Regulation of extracellular serotonin levels and brain-derived neurotrophic factor in rats with high and low exploratory activity

Abstract

Serotonin (5-HT) system has a significant role in anxiety- and depression-related states and may be influenced by brain-derived neurotrophic factor (BDNF). This study examined extracellular 5-HT levels and expression of BDNF in rats with persistently low or high levels of exploratory activity (LE and HE, respectively). Baseline extracellular levels of 5-HT as assessed by in vivo microdialysis in conscious animals were similar in both groups in medial prefrontal cortex (PFC) and dentate gyrus (DG). No differences were found in parachloroamphetamine-induced 5-HT release in either region. However, LE animals had significantly higher levels of 5-HT transporter (5-HTT) binding in PFC and a larger increase in extracellular 5-HT levels after administration of citalopram (1 microM) into this area by retrograde dialysis. No difference in 5-HTT levels was found in hippocampus, while perfusion with citalopram was accompanied by a greater increase in extracellular 5-HT in the HE group in this brain region. LE-rats had higher levels of BDNF mRNA in the PFC but not hippocampus. In contrast, levels of nerve growth factor mRNA were similar in these brain regions of LE- and HE-rats. The differential regulation of 5-HT-ergic system in LE- and HE-rats in PFC and hippocampus may form the basis for their distinct anxiety-related behaviours.

Fig. 1

Extracellular serotonin levels in the medial prefrontal cortex (A) and dentate gyrus (B) of LE- and HE-rats after parachloroamphetamine (PCA) treatment. Samples were collected every 15 min and are presented as percentage of baseline levels (mean of samples 4.–6.). PCA (2 mg/kg, intraperitoneally) was administered before the collection of sample 8. LE – low exploratory activity rats (filled squares, n = 4 and 9 in PFC and HI, respectively); HE – high exploratory activity rats (open squares, n = 6 and 10 in PFC and HI, respectively).

Fig. 2

5-HTT levels measured with [³H]citalopram binding in membranes of the medial prefrontal cortex (PFC) and hippocampus (HI) of LE- and HE-rats. ^∗P < 0.05 compared to the HE group. LE – low exploratory activity rats (filled bars, n = 6 in both regions); HE – high exploratory activity rats (open bars, n = 6 and 7 in PFC and HI, respectively).

Fig. 3

Extracellular serotonin levels in the medial prefrontal cortex (A) and dentate gyrus (B) of LE- and HE-rats, after local infusion of citalopram. Samples were collected every 15 min and are presented as percentage of baseline levels (mean of samples 4.–6.). Infusion with 1 μM solution of citalopram was made during the collection of samples 7.–16. ^∗P < 0.05; ^∗∗P < 0.01; ^∗∗∗P < 0.0001 difference between LE and HE groups. LE – low exploratory activity rats (filled squares, n = 6 in both regions); HE – high exploratory activity rats (open squares, n = 6 and 7 in PFC and HI, respectively).

Fig. 4

Relative levels of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) mRNA in prefrontal cortex (PFC) and hippocampus (HI) of LE- and HE-rats separately in left and right hemisphere: (A) BDNF in PFC; (B) NGF in PFC; (C) BDNF in HI; (D) NGF in HI. BDNF and NGF mRNA were normalized to β-actin. ^∗P < 0.05 difference compared to the respective LE group. LE – low exploratory activity rats (filled bars, n = 5–6); HE – high exploratory activity rats (open bars, n = 5–6).