4.5 Article

Medroxyprogesterone acetate positively modulates specific GABAA-receptor subtypes-affecting memory and cognition

Journal

PSYCHONEUROENDOCRINOLOGY
Volume 141, Issue -, Pages -

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.psyneuen.2022.105754

Keywords

Medroxyprogesterone-acetate; GABA-A receptor; Alpha5 GABA-A receptor; Neurosteroids; Dementia; Positive GABA-AR modulator

Funding

  1. Umecrine AB, Umecrine Cognition AB [721802]
  2. Ume-crine Cognition AB
  3. EU-grant
  4. H2020 project [721802]
  5. Umea University Medical Faculty (Karin and Harald Silvander fund)

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MPA acts as a positive modulator of specific GABAA receptor subtypes and increases responses to GABA in single cells from the hypothalamic area, indicating its potential role in cognitive processes and neural modulation.
Medroxyprogesterone acetate (MPA) is a progestin widely used in humans as hormone replacement therapy and at other indications. Many progestin metabolites, as the progesterone metabolite allopregnanolone, have GABAAreceptor modulatory effects and are known to affect memory, learning, appetite, and mood. In women, 4 years chronic treatment with MPA doubles the frequency of dementia and in rats, MPA causes cognitive impairment related to the GABAergic system. Activation of the membrane bound GABAA receptor results in a chloride ion flux that can be studied by whole-cell patch-clamp electrophysiological recordings. The purpose of this study was to clarify the modulatory effects of MPA and specific MPA metabolites, with structures like known GABAA-receptor modulators, on different GABAA-receptor subtypes. An additional aim was to verify the results as steroid effects on GABA response in single cells taken from rat hypothalamus. HEK-293 cell-lines permanently expressing the recombinant human GABAA-receptor subtype alpha 1 beta 2 gamma 2L or alpha 5 beta 3 gamma 2L or alpha 2 beta 3 gamma 2S were created. The MPA metabolites 3 alpha 5 alpha-MPA,3 beta 5 alpha-MPA and 3 beta 5 beta-MPA were synthesised and purified for electrophysiological patchclamp measurements with a Dynaflow system. The effects of MPA and tetrahydrodeoxycorticosterone were also studied. None of the studied MPA metabolites affected the responses mediated by alpha 1 beta 2 gamma 2L or alpha 5 beta 3 gamma 2L GABAA receptors. Contrary, MPA clearly acted both as a positive modulator and as a direct activator of the alpha 5 beta 3 gamma 2L and alpha 2 beta 3 gamma 2S GABAA receptors. However, in concentrations up to 10 mu M, MPA was inactive at the alpha 1 beta 2 gamma 2L GABAA receptor. In the patch-clamp recordings from dissociated cells of the preoptic area in rats, MPA increased the amplitude of responses to GABA. In addition, MPA alone without added GABA, evoked a current response. In conclusion, MPA acts as a positive modulator of specific GABAA receptor subtypes expressed in HEK cells and at native GABA receptors in single cells from the hypothalamic preoptic area.

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