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Effect of chronic lithium treatment on glucocorticoid and 5-HT1A receptor messenger RNA in hippocampal and dorsal raphe nucleus regions of the rat brain

Psychobiology Research Group, School of Neurology, Neurobiology and Psychiatry, The Medical School, Newcastle Upon Tyne, UK, richard.mcquade{at}ncl.ac.uk

Mel M. Leitch

Psychobiology Research Group, School of Neurology, Neurobiology and Psychiatry, The Medical School, Newcastle Upon Tyne, UK

Sarah E. Gartside

Psychobiology Research Group, School of Neurology, Neurobiology and Psychiatry, The Medical School, Newcastle Upon Tyne, UK

Allan H. Young

Psychobiology Research Group, School of Neurology, Neurobiology and Psychiatry, The Medical School, Newcastle Upon Tyne, UK

The therapeutic mechanism of action of lithium in the treatment of bipolar disorder is not well understood. Dysfunction of both 5-HT_1A receptor mediated neurotransmission and the glucocorticoid receptor is associated with mood disorders, and preclinical studies suggest that lithium treatment can modulate these receptor subtypes. In this study, we investigated the effect of chronic lithium treatment on 5-HT_1A receptors and glucocorticoid receptors in the rat brain. Male Sprague-Dawley rats were treated with lithium (3 mmol/kg/day) or saline for 28 days via subcutaneous implanted mini-osmotic pumps. After 28 days of treatment, the expression of mRNA for 5-HT_1A receptors and glucocorticoid receptors in the rat hippocampus and dorsal raphe nucleus was determined by in situ hybridization histochemistry. Chronic administration of lithium decreased mRNA coding for post-synaptic 5-HT_1A receptors in hippocampal subregions but not for somatodentritic 5-HT_1A receptors in the dorsal raphe nucleus. Chronic administration of lithium did not affect mRNA coding for glucocorticoid receptors in hippocampal subregions or in the dorsal raphe nucleus. Mean plasma lithium levels in the lithium-treated group were 0.50 ± 0.03 mmol/l; all animals appeared healthy and maintained a normal increase in body weight. Given recent reports implicating hypersensitive post-synaptic 5-HT_1A receptors in bipolar manic patients, the present study suggests that down-regulation of this receptor population may be important in the therapeutic mechanism of action of lithium.

Key Words: bipolar disorder • dorsal raphe nucleus • glucocorticoid receptors • 5-HT1A • hippocampus • lithium

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