Tolerance development to Morris water maze test impairments induced by acute allopregnanolone
Şahruh Türkmen; Mats Löfgren; Vita Birzniece; Torbjörn Bäckström; Inga-Maj Johansson
Neuroscience2006
Summary (paraphrased)
Rats given repeated acute allopregnanolone develop rapid tolerance to its impairment of spatial memory in the Morris water maze, requiring escalating doses to maintain the effect. The tolerance persists for about a day after induction and is accompanied by reduced GABA-A receptor α4-subunit mRNA in the thalamic ventral-posteromedial nucleus. The work shows tolerance is a receptor-level adaptation rather than altered drug kinetics. For an excess-neurosteroid model, it documents that sustained high neurosteroid exposure remodels the very receptors it acts on.
Why it’s in the systems review
A neurosteroid-excess model needs evidence that sustained high neurosteroid exposure produces lasting adaptation rather than just acute sedation; this tolerance study provides it at the behavioral level. The persistence of tolerance beyond drug clearance parallels the clinical puzzle of symptoms outlasting exposure. It motivates the receptor-level studies (MECH-005) that reveal the adaptation's substrate.
Related records
- Peer-reviewed paper
GABAA receptor changes in acute allopregnanolone tolerance
Vita Birzniece; Şahruh Türkmen; Charlotte Lindblad; Di Zhu; Inga-Maj Johansson; Torbjörn Bäckström; Göran Wahlström · European Journal of Pharmacology
This companion mechanistic study links acute allopregnanolone tolerance to concrete GABA-A receptor plasticity: after tolerance induction, α4 subunit abundance and mRNA fall in thalamic relay nuclei, correlating with the dose escalation needed to sustain the…
MECH-0052006Systems review · Oct 2026 - Peer-reviewed paper
Tolerance to allopregnanolone with focus on the GABA-A receptor
Sahruh Turkmen; Torbjorn Backstrom; Goran Wahlstrom; Lotta Andreen; Inga-Maj Johansson · British Journal of Pharmacology
Allopregnanolone is among the most potent endogenous modulators of the GABA-A receptor, and fluctuations in its levels create vulnerability to mood and emotional pathology. This review focuses on how the GABA-A receptor adapts — developing tolerance — under…
LIT-0552011Literature sweep · Oct 2026 - Peer-reviewed paperPSSD Discord pick
Forty Years Searching for Neurosteroid Binding Sites on GABAA Receptors
Mortensen M, Bright DP, Fagotti J, Dorovykh V, Cerna B, Smart TG · Neuroscience
Review summarizing four decades of research locating where neurosteroids act on GABA-A receptors. It walks through mutagenesis, chimeric receptors, and electrophysiology work that mapped potentiation and direct-activation pockets within the receptor's…
DISC-0022025 (epub 2024 Jun 7)PFSPSSDPSSD Discord picks