Bilateral distribution of enkephalinase activity in the medial prefrontal cortex differs between WKY and SHR rats unilaterally lesioned with 6-hydroxydopamine

https://doi.org/10.1016/j.pnpbp.2017.02.015Get rights and content

Highlights

  • Asymmetry is intrinsic to normal brain function but changes with brain disorders.

  • WKY and SHR strains and brain lesions with 6-OHDA are models of mood disorders.

  • Modifications of dopamine and enkephalins are involved in mood disorders.

  • Unilateral dopamine depletions modify basal brain asymmetry of enkephalinase activity.

  • Bilateral distribution of enkephalinase depends on injured side and strain studied.

Abstract

Changes in the basal brain bilateral morphologic, neurochemical and/or functional patterns may be partly responsible for some brain disorders such as those involving mood. WKY and SHR strains as well as 6-hydroxydopamine (6-OHDA)-lesioned animals are validated models for the study of mood disorders. Because dopamine and enkephalins are involved in anxiety-related behaviors, the aim of our study was to analyze enkephalinase activity, assayed as aminopeptidase M activity, in the left and right medial prefrontal cortex (mPFC) of WKY and SHR treated with saline (sham group) or following left or right intrastriatal injections of the neurotoxic 6-OHDA. Sham left and sham right WKY exhibited a significant left predominance. Left 6-OHDA-lesioned rats inverted the left predominance of sham to right predominance. In right 6-OHDA-lesioned rats, the left predominance in sham right rats disappeared. Sham left as well as sham right SHR did not show any bilateral differences. In contrast, while the left lesion demonstrated a highly significant left predominance, the right lesion showed a slight but significant right predominance. A significant negative correlation between enkephalinase activity of the right mPFC and blood pressure and heart rate was observed only in left-lesioned SHR. Our results demonstrate that unilateral nigrostriatal injections of 6-OHDA influence the bilateral distribution of enkephalinase activity depending on both the side of the lesion and the strain analyzed. These results support the hypothesis that DA pathways may interact asymmetrically with enkephalins in the mPFC and that enkephalinase activity may play a role in the regulatory mechanisms underlying this interaction.

Introduction

The brain is bilaterally organized, and the processing of virtually all of its functions is performed asymmetrically. This asymmetry is definitely not static; it is a dynamic process that is modulated by physiologic or pathologic endogenous or exogenous factors. Although it has been suggested that morphologic and functional asymmetries underlie neurochemical brain lateralization, the link between these three aspects of brain asymmetry is not yet sufficiently understood (Ramírez et al., 2004, Toga and Thompson, 2003). For example, emotional processing, in which the dopaminergic systems and cortico-limbic regions such as the prefrontal cortex are directly involved, is lateralized in physiologic conditions (Thiel and Schwarting, 2001). In the early stages of Parkinson's disease (PD), the basal brain bilateral pattern of dopamine (DA) distribution is disrupted, and in addition to the classic motor symptoms of PD, these patients exhibit behavioral alterations such as depression or anxiety (Farina et al., 1994). Similar observations have been reported in animal models of hemiparkinsonism (Sullivan et al., 2014). These alterations may not only be related to the disturbance of the basal bilateral distribution of DA but also to disruption in the distribution of other neurotransmitters such as enkephalins that are directly involved in anxiety-related behaviors (Sandyk, 1988). Such changes in the basal brain bilateral pattern may be partly responsible for brain disorders such as PD, schizophrenia, depression or attention-deficit hyperactive disorder (ADHD) (Bonvicini et al., 2016, Molochnikov and Cohen, 2014).

Two rat strains that have been classically used for blood pressure studies are the spontaneously hypertensive rat (SHR) and its corresponding Wistar-Kyoto (WKY) rat, used as a control. Both strains also markedly differ in their anxiety-related behaviors. Moreover, SHR is a validated model for ADHD, as these animals show hyperactivity, inattention and impulsivity in comparison with WKY controls (Fan et al., 2012). Important differences in the brain content of dopamine between WKY and SHR have been identified (Fan et al., 2012). In addition, 6-hydroxydopamine (6-OHDA)-lesioned rats not only show hyperactivity but also inattention. They are therefore also considered to be a model for ADHD (Fan et al., 2012). Furthermore, this model reflects anxious-like behavior (Carvalho et al., 2013).

Because enkephalins have been shown to be involved in anxiety-related behaviors, the aim of our study was to analyze aminopeptidase M (EC 3.4.11.2, AP M, AP N, enkephalinase) activity, which is considered to be the major enkephalin-degrading enzyme in the brain (Hersh, 1985). Its brain distribution parallels the one of enkephalin receptors (Hersh, 1985) and it is believed to act at the synaptic level (Ramírez et al., 2008) degrading synaptically the released enkephalins (Hersh et al., 1987). In addition to enkephalins, this enzyme hydrolyzes the artificial substrate alanine-β-naphthylamide (Hersh et al., 1987), endorphins (Danziger, 2008) and angiotensin III in hypothalamus (Zini et al., 1996). It is therefore involved in the central control of blood pressure (Wright et al., 1990). The enzymatic activity of AP M was measured in the left and right medial prefrontal cortex (mPFC) of WKY and SHR treated with left or right-intrastriatal injections of 6-OHDA. These results were compared with the corresponding sham-operated controls that received an injection of saline, instead of 6-OHDA, into the left or right striatum. In addition, because mPFC has been shown to be involved in the modulation of the autonomic nervous system (ANS) (Sullivan et al., 2014) and a striking asymmetrical blood pressure (BP) response has been observed following left or right 6-OHDA lesioning of WKY and SHR (Banegas et al., 2011), the relationship between left and right mPFC, BP and heart rate (HR) should also be considered.

Section snippets

Animals and experimental design

Forty adult male WKY and forty adult male SHR were initially used as the sham and lesioned groups. The following groups were then designated (n = 10 each): four groups of WKY and four groups of SHR including sham left (SL), sham right (SR), lesioned left (LL) and lesioned right (LR). Degeneration of the left or right nigrostriatal dopaminergic pathways was accomplished using the catecholaminergic neurotoxin 6-OHDA (Jolicoeur and Rivest, 1992). Sham groups were similarly treated with saline. The

Motor performance after 6-OHDA lesions

Compared to sham controls, a marked ipsilateral rotational behavior was observed in left or right 6-OHDA lesioned WKY and SHR animals (p < 0.001) (Banegas et al., 2009), suggesting an almost complete left or right hemispheric depletion of DA (Carvalho et al., 2013, Kane et al., 2011). Considered individually, left or right sham WKY and SHR exhibited a randomly ipsilateral or contralateral turning behavior to the left or right intrastriatal injection of saline, with low values ranging from a

Discussion

Although DA levels were not measured in the present study, the values for turning behavior were elevated, clear and systematic enough to be confident of the marked DA depletion in the lesioned groups (Carvalho et al., 2013, Kane et al., 2011).

The present results demonstrated that unilateral nigrostriatal injections of 6-OHDA influenced the bilateral distribution of enkephalinase activity. It was clearly dependent on the side of the lesion and also on the strain analyzed. Therefore, our results

Conflict of interest

The authors declare that they have no conflict of interest.

Acknowledgements

This work was supported by Junta de Andalucía through PAI CVI-221 (Peptides and Peptidases) and CTS 438 (Group for Neurological Diseases Research in Southern Spain).

References (37)

  • R.M. Sullivan et al.

    Mesocortical dopamine depletion and anxiety related behavior in the rat: sex and hemisphere differences

    Prog. Neuro-Psychopharmacol. Biol. Psychiatry

    (2014)
  • M.T. Tadaiesky et al.

    Emotional, cognitive and neurochemical alterations in a premotor stage model of Parkinson's disease

    Neuroscience

    (2008)
  • C. Bonvicini et al.

    Attention-deficit hyperactivity disorder in adults: a systematic review and meta-analysis of genetic, pharmacogenetic and biochemical studies

    Mol. Psychiatry

    (2016)
  • I. Branchi et al.

    Nonmotor symptoms in Parkinson's disease: investigating early-phase onset of behavioral dysfunction in the 6-hydroxydopamine-lesioned rat model

    J. Neurosci. Res.

    (2008)
  • J.B. Byrd et al.

    Anxiety in the “age of hypertension”

    Curr. Hypertens. Rep.

    (2014)
  • M.M. Carvalho et al.

    Behavioral characterization of the 6-hydroxidopamine model of Parkinson's disease and pharmacological rescuing of non-motor deficits

    Mol. Neurodegener.

    (2013)
  • R.S. Danziger

    Aminopeptidase N in arterial hypertension

    Heart Fail. Rev.

    (2008)
  • S. Draca

    Gender-specific functional cerebral asymmetries and unilateral cerebral lesion sequelae

    Rev. Neurosci.

    (2010)
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