Article
3.3 Text
3.3.4 Discussion
The present study used a genetic animal model of depression, viz. the FSL rat, to investigate the long-term effects of the SNRI, venlafaxine, on behaviour and/or cognition later in life, following early pre- and/or postnatal exposure as well as the age at which these effects were most robust.
By targeting both the serotonin and norepinephrine transmitter systems in the juvenile brain, it may be possible to affect the overall development of the brain and its corresponding effects on neurotransmission (Feeney and Westerberg, 1990; Kline et al., 1994) and only to observe the resulting effects later in life when maturity is reached (Andersen and Navalta, 2004).
The data from the FST and nORT supported the face validity of the FSL rats as an animal model for depression. Although previous studies have demonstrated increased anxiety-like behaviour in FSL controls compared to FRL controls, following induced stress, it has been suggested that increased anxiety may not be a predominant feature of FSL rats compared to FRL rats under baseline conditions (Overstreet et al., 2005). Furthermore Braw and colleagues (2006) indicated that anxiety levels observed in adult FSL rats are not observed in pre-pubertal pups, who display significantly decreased anxiety compared to FRL controls. Following chronic saline administration to the FRL and FSL control rats in the current study, the anxiety-like behaviour of the FSL rats were comparable to that of the FRL control.
This is the first time, to the knowledge of the authors, that such behaviour has been reported following chronic stress in the FSL rats.
Data on the long-term safety and efficacy of serotonin targeting antidepressants are numerous, while the data regarding noradrenergic targeting drugs are limited.
Treatment with SSRIs during foetal development has suggested no risk for any major malformations (Louik et al., 2007), but increased risk of preterm delivery, lower birth weight and pulmonary hypertension in new-born babies still remain a concern (Chambers et al., 2006; Rahimi et al., 2006). As mentioned the available data on
Page | 52 noradrenergic targeting drugs are very limited, especially in studies investigating the long term effects following chronic pre- and postnatal exposure to these drugs.
As mentioned, the FSL rat is a validated animal model for depression (Janowsky et al., 1980; Overstreet et al., 1995; Dremencov et al., 2004) and presents with a natural increase in immobility time during the FST, compared to the FRL rats (Liebenberg et al., 2010). This was confirmed by the current study (Figure 1).
The current study identified PostND60 as the age at which the most robust behavioural and cognitive alterations were observed, following chronic treatment with an SNRI (i.e. venlafaxine) during juvenile development (Table 1 and Figure 1).
Furthermore the study suggested that early-life treatment with venlafaxine (pre- and/or postnatal) did not significantly alter the anxiety-like behaviour of the stress- sensitive FSL rats or FRL rats, compared to their respective controls (Figure 3).
However, despite their increased sensitivity to stressful conditions, increased anxiety has not been documented to be a prominent feature of the FSL strain (Neumann et al., 2011; Overstreet et al., 2005), which may explain the conflicting data of the unaffected anxiety-like behaviour observed in the current study versus the increased anxiety documented in previous studies (Kokras et al., 2011).
Regarding memory consolidation of the animals, as measured in the nORT, the current study confirmed the FSL rat as an animal model for depression, since they spent significantly less time exploring the novel object compared to the FRL control group (Figure 2). In fact, is has been well established that depressed patients show a general loss of interest in activities of normal life (Günther et al., 2004), so that the findings of the current study in in accordance with human behaviour. Chronic administration of venlafaxine during pre- and/or postnatal development did not significantly change this cognitive deficit evident in FSL rats compared to the FSL control group (Figure 2(c)). These results are conflicting with previous studies, indicating a significant increase in both spatial and working memory, following chronic venlafaxine treatment to Wistar and albino mice, respectively (Nowakowska et al., 2002; Dhir & Kulkarni, 2008; Monleón et al., 2008). It is important to notice that the study design (i.e. treatment period and administration route) differed between the current study and previous ones, which may explain the conflicting data.
Page | 53 The most important observation of the current study is that early-life exposure to venlafaxine engenders a significant decrease in the natural depressive-like behaviour in two of the three FSL venlafaxine-treated groups (i.e. prenatal and pre- and postnatal). Interestingly, this was not observed in any of the FRL venlafaxine- treated groups (Figure 1). As the reversal of depressive-like behaviour was only observed in the FSL and not in the FRL rats, it may indicate that the animals, more prone to depressive-like behaviour, gain from early-life treatment, without any adverse effects. The more resistant type of animals (i.e. FRL rats) did not present with any advantages or disadvantages when exposed to venlafaxine-treatment during early-life development. This significant decrease of depressive-like behaviour in FSL rats was supported by the data of the locomotor activity of the animals in the DAAM, as no significant difference in the FSL vehicle-treated group (i.e. pre- and postnatal), compared to the FRL vehicle control group was observed (Table 2).
Previous studies have demonstrated increased locomotor activity later in life, following venlafaxine treatment during early postnatal development (Larsen et al., 2010). This is in contrast to the results obtained in the current study, but might be the result of different treatment regimens and administration routes.
Dawson and Tricklebank (1995) suggested that the number of open arm entries may act as a parameter of locomotor activity of the animal and as there were no significant differences in the number of open arm entries in the EPM (data not shown), the data of the current study remains valid. In addition, no significant difference in the overall locomotor activity in any of the drug-treated groups (i.e. pre- and/or postnatal), FSL or FRL, were observed on PostND60 (Table 2) and thus supporting the decrease of depressive-like behaviour, as it is clear that the increase in mobility was not a result of increased overall locomotor activity of the FSL rats.
In conclusion, early-life venlafaxine administration has favourable effects on the depressive-like behaviour of the stress-sensitive FSL rats later in life i.e. early adulthood. However, this beneficial effect does not extend to alteration in anxiety- like behaviour or improvements of cognitive function later in life. If the data from the study could be directly related to human patients, it would suggest that patients, who have a predisposition to MDD, may benefit from early-life treatment by significantly decreasing natural depressive-like behaviour without altering cognition, anxiety or locomotor activity in adulthood. Future studies, investigating the neurochemical
Page | 54 effects of pre- and postnatal administration as well as other age groups, may further expand our knowledge into the long-term safety, efficacy and adverse effects caused by antidepressant use during early-life development.
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