A Biphasic and Brain-Region Selective Down-Regulation of Cyclic Adenosine Monophosphate Concentrations Supports Object Recognition in the Rat

Background: We aimed to further understand the relationship between cAMP concentration and mnesic performance. Methods and Findings: Rats were injected with milrinone (PDE3 inhibitor, 0.3 mg/kg, i.p.), rolipram (PDE4 inhibitor, 0.3 mg/ kg, i.p.) and/or the selective 5-HT4R agonist RS 67333 (1 mg/kg, i.p.) before testing in the object recognition paradigm. Cyclic AMP concentrations were measured in brain structures linked to episodic-like memory (i.e. hippocampus, prefrontal and perirhinal cortices) before or after either the sample or the testing phase. Except in the hippocampus of rolipram treated-rats, all treatment increased cAMP levels in each brain sub-region studied before the sample phase. After the sample phase, cAMP levels were significantly increased in hippocampus (1.8 fold), prefrontal (1.3 fold) and perirhinal (1.3 fold) cortices from controls rat while decreased in prefrontal cortex (,0.83 to 0.62 fold) from drug-treated rats (except for milrinone+RS 67333 treatment). After the testing phase, cAMP concentrations were still increased in both the hippocampus (2.76 fold) and the perirhinal cortex (2.1 fold) from controls animals. Minor increase were reported in hippocampus and perirhinal cortex from both rolipram (respectively, 1.44 fold and 1.70 fold) and milrinone (respectively 1.46 fold and 1.56 fold)-treated rat. Following the paradigm, cAMP levels were significantly lower in the hippocampus, prefrontal and perirhinal cortices from drug-treated rat when compared to controls animals, however, only drug-treated rats spent longer time exploring the novel object during the testing phase (inter-phase interval of 4 h)

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Locomotor activity measured during the sample and the testing trails in the object recognition task.

<p>Locomotor activity measured during the sample and the testing trails in the object recognition task.</p

Time of exploration of objects measured during the sample and the testing trails in the object recognition task.

<p>Time of exploration of objects measured during the sample and the testing trails in the object recognition task.</p

Distribution of the total PP2 activities between particulate and soluble fractions from rat hippocampus, prefrontal cortex and perirhinal cortex.

<p>Values are means ± SEM.</p>§§§<p><i>P</i><0.001 (ANOVA followed by Fisher's LSD test): different from the corresponding particulate fraction.</p

Object recognition task after a 4 h-delay in saline, rolipram- or milrinone- treated rats with or without RS 67333 co-treatment.

<p>Time of exploration of the familiar and novel objects during the testing phase of the object recognition memory task of saline (n = 32), RS 67333 (n = 32), rolipram (n = 27), rolipram+RS 67333 (n = 27), milrinone (n = 27), or milrinone+RS 67333 (n = 27)-treated rats. Rats were injected with the PDE inhibitor (0.3 mg/kg, i.p.) solution 45 minutes before the sample phase and with saline or RS 67333 (1 mg/kg, i.p.) solution 30 minutes before the sample phase. Object recognition was assayed after a 4 h-delay. Values are means in s ± SEM. NS: non significant, (*) indicates a significant difference in comparison with saline treatment. (*, P<0.05, **, P<0.01, ***, P<0.001, ANOVA followed by Fisher's PLSD test).</p