The effect of early–life exposure of stress–sensitive rats to the serotonin–norepinephrine reuptake inhibitor vanlafaxine on behaviour in adulthood / Steyn S.F.

• Main Author: Steyn, Stephanus Frederik
• Published: North-West University 2012
• Online Access: http://hdl.handle.net/10394/7562

Major depressive disorder (MDD) is a serious psychiatric disorder with an increasing prevalence world–wide. It is estimated to affect 5% of the world's population, and has been estimated that by the year 2020 it will have become the second leading cause of disability in age groups 15 to 44 across both genders. MDD affects children and adolescents at an equally alarming rate, with the treatment options for these young patients mainly restricted to selective serotonin reuptake inhibitors (SSRIs) which have shown escalating prescription numbers of alarming proportion over the past few decades. Of further concern is that many human foetuses are exposed to antidepressants already in utero. Although available data have not suggested any major adverse effects in new–born babies following antidepressant–use by pregnant mothers, there is still a great deal of uncertainty with regard to any potential neurodevelopmental or other long–term effects that may manifest later in life. The aim of the current study was to investigate, in stress–sensitive and control resistant rats, the long–term effects of early–life administration of the serotonin–norepinephrine reuptake inhibitor (SNRI) venlafaxine on cognition and behaviour later in life. Pregnant dams of stress–sensitive Flinders sensitive line (FSL) rats, and their behavioural control Flinders resistant line (FRL) rats, received daily subcutaneous (s.c.) injections for fourteen days either saline (Sal) or 10 mg/kg venlafaxine (Ven), starting on prenatal day 15 (PreND–15). Similarly, new–born pups received daily s.c. injections for fourteen days either Sal or 3 mg/kg Ven, starting on postnatal day 3 (PostND03). In all cases there were four treatment groups respectively receiving prenatal plus postnatal injections as follows: Sal+Sal, Ven+Sal, Sal+Ven or Ven+Ven. For all treatment groups of both rat lines behavioural and cognitive tests were performed on PostND21, 35 and 60 and consisted of the forced swim test (FST), locomotor activity test (Digiscan®), novel object recognition test (nORT) and elevated plus maze (EPM). The behavioural tests measured the depressive–like behaviour (FST), locomotor activity (Digiscan®), memory consolidation (nORT) and anxiety–like behaviour (EPM) of the animals, following venlafaxine treatment during the different developmental stages in life. A pilot study confirmed that roughly four male pups, on average, are delivered by a pregnant dam, but with recorded variation of between 2 and 5.8 male pups per litter. The sex distribution per litter was also found to be approximately 50:50 for both FRL and FSL dams. This data were used to determine the number of dams to include per treatment group, yielding the required number of male pups. Early–life venlafaxine treatment did not induce any significant changes in the depressive–like behaviour of FRL rats on PostND21, 35 or 60, or in that of FSL rats tested on PostND21 or 35. The treatment did, however, significantly decrease the depressive–like behaviour of the FSL rats on PostND60. This decrease was not accompanied by alterations in the overall locomotor activity. In fact, locomotor activity was altered only in FSL rats on PostND21 following pre– and postnatal venlafaxine treatment, suggesting a transient change during neurodevelopment. Cognition, as measured in the novel object recognition test, was reduced only in FRL rats at PostND60 following pre– and postnatal venlafaxine treatment. Since a similar change was not observed in FSL rats, the data suggest that the neurodevelopmental consequences of early–life antidepressant administration on cognition may be less harmful in stress–sensitive rats than in normal controls, i.e. pathology–dependent pharmacology. Finally, whereas the FSL rats displayed significantly decreased anxiety–like behaviour at PostND21, compared to FRL controls and not at any other age, it was concluded that this may also be a transient behaviour. The anxiety–like behaviour of both rat lines remained unaffected, following pre– and/or postnatal venlafaxine treatment, at any age. In conclusion, early–life venlafaxine administration induced selective behavioural and cognitive effects in stress–sensitive rats, most likely due to effects on neurodevelopment. Whereas the most prominent effects manifested at PostND60, these effects may also be dependent on rat line, further suggesting a role for genetic predisposition in drug response. === Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2012.