A microdialysis study of the medial prefrontal cortex of adolescent and adult rats

Abstract

The medial prefrontal cortex (mPFC) of the rat has become a key focus of studies designed to elucidate the basis of behavior involving attention and decision-making, i.e. executive functions. The adolescent mPFC is of particular interest given the role of the mPFC in impulsivity and attention, and disorders such as attentional deficit disorder. In the present study we have examined the basal extracellular concentrations of the neurotransmitters 5-hydroxytryptamine (5-HT), dopamine (DA) and norepinephrine (NE) in the ventral portion of the mPFC (vmPFC) in both adolescent (post-natal day 45–50) and adult, and male and female rats using in vivo microdialysis. We have also examined both the left and right vmPFCs given reports of laterality in function between the hemispheres. Basal extracellular concentrations of 5-HT differed significantly between male and female rats. Extracellular DA also differed significantly between male and female rats and between the left and the right vmPFC in adult males. No differences were seen in basal extracellular NE. There was a significant age difference between groups in the laterality of extracellular NE levels between right and left vmPFC. Infusion of 100 μM methamphetamine through the dialysis probe increased the extracellular concentration of all the monoamines although there were no differences between groups in methamphetamine stimulated release. The findings from this study demonstrate that there are differences in monoaminergic input to the mPFC of the rat based on age, gender and hemisphere. This work sets the neurochemical baseline for further investigations of the prefrontal cortex during development.

This article is part of a Special Issue entitled ‘Serotonin’.

Introduction

The prefrontal cortex is a forebrain region associated with executive function, including decision-making, attention control, working memory, stress response, and behavioral inhibition (Yamasaki et al., 2002, Heidbreder and Groenewegen, 2003, Morgane et al., 2005, Rossetti and Carboni, 2005). Impairments in the prefrontal neuronal circuitry are implicated in the pathology of impulse control disorders such as attention deficit disorder (ADD) and drug abuse (Russell, 2002, Sullivan and Brake, 2003). An association has also been established between ADD and substance abuse in adulthood (Robbins, 2002). Furthermore, pathology in the prefrontal cortex has been proposed to be involved in other psychiatric disorders such as anxiety, depression and schizophrenia (Adriani and Laviola, 2004, Schoenbaum et al., 2006, Morgane and Mokler, 2006a). Although the rat prefrontal cortex has not developed to the extent of the primates, the function and structure do allow us to use the rat as a model to discover the workings of this important forebrain area (Dalley et al., 2004). In separate reviews we have discussed the structure and function of the rat prefrontal cortex (Morgane et al., 2005, Morgane and Mokler, 2006b).

The development of the prefrontal cortex is considered to be the last area of the cortex to mature, continuing to develop into early adulthood (Cunningham et al., 2002). This delay has been suggested to be linked to behaviors such as impulsivity in adolescence that lead to substance abuse and risk taking (Benes et al., 2000, Adriani and Laviola, 2004, Andersen and Teicher, 2008).

The neurotransmitters norepinephrine (NE), dopamine (DA) and serotonin (5-HT) in the prefrontal cortex have long been the subject of intense investigation (Davids et al., 2003, Robbins and Arnsten, 2009). Relationships have been proposed between NE and DA in attention and 5-HT in impulsivity. Decreased DA function in the prefrontal cortex has been suggested as an independent trait marker of attentional deficits and impulsivity (Adriani and Laviola, 2004). Sullivan and Brake (2003) have described the important modulatory role of dopamine in prefrontal cortical function, with decreased function in this system predisposing persons to ADD. In microdialysis studies by Dalley et al. (2002), highly impulsive rats had impairment in dopamine release in the prefrontal cortex. Previous microdialysis studies have also shown that basal dopamine levels differ between the ventral and dorsal medial prefrontal cortex (Heidbreder and Groenewegen, 2003, Morgane et al., 2005).

Impulsivity has been associated with alterations in 5-HT in the prefrontal cortex. It has been suggested that 5-HT is involved in impulse control from the observation that drugs which suppress 5-HT function reduce behavioral inhibition, making the animals more impulsive (Winstanley et al., 2005). Low levels of 5-HT in cerebrospinal fluid have been associated with impulsive aggression and violence in humans and risk taking behaviors in monkeys (Cardinal et al., 2004). Other studies, however, have suggested that elevated 5-HT may also contribute to impulsivity. Elevated 5-HT in the rat prefrontal cortex has been associated with a deficit in impulsive control and an impulsive trait (Adriani et al., 2003). In microdialysis studies, Dalley et al. (2002) found that there was increased 5-HT outflow in this brain region during visual performance tasks, which they associated with impulsive behaviors. Further work needs to be done to verify the role of PFC 5-HT in impulsivity.

In this study, we examined extracellular serotonin, dopamine, and norepinephrine in the ventral medial PFC of male and female adolescent and adult rats, utilizing dual-probe in vivo microdialysis. The ventral region of the medial prefrontal cortex was examined due to its relation to attentional functions, including attention to stimulus features and task contingencies, attentional set-shifting, and behavioral flexibility (Heidbreder and Groenewegen, 2003, Dalley et al., 2004). The specific ventral portion of the medial PFC studied in these experiments includes the infralimbic prefrontal cortex and the ventral half of the prelimbic prefrontal cortex. Based on the decreased attention and increased impulsivity in the adolescent animal, our main hypothesis is that in adolescent brains there is a lower extracellular concentration of dopamine and norepinephrine and a higher extracellular concentration of serotonin in the mPFC. It is predicted there would be differences in the extracellular concentrations of neurotransmitters between all four groups: adolescent males and adolescent females, adult male and adult female rats. In addition, recent work by Sullivan et al. has shown hemispheric differences in the rat prefrontal cortex in response to stress (Sullivan, 2004). Thus, we have examined the left and right vmPFC and hypothesized that differences will be seen in hemispheric laterality in all groups studied.

While basal extracellular concentrations of neurotransmitters are valuable information, we have also stimulated neurotransmitter release in these animals using reverse dialysis of methamphetamine to assess further the function of neurons in this brain region. These data will lead to further investigations of the prefrontal cortex and its function through development.