The dopamine D1 receptor agonist SKF 38393 improves temporal order memory performance in maternally deprived rats

Highlights

• A receptor D1 agonist corrected memory deficits induced by maternal deprivation.

• Maternal deprivation induced lower D1 receptor density in the medial prefrontal cortex.

• Reduced extracellular level of DOPAC were assessed in the medial prefrontal cortex.

Abstract

Previously, we showed that maternal deprivation (MD) (3 h/day, postnatal-day 1–14) impaired the performance at adulthood in the object temporal order memory task (TMT) that principally implicates the medial prefrontal cortex (mPFC). Dopamine (DA) transmission in the PFC may play a critical role in the achievement of the TMT. Here, to investigate whether MD could results in dysfunction of the DA system in the mPFC, we assessed in this region the tissue contents and extracellular levels of DA and its metabolites, as the density of D1 receptor. Besides we examined whether an agonist of the DA receptor D1, the SKF38393, could have a beneficial effect on the performance of deprived (D) rats in the TMT. We observed that MD induced a significant reduction of the extracellular level of DOPAC in the mPFC and in the density of the D1 receptor in the anterior cingulate cortex, a sub-region of mPFC. On the other hand, we observed that an acute systemic injection of a D1 receptor agonist, SKF38393, was effective to correct the memory deficiency of D rats in the TMT, when administered before the retrieval phase. We showed that a stress suffered by rats during the perinatal period led to dysfunction of the adult DA system, possibly triggering greater vulnerability to cognitive and mood disorders. Interestingly, an acute administration of a D1 receptor agonist in adulthood was sufficient to improve the deficit in the temporal memory. A better understanding of this phenomenon would permit the development of treatments adapted to patients with a history of early traumatic experiences.

Introduction

Early life stress and childhood maltreatment increases the risk of developing psychopathology accompanied by reduced cognitive function in later life (Teicher et al., 2003). For the infant, the interaction with his mother is the most important environmental factor, since a variety of his physiological systems responds to specific elements of this interaction. Maternal separation is a commonly used model of early life neglect.

Our model of maternal deprivation (MD), a variant of maternal separation, consists of a daily separation of newborn Long-Evans pups from their mother and from their littermates for 3 h per day from postnatal days 1 to 14. In adulthood, maternally deprived (D) rats are compared with animal facility rearing (AFR) rats, which have experienced human intervention for animal care (Pryce & Feldon, 2003). We have shown that MD leads in male rats to different type of impairments or neurobiological alterations. An enhanced anxiety and reactivity to stress was observed as well as an increased preference for sucrose, a hypersensitivity to the rewarding effect of morphine, a morphine dependence, a hyposensitivity of the effect of a dopamine D3 receptor agonist, deficits in cognitive flexibility and an exaggerated synaptic plasticity in the medial prefrontal cortex (mPFC) (Baudin et al., 2012, Mourlon et al., 2010, Vazquez et al., 2005a, Vazquez et al., 2006, Vazquez et al., 2005b, 2007).

During the last decade, several studies using different behavioural tasks have shown that maternal separation can lead to memory impairments in adult rat. This was demonstrated with the novel object recognition task (Aisa et al., 2008, Hulshof et al., 2011), the Morris water maze task (Aisa et al., 2007, Hui et al., 2011, Huot et al., 2002, Mello et al., 2009, Uysal et al., 2005, Zhu et al., 2010) and the radial arm maze task (Sandstrom & Hart, 2005). In addition, we have recently demonstrated that rats subjected to MD performed poorly in the object temporal order memory task (TMT) (Baudin et al., 2012). This task, adapted from the object recognition task by Mitchell and Laiacona (1998), assesses the ability to remember the temporal order of appearance of items and thus discriminate objects encountered at different times in the past.

In rat, several studies provided support that the mPFC is involved in memory for temporal order. It was initially shown that mPFC lesions induced memory deficits on tests of temporal order memory for spatial locations (Chiba et al., 1994, Kesner and Holbrook, 1987). Moreover, performance in the TMT relies critically on the mPFC and its networks as demonstrated by inactivation or lesion of the mPFC (Barker et al., 2007, Hannesson et al., 2004, Mitchell and Laiacona, 1998). On the other hand, experimental data suggest the involvement of dopamine (DA) transmission in the object temporal order memory. Indeed, administration of an agonist of the D1 receptor before the memory testing trial of the TMT improves the abilities to retrieve previously acquired temporal information (Hotte, Naudon, & Jay, 2005). In the present study, we investigated whether MD resulted in changes in the contents of DA and its metabolites in the mPFC, as well as in their extracellular levels quantified after microdialysis and in the density of D1 receptors. Finally, we investigated whether the D1 agonist SKF 38393 administered before the retrieval phase in the TMT, could have a beneficial effect on the performance of D rats.