available ELISA assay.ResultsBoth kynurenine levels and the kynurenine:tryptophan ratio were significantly increased in the IBS cohort compared with healthy controls. Neopterin was also increased in the IBS subjects and the concentration of the neuroprotective metabolite kynurenic acid was decreased, as was the kynurenic acid:kynurenine ratio.ConclusionThese findings suggest that the activity of IDO, the immunoresponsive enzyme which is responsible for the degradation of tryptophan along this pathway, is enhanced in IBS patients relative to controls. This study provides novel evidence for an immune-mediated degradation of tryptophan in a male IBS population and identifies the kynurenine pathway as a potential source of biomarkers in this debilitating condition.

Impact of gender and menstrual cycle phase on plasma cytokine concentrations.

Objective: The lifetime prevalence of major depression is twice as high in females as in males. Depression is known to increase at periods where there are changes in gonadal hormones. We examined pro- and anti-inflammatory cytokine levels during the normal menstrual cycle of healthy females compared to similar time points in healthy males. Methods: Plasma concentrations of interleukin (IL)-4, IL-6, IL-8, IL-10, tumour necrosis factor-α (TNF-α) and soluble IL-6 receptor (sIL-6R) were measured with enzyme-linked immunosorbent assays in healthy females during the normal ovulatory menstrual cycle and also in males at similar time points. Results: The luteal phase of the menstrual cycle is associated with increased production of sIL-6R, IL-4 and TNF-α compared to the early follicular phase. No change was observed in IL-6, IL-8 and IL-10 concentration throughout the menstrual cycle. We found IL-4 positively correlated with oestrogen while TNF-α positively correlated with progesterone. Females were found to have significantly higher concentrations of TNF-α and sIL-6R across all phases of the menstrual cycle, compared to males across similar time points. Conclusion: The normal menstrual cycle is associated with increased production of sIL-6R, IL-4 and TNF-α in the luteal phase compared to the early follicular phase. Females have significantly higher concentrations of sIL-6R and TNF-α at all time points across the menstrual cycle than males.

Cutaneous glucocorticoid receptor sensitivity and pro-inflammatory cytokine levels in antidepressant-resistant depression

BACKGROUND There is evidence to indicate that peripheral glucocorticoid receptor (GR) function is reduced in major depression, and a possible molecular explanation for this is the impact of raised pro-inflammatory cytokines. The topical steroid vasoconstriction assay provides a convenient probe of peripheral GR function. The present study sought to assess the sensitivity of peripheral GRs in antidepressant-resistant major depressives and investigate the association between GR sensitivity and circulating plasma cytokines. METHOD Nineteen antidepressant-resistant depressives together with age- and sex-matched healthy controls underwent the steroid vasoconstriction assay using three commercial preparations of corticosteroids containing clobetasol propionate 0.05%, betamethasone valerate 0.1%, and clobetasone butyrate 0.05%, corresponding to very potent, potent, and moderately potent steroid creams respectively. The pro-inflammatory cytokines, tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were measured using enzyme-linked immunosorbent assays. The severity of the depressive episode was assessed using the Hamilton Depression Scale (HAMD). RESULTS Depressed subjects had a significantly reduced vasoconstriction response across all three strengths of steroid. They also had significantly higher concentrations of TNF-alpha and IL-6. There was a significant inverse correlation between TNF-alpha concentration and vasoconstriction response and also between the HAMD score and vasoconstriction response. CONCLUSIONS These findings suggest that cutaneous GR function is abnormal in antidepressant-resistant depression, that circulating TNF-alpha may play a significant role in this abnormality and that the efficacy of topical steroids in antidepressant-resistant depressives is reduced.

Marked elevations in pro-inflammatory polyunsaturated fatty acid metabolites in females with irritable bowel syndrome

Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder referred to gastroenterologists. Although the pathophysiology remains unclear, accumulating evidence points to the presence of low-level immune activation both in the gut and systemically. Circulating polyunsaturated fatty acids (PUFA) have recently attracted attention as being altered in a variety of disease states. Arachidonic acid (AA), in particular, has been implicated in the development of a pro-inflammatory profile in a number of immune-related disorders. AA is the precursor of a number of important immunomodulatory eicosanoids, including prostaglandin E2 (PGE2) and leukotriene B4 (LTB4). We investigated the hypothesis that elevated plasma AA concentrations in plasma contribute to the proposed pro-inflammatory profile in IBS. Plasma AA and related PUFA were quantified by gas chromatography analysis in IBS patients and controls. Both PGE2 and LTB4 were measured in serum using commercially available ELISA assays. AA concentrations were elevated in our patient cohort compared with healthy controls. Moreover, we demonstrated that this disturbance in plasma AA concentrations leads to downstream elevations in eicosanoids. Together, our data identifies a novel proinflammatory mechanism in irritable bowel syndrome and also suggests that elevated arachidonic acid levels in plasma may serve as putative biological markers in this condition.

Hyperprolactinaemia Associated with Antipsychotic Medications

Hyperprolactinaemia is now recognised as one of the most common adverse effects of antipsychotic medications. It is a potentially serious adverse outcome associated with significant morbidity, but can