Elsevier

Behavioural Brain Research

Volume 256, 1 November 2013, Pages 229-237
Behavioural Brain Research

Research report
Ketamine increases striatal dopamine release and hyperlocomotion in adult rats after postnatal functional blockade of the prefrontal cortex

https://doi.org/10.1016/j.bbr.2013.08.017Get rights and content

Highlights

  • This study deals with animal modeling of the pathophysiology of schizophrenia

  • Consequences of early prefrontal blockade for ketamine challenge were investigated

  • TTX blockade increased striatal dopaminergic reactivity to ketamine at adulthood

  • TTX blockade enhanced locomotor activity with the highest ketamine dose

  • A disruption of glutamate-dopamine relationships in schizophrenia could be considered

Abstract

Schizophrenia is a complex psychiatric disorder that may result from defective connectivity, of neurodevelopmental origin, between several integrative brain regions. Different anomalies consistent with brain development failures have been observed in patients’ left prefrontal cortex (PFC). A striatal dopaminergic functional disturbance is also commonly acknowledged in schizophrenia and could be related to a dysfunctioning of dopamine–glutamate interactions. Non-competitive NMDA antagonists, such as ketamine, can induce psychotic symptoms in healthy individuals and worsen these symptoms in patients with schizophrenia. Our study set out to investigate the consequences of neonatal functional blockade of the PFC for dopaminergic and behavioral reactivity to ketamine in adult rats. Following tetrodotoxin (TTX) inactivation of the left PFC at postnatal day 8, dopaminergic responses induced by ketamine (5 mg/kg, 10 mg/kg, 20 mg/kg sc) were monitored using in vivo voltammetry in the left part of the dorsal striatum in freely moving adult rats. Dopaminergic responses and locomotor activity were followed in parallel. Compared to PBS animals, in rats microinjected with TTX, ketamine challenge induced a greater release of dopamine in the dorsal striatum for the highest dose (20 mg/kg sc) and the intermediate dose (10 mg/kg sc). A higher increase in locomotor activity in TTX animals was observed only for the highest dose of ketamine (20 mg/kg sc). These data suggest transient inactivation of the PFC during early development results in greater behavioral and striatal dopaminergic reactivity to ketamine in adulthood. Our study provides an anatomo-functional framework that may contribute toward a better understanding of the involvement of NMDA glutamatergic receptors in schizophrenia.

Introduction

Schizophrenia is a complex and devastating neuropsychiatric disorder that may result from defective connectivity between several integrative brain regions [1], [2]. The prefrontal cortex (PFC) appears to be one integrative region crucially affected in this disorder. Recently, cytoarchitectural and neuronal morphometric abnormalities have been described in patients with schizophrenia, reminiscent of early neurodevelopment defects at the level of the PFC, particularly in the left hemisphere [3], [4], [5], [6]. In addition, for several decades now a striatal dopaminergic imbalance has been acknowledged in schizophrenia [7], [8], [9], as supported by several brain imaging studies [8], [10], [11], [12], [13], [14], [15], [16], [17]. The dopaminergic dysregulation may result from prefronto-striatal disconnectivity [1], [18], [19], [20]. Moreover, a dysfunction of dopamine–glutamate interactions has also been suggested in schizophrenia [21], [22], [23]. Consistent with this suggestion, non-competitive antagonists of the NMDA (N-Methyl-d-Aspartate) glutamatergic receptor administered at subanesthetic doses, such as phencyclidine (PCP) and ketamine, have been shown to induce schizophrenia-like symptoms in healthy individuals [24], [25], [26], [27] and to exacerbate psychotic symptoms in patients with schizophrenia [28], [29]. The striatal dopaminergic dysregulation in schizophrenia could result from a prefronto-striatal disconnectivity involving NMDA receptors [8], [30].

Taking the aforementioned data into account, the aim of the present study was to investigate the consequences of early functional inactivation of the left PFC for dopaminergic and locomotor reactivity to ketamine challenge in adult rats. At postnatal day (PND) 8, we carried out a functional blockade of the left PFC (infralimbic/prelimbic region) by local microinjection of tetrodotoxin (TTX), a well-known Na+ channel blocker [31]. PND8 is a critical time for brain development in rats, comparable to the middle of the second trimester of human gestation, which is considered a period of high vulnerability for developing schizophrenia at least in some cases [32], [33]. During brain development impulse neuronal activity, which is interrupted by TTX in the present study, is crucial for shaping connections in the target structures [34], [35], [36], [37], [38]. Behavioral reactivity to ketamine was assessed by locomotor activity, a good index for animal modeling for schizophrenia [39], [40]. Ketamine-induced dopamine release was monitored, parallel to locomotor activity, in the left part of the dorsal striatum using in vivo voltammetry in freely moving adult animals (11 weeks).

Section snippets

Animals

All animals were housed in a temperature-controlled room (22 ± 2 °C) with access to water and food ad libitum. A total of 74 male Sprague-Dawley rats born to mothers from the R. Janvier breeding center (Le Genest-Saint-Isle, France) were used. The mothers were kept during gestation in individual cages on a 12 h light/dark cycle (lights on at 7 am). All the experimental procedures were conducted in accordance with European Community guidelines for the care and use of experimental animals (Council

Histology

The qualitative macroscopic analysis of brain sections at the level of the dorsal striatum (Fig. 1, upper sections) or PFC (Fig. 1, lower sections) showed no gliosis, damage or anatomical changes between animals that received a neonatal microinjection of PBS in the PFC at PND8 and those that were microinjected at PND8 with TTX in the PFC.

Ketamine-induced locomotor activity

Only animals that were successfully microinjected at PND8 in the prelimbic/infralimbic part of the left PFC (see [43]; Supplementary Fig. S1) were considered

Discussion

The aim of the present study was to test the hypothesis that functional inactivation of the PFC during early development leads in adulthood to increased striatal dopaminergic and locomotor reactivity to the non-competitive NMDA antagonist, ketamine, administered in subanesthetic doses. The data obtained suggest that, following ketamine challenge, the intermediate and highest doses (10 mg/kg, 20 mg/kg) induced a larger release of dopamine in the left dorsal striatum of rats microinjected in the

Conflict of interest

In matters relating to the experiments presented in this manuscript, the authors have no conflicts of interest to report, nor any involvement to disclose.

Acknowledgements

This research was supported by Fondation de France (F.M.), and Electricité de France (EDF) (A.L.). The authors thank helpful assistance of Gizem Dedeoglu.

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    Present address: Radboud University Nijmegen, Donders Institute for Brain, Cognition and Behaviour, NCMLS, Geert Grooteplein Zuid 28, 6525GA Nijmegen, The Netherlands.

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