Morris water maze performance deficit produced by intermittent swim stress is partially mediated by norepinephrine Timothy A. Warner ⁎, Robert C. Drugan Department of Psychology, University of New Hampshire, Durham, NH, USA abstract article info Article history: Received 12 November 2010 Received in revised form 18 October 2011 Accepted 12 November 2011 Available online 18 November 2011 Keywords: Rat Behavioral depression Stress Clonidine Desipramine Reboxetine Morris water maze Intermittent swim stress (ISS) exposes a rat to cold water and the effects of the procedure produce detrimen- tal results on activity measures 24 h later. The ISS model can be used with the Morris water maze (MWM) to investigate the impact of stress on a spatial learning and memory task, known to involve the hippocampus. We investigated if the ISS model produced performance deficits in the MWM (experiments 1 and 2). We also investigated the role of norepinephrine by using an alpha-2 adrenergic agonist (i.e., clonidine) to exac- erbate ISS-induced deficits (experiment 3), and using antidepressants (i.e., desipramine and reboxetine) that enhance the synaptic availability of norepinephrine to reduce ISS-induced deficits (experiments 4 and 5). Re- sults indicated a main effect for stress in all experiments, with the exception of experiment 2, as ISS did in- duce performance deficits in the MWM. Clonidine enhanced ISS-induced deficits only in the learning trials, while desipramine and reboxetine reduced ISS-induced deficits in the learning trials. Additionally, only reboxetine reduced memory deficits in the MWM. These findings provide evidence that norepinephrine may act as a partial mediator of ISS-induced deficits in MWM performance. © 2011 Published by Elsevier Inc. 1. Introduction Learning and memory are greatly affected by stress and depres- sion. Experiences of acute (Kuhlmann et al., 2005) or chronic stress may be more susceptible to memory deficits in comparison to situa- tions of no stress, especially in hippocampally-dependent spatial tasks (Conrad, 2010). The hippocampus also appears to be an anatom- ical site correlated with depression (Xu et al., 1997; Yang et al., 2005). The impact of stress activates the release of cortisol and various neuro- transmitters, specifically increasing levels of norepinephrine in the brain (Bremner et al., 1996; Finlay et al., 1995; Weiss et al., 1980). Stress also activates neuropeptides in various brain regions (e.g., pre- frontal cortex, amygdala, hippocampus, and hypothalamus) (Gold et al., 2002). Anatomically, the brainstem nucleus, the locus coeruleus, is a signif- icant source of norepinephrine to the hippocampus (Berridge and Waterhouse, 2003). In addition, neuronal damage or lesion in the locus coeruleus is highly correlated with deficits in memory processes (Compton et al., 1995; Luine et al., 1990; Wenk et al., 1987). This pro- vides further evidence for the importance of norepinephrine in memory processes (Sara, 2009) with several studies suggesting the involvement of the noradrenergic system in spatial learning and memory (Arnsten and Cai, 1993; Compton et al., 1995; Khakpour-Taleghani et al., 2009). An alpha-2 adrenergic agonist, clonidine (Catapres), has been shown to inhibit the functioning of the locus coeruleus with the dose of clonidine playing a vital role in inhibiting norepinephrine re- lease, as the effects tend to be caused by lower doses acting on pre- synaptic autoreceptors (Solanto, 1998). Higher doses of clonidine are believed to act on postsynaptic receptors, are ineffective at inhibiting norepinephrine, and actually facilitate the release of norepinephrine (Ramos and Arnsten, 2007). For example, in the continuous swim forced swim test at a lower dose (0.15 mg/kg), clonidine increased im- mobility (Shah et al., 2006), but reduced immobility at a higher dose (1 mg/kg) (Malinge et al., 1988). Therefore, a low dose of clonidine is vital to impair the functioning of the locus coeruleus to prevent the re- lease of norepinephrine to the hippocampus. Both norepinephrine and serotonin appear to be important in ani- mal models of behavioral depression such as the forced swim test (Detke et al., 1995; Porsolt et al., 1977), and learned helplessness (Maier and Seligman, 1976; Maier and Watkins, 2005). Focusing on the learned helplessness paradigm, the resulting behavior of a rat re- ceiving inescapable shock is associated with a depletion of brain norepi- nephrine (Weiss et al., 1980). This neurotransmitter seems to be an important factor for dealing with aversive situations (Aston-Jones and Cohen, 2005). Animals that are able to cope with stress (escape from the shock) do not display depleted levels of brain norepinephrine (Weiss et al., 1970). In addition, inescapable shock exposure results in serotonergic overactivation and subsequent hypersensitivity of the dor- sal raphe nucleus (Amat et al., 1998). Animals that are able to cope with stress only show a transient elevation of serotonin levels in the dorsal raphe nucleus (Maier and Watkins, 2005). Pharmacology, Biochemistry and Behavior 101 (2012) 24–34 ⁎ Corresponding author at: Department of Psychology, Conant Hall, 10 Library Way, Durham, NH 03824-3567, USA. Tel.: +1 603 862 2128; fax: +1 603 862 4986. E-mail address: tim.warner@unh.edu (T.A. Warner). 0091-3057/$ – see front matter © 2011 Published by Elsevier Inc. doi:10.1016/j.pbb.2011.11.009 Contents lists available at SciVerse ScienceDirect Pharmacology, Biochemistry and Behavior journal homepage: www.elsevier.com/locate/pharmbiochembeh