title: Elevation of brain allopregnanolone rather than 5-HT release by short term, low dose fluoxetine treatment prevents the estrous cycle-linked increase in stress sensitivity in female rats.
abstract: Withdrawal from long-term dosing with exogenous progesterone precipitates increased anxiety-linked changes in behavior in animal models due to the abrupt decrease in brain concentration of allopregnanolone (ALLO), a neuroactive metabolite of progesterone. We show that a withdrawal-like effect also occurs during the late diestrus phase (LD) of the natural ovarian cycle in rats, when plasma progesterone and ALLO are declining but estrogen secretion maintains a stable low level. This effect at LD was prevented by short-term treatment with low dose fluoxetine. During LD, but not at other stages of the estrous cycle, exposure to anxiogenic stress induced by whole body vibration at 4 Hz for 5 min evoked a significant decrease in tail flick latency (stress-induced hyperalgesia) and a decrease in the number of Fos-positive neurons present in the periaqueductal gray (PAG). The threshold to evoke fear-like behaviors in response to electrical stimulation of the dorsal PAG was lower in the LD phase, indicating an increase in the intrinsic excitability of the PAG circuitry. All these effects were blocked by short-term administration of fluoxetine (2 × 1.75 mg kg(-1) i.p.) during LD. This dosage increased the whole brain concentration of ALLO, as determined using gas chromatography-mass spectrometry, but was without effect on the extracellular concentration of 5-HT in the dorsal PAG, as measured by microdialysis. We suggest that fluoxetine-induced rise in brain ALLO concentration during LD offsets the sharp physiological decline, thus removing the trigger for the development of anxiogenic withdrawal effects.
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Devall
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK; Laboratório de Psicobiologia, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo (USP), 14040-901 Ribeirão Preto, SP, Brazil; Instituto de Neurociências e Comportamento-INeC, Campus USP, 14040-901 Ribeirão Preto, SP, Brazil.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Santos
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, London W1E 6BT, UK.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Fry
authors.affiliation: University College London Hospital, London NW1 2BU, UK.
authors.forename: John W
authors.initials: JW
authors.lastname: Honour
authors.affiliation: Laboratório de Psicobiologia, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo (USP), 14040-901 Ribeirão Preto, SP, Brazil; Instituto de Neurociências e Comportamento-INeC, Campus USP, 14040-901 Ribeirão Preto, SP, Brazil.
authors.forename: Marcus L
authors.initials: ML
authors.lastname: Brandão
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, UK; Instituto de Neurociências e Comportamento-INeC, Campus USP, 14040-901 Ribeirão Preto, SP, Brazil. Electronic address: thelma.lovick@bristol.ac.uk.
authors.forename: Thelma A
authors.initials: TA
authors.lastname: Lovick
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage*; D029681:Arabidopsis Proteins; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001923:Brain Chemistry; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000009:adverse effects; D004924:Escape Reaction / Q000187:drug effects; D030762:Estrous Cycle; D005260:Female; D005473:Fluoxetine / Q000008:administration & dosage*; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects; D006930:Hyperalgesia / Q000209:etiology; D009687:Nuclear Proteins; D010487:Periaqueductal Gray / Q000502:physiology; D011280:Pregnanolone / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D013315:Stress, Psychological / Q000150:complications / Q000209:etiology / Q000517:prevention & control*
chemical_list: D018687:Antidepressive Agents, Second-Generation; D029681:Arabidopsis Proteins; D009687:Nuclear Proteins; C523534:TIC protein, Arabidopsis; D005473:Fluoxetine; D012701:Serotonin; D011280:Pregnanolone
keywords: Allopregnanolone; Anxiety; Estrous cycle; Fluoxetine; Periaqueductal grey matter; c-fos