Desipramine and citalopram attenuate pretest swim-induced increases in prodynorphin immunoreactivity in the dorsal bed nucleus of the stria terminalis and the lateral division of the central nucleus of the amygdala in the forced swimming test
Introduction
The forced swimming test (FST) has been widely used as an effective behavioral test for screening of antidepressant efficacy (Cryan et al., 2005, Lucki, 1997). Rodents previously subjected to a 15-min pretest swim tended to show prodepressive behavior as evidenced by increased immobility in a 5-min test swim conducted 24 h later. However, antidepressant treatments administered during the 24 h after the pretest swim reduce immobility during the test swim (Detke et al., 1995). These results suggest that some neuroplastic changes occur between the pretest swim and test swim, and that antidepressant treatment after the pretest swim may alter these neuroplastic changes, thereby reducing immobility during the test swim. Therefore, to observe antidepressant-induced alterations in neuroplastic changes after the pretest swim, it is plausible to monitor the alterations in neuroplastic changes before the test swim because the antidepressant is administered as late as 1 h before the test swim.
One of the probable neuroplastic changes occurring before the test swim for mediating immobility appears to be the expression of dynorphin. Dynorphin is distributed in stress-related brain areas such as the nucleus accumbens shell (AcbSh), the bed nucleus of the stria terminalis (BNST), and the central nucleus of the amygdala (CeA) (Fallon and Leslie, 1986, Hurd, 1996, Knoll and Carlezon, 2010, Mansour et al., 1995). Dynorphin is known to be involved in mood regulation through the kappa opioid receptor (Knoll and Carlezon, 2010). Overexpression of cyclic AMP response element binding (CREB) protein in the AcbSh, which results in elevated prodynorphin mRNA level, induces prodepressive behavior in the FST (Pliakas et al., 2001), and this effect is blocked by prior intracerebroventricular administration of nor-binaltorphimine, a kappa opioid receptor antagonist (Pliakas et al., 2001). This result suggests that dynorphin upregulation in the AcbSh may be involved in an increase in immobility during the test swim (Pliakas et al., 2001).
These results raise the possibility that alterations in dynorphin expression before the test swim may mediate the antidepressant-like effect observed during the test swim of FST. Moreover, in addition to desipramine, other antidepressants with different mechanisms of action could exert similar effects on dynorphin expression. To explore this possibility, we investigated the treatment effects of desipramine and citalopram on changes in prodynorphin immunoreactivity in mice before the test swim of FST, as these drugs are known as highly selective reuptake inhibitors of norepinephrine and serotonin, respectively (Delgado and Moreno, 2000, Wong et al., 2000). Desipramine and citalopram were administered 0.5, 19, and 23 h after the pretest swim in mice, and then prodynorphin immunoreactivity was observed 24 h after the pretest swim, just before the test swim, in the AcbSh, dorsal BNST (dBNST), ventral BNST (vBNST), lateral division of CeA (CeL), medial division of CeA (CeM), and hypothalamus including the dorsomedial hypothalamic nucleus (DMH) and arcuate nucleus (ARC). Prodynorphin is a precursor of dynorphin A and dynorphin B (Fallon and Leslie, 1986, Kakidani et al., 1982, Tejeda et al., 2012), and a previous study demonstrated that desipramine treatment after the pretest swim blocks upregulation of prodynorphin mRNA level in the AcbSh before the test swim (Chartoff et al., 2009). In the present study, we found that prodynorphin immunoreactivity in the dBNST and CeL was significantly increased before the test swim. This increase in prodynorphin immunoreactivity in the dBNST and CeL before the test swim was blocked by desipramine and citalopram treatments. As phosphorylated CREB at Ser133 (pCREB) binds the CRE promoter of prodynorphin and increases prodynorphin expression, we also observed changes in levels of pCREB immunoreactivity and prodynorphin mRNA in the dBNST and CeA in order to clarify the underlying mechanism.
Section snippets
Animals
Male Imprinting Control Region (ICR) mice (25–28 g, Orient, Seoul, Korea) were acclimated to housing conditions for one week before the experiments. Animals were housed six per cage under standard conditions at 21–22 °C with a 12-h light/dark cycle (lights on at 6:00 am) and were randomly assigned to a treatment condition. Food and water were provided to mice ad libitum. Mice were transported and adapted to the experiment room between 8:00 and 17:00 for five days in order to avoid the stress of a
Effects of antidepressant treatments on pretest swim-induced changes in prodynorphin immunoreactivity in the BNST
Pretest swim with subsequent saline treatment significantly increased prodynorphin immunoreactivity in the dBNST before the test swim relative to baseline controls [151.3% of control; F (3, 47) = 6.30, p < 0.01] (Fig. 2, Fig. 3). This increase in prodynorphin before the test swim was blocked by treatment with either desipramine (p < 0.01) or citalopram (p < 0.001). Neither pretest swim nor antidepressant treatment after the pretest swim had an effect on prodynorphin immunoreactivity in the vBNST (Fig. 2
Discussion
The results of the present study demonstrate that the pretest swim increases prodynorphin immunoreactivity in the dBNST and CeL in mice before the test swim and that this increase is blocked by treatment with desipramine or citalopram after the pretest swim. These results suggest that attenuation of prodynorphin elevation in the dBNST and CeL before the test swim may be involved in the antidepressant-like effects of desipramine and citalopram in the FST.
To be effective in the FST, an
Acknowledgments
This study was supported by grants from the National Research Foundation of Korea (NRF-2010-0024048) and Korea University (K1421451).
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