Abstract
Introduction The goal of this work is to develop an animal model of depression through a methodical approach of inducing malfunctioning of the Muscarinic Cholinergic System (MChS) in rat pups during early postnatal period. We believed that experimentally induced early post-natal deficiency in MChS functioning would produce lasting super-sensitivity of MChS in adult age. We studied behavioral and sleep disturbances, as well as changes in the rate of M2/M4 muscarinic cholinoreceptors in neocortex and hippocampus of adult rats exposed postnatally to Atropine (Atr) and/or Scopolamine (Scop). Materials and methods Rat pups ( n = 30) received subcutaneously Atr and/or Scop (15 mg/kg) injections daily for 2 weeks starting at postnatal days 7 (P7) and/or at P14. Adult control rats received saline injection during the same period of postnatal development. After discontinuing the drugs, rat pups were maintained in home cages under special care. Staring 8–12 weeks after treatment, EEGs, conducted for 10 h daily over 7 consecutive days, recorded the sleep cycles. Assessments of behavioral changes were take by open filed test, and forced swim. Density of M2/M4 Muscarinic Cholinoreceptors in synaptic membranes of the Hippocampus and Neocortex were measured by Western Blotting through the use of specific antibodies. Statistical processing was made by Students’ t -test with computer program ”Farm”. Results Adult rats exposed post-nataly to anticholinergic drugs showed motor retardation in open field, increased immobilization time, ”behavioral despair” in forced swim condition, and signs of anhedonia assessed by sucrose preference test. Slow wave sleep became fragmented and superficial. REM latency appeared four times shorter than in control rats. Sleep was frequently started by REM episodes. REM incidence was significantly more frequent and REM total time was increased for three times. The rate of M2/M4 sub-types of muscarinic cholinoreceptors appeared significantly higher in hippocampal plasma membranes in rats with postnatal exposure to muscarinic antagonists. Conclusion Malfunctioning of brain MChS in early period of postnatal development leads to adult age MChS super sensitivity, behavioral and sleep disturbances similar to depression, and significant up-regulation of M2/M4 cholinoreceptors. Interrelationship between up-regulation of M2/ M4 Cholinoreceptors and pathogenesis of depression is supported. Acknowledgements Supported by Science and Technology Center in Ukraine and Shota Rustaveli National Science Foundation , Grants # 545 and 6-465.
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