Synergistic effects of dehydroepiandrosterone and fluoxetine on proliferation of progenitor cells in the dentate gyrus of the adult male rat.

The 5-HT re-uptake inhibitor (SSRI) fluoxetine and the adrenal hormone dehydroepiandrosterone (DHEA) both increase the proliferation of progenitor cells in the adult hippocampus and also have antidepressant activity. This paper explores the combined ability of fluoxetine and DHEA to affect this process in the dentate gyrus of adult rats. We show that DHEA can render an otherwise ineffective dose of fluoxetine (2.5 mg/kg) able to increase progenitor cell proliferation to the same extent as doses four times higher (10 mg/kg). This synergistic action does not appear to be mediated by alterations in brain-derived neurotrophic factor (BDNF) gene expression; or by TrkB, mineralocorticoid, glucocorticoid, or 5-HT (5HT1A) receptor expression in the dentate gyrus; or by altered levels of plasma corticosterone. In a second experiment, the synergism between DHEA and fluoxetine was replicated. Furthermore, flattening the diurnal rhythm of plasma corticosterone by implanting additional corticosterone pellets s.c. prevented the effect of fluoxetine on progenitor cell division. This was not overcome by simultaneous treatment with DHEA, despite the latter's reported anti-glucocorticoid actions. The cellular mechanism for the potentiating action of DHEA on the pro- proliferative effects of fluoxetine in the adult hippocampus remains to be revealed. Since altered neurogenesis has been linked to the onset or recovery from depression, one consequence of these results is to suggest DHEA as a useful adjunct therapy for depression.

Hand tapping: a simple, reproducible, objective marker of motor dysfunction in Huntington's disease.

Huntington's disease (HD) is a severe neurodegenerative condition in which the impairment in voluntary movement is related to functional disability. Clinical assessment of motor deficit currently relies largely on subjective rating scales without objective measurement. We have developed a quick and easy-to-use hand tapping device that enables measurement of (a) the number of taps in 30 seconds, (b) variability in tapping rhythm and (c) fatigue over the testing period. Initial cross-sectional testing of 178 consecutive HD clinic patients using an early model of the device showed that the total number of taps in 30 seconds correlated with the motor UHDRS (Spearmann's rho, r(s) = -0.81, p < 0.0001) and independence scores (r(s) = 0.78, p = 0.01). Longitudinal data from a small cohort followed over 10 years reveals a correlation between total number of taps in 30 seconds and motor UHDRS over time (rs = -0.49, p < 0.001), and suggests the technique may provide an objective measure of disease progression. Further tests on 15 HD patients and 9 controls were repeated three times in a single day using an updated device. The HD group made significantly fewer taps in 30 seconds (median HD = 79, control = 104, p = 0.009) and had greater variability of inter-tap interval (mean interdecile range HD = 148, control = 56, p = 0.016) compared to controls. Both the total number of taps and variability of inter-tap interval correlated with motor UHDRS. Of vital importance for any potential marker of disease progression is that these tapping parameters were reproducible with repeated measurement. Given that hand tapping parameters differ between HD and control populations, they correlate with motor UHDRS over time and are reproducible, we propose that assessment of hand tapping represents a useful objective adjunct to the clinical assessment of HD patients.