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N-methyl-d-aspartate receptor dysfunction in the prefrontal cortex of stroke-prone spontaneously hypertensive rat/Ezo as a rat model of attention deficit/hyperactivity disorder.

ABSTRACT: Aim: We previously reported that stroke-prone spontaneously hypertensive rat/Ezo (SHRSP/Ezo) has high validity as an attention deficit/hyperactivity disorder (AD/HD) animal model, based on its behavioral phenotypes, such as inattention, hyperactivity, and impulsivity. Fronto-cortical dysfunction is implicated in the pathogenesis of AD/HD. In this study, we investigated prefrontal cortex (PFC) function in SHRSP/Ezo rats by electrophysiological methods and radioreceptor assay.

Methods: We recorded excitatory postsynaptic potential in layer V pyramidal neurons in the PFC by intracellular recording method to assess synaptic plasticity in the form of long-term potentiation (LTP). We also performed N-methyl-d-aspartate acid (NMDA) receptor binding assay in the PFC and hippocampus using radiolabeled NMDA receptor antagonist [³ H]MK-801.

Results: Theta-burst stimulation induced LTP in the PFC of genetic control, WKY/Ezo, whereas failed to induce LTP in that of SHRSP/Ezo. The K_d value of [³ H]MK-801 binding for NMDA receptors in the PFC of SHRSP/Ezo was higher than in the WKY/Ezo. Neither the B_max nor K_d of [³ H]MK-801 binding in the SHRSP/Ezo hippocampus was significantly different to WKY/Ezo.

Conclusion: These results suggest that the AD/HD animal model SHRSP/Ezo has NMDA receptor dysfunction in the PFC.

SUBMITTER: Shikanai H

PROVIDER: S-EPMC7292284 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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N-methyl-d-aspartate receptor dysfunction in the prefrontal cortex of stroke-prone spontaneously hypertensive rat/Ezo as a rat model of attention deficit/hyperactivity disorder.

Shikanai Hiroki H Oshima Nobuhiro N Kawashima Hidekazu H Kimura Shin-Ichi SI Hiraide Sachiko S Togashi Hiroko H Iizuka Kenji K Ohkura Kazue K Izumi Takeshi T

Neuropsychopharmacology reports 20180226 2

<h4>Aim</h4>We previously reported that stroke-prone spontaneously hypertensive rat/Ezo (SHRSP/Ezo) has high validity as an attention deficit/hyperactivity disorder (AD/HD) animal model, based on its behavioral phenotypes, such as inattention, hyperactivity, and impulsivity. Fronto-cortical dysfunction is implicated in the pathogenesis of AD/HD. In this study, we investigated prefrontal cortex (PFC) function in SHRSP/Ezo rats by electrophysiological methods and radioreceptor assay.<h4>Methods</h ...[more]

PMID: 30106260

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Project description:The spontaneously hypertensive rat is thought to show good validity as a model of attention deficit hyperactivity disorder, in part because of impaired delayed reinforcement behaviour, corresponding to the dynamic developmental theory of the disorder. However, some previous studies may have been confounded use of fluid reward. Therefore, the objective of this study was to assess the spontaneously hypertensive rat and two comparison strains (Wistar and Wistar Kyoto) using a non-delayed food reinforcement paradigm in an attempt to advance knowledge of basic learnt behaviour in this strain, without potentially confounding reward sensitivity, which could impact on motivation to learn. Rats were trained on a fixed ratio 1 two choice discrimination schedule, extinction, reacquisition and reversal. We also tested non-reinforced spontaneous alternation to facilitate data interpretation.The spontaneously hypertensive rat displayed slower shaping and reduced on task activity during task acquisition, contrasting with previous results which indicate either enhanced responding and an impairment only when a delay is used; we suggest several reasons for this. In line with previous work, the same strain exhibited poor extinguishing of behaviour but were not impaired to the same extent on reversal of the discrimination. Finally, non-reinforced alternations on a Y-maze were also reduced in the spontaneously hypertensive rat.In sum, the spontaneously hypertensive rat appear to show poor response inhibition in reinforced and non-reinforced contexts. However, impaired response inhibition was reduced during reversal when an opposite response produced food reward alongside presentation of the conditioned stimulus. We discuss the possibility of enhanced attribution of incentive salience to cues in this strain and highlight several points of caution for researchers conducting behavioural assessments using the spontaneously hypertensive rat and their associated comparison strains.

Project description:BackgroundMethylphenidate is the most commonly used stimulant drug for the treatment of attention-deficit/hyperactivity disorder (ADHD). Research has found that methylphenidate is a "reinforcer" and that individuals with ADHD also abuse this medication. Nevertheless, the molecular consequences of long-term recreational methylphenidate use or abuse in individuals with ADHD are not yet fully known.MethodsSpontaneously hypertensive rats (SHR), the most validated and widely used ADHD animal model, were pretreated with methylphenidate (5 mg/kg, i.p.) during their adolescence (post-natal day [PND] 42-48) and tested for subsequent methylphenidate-induced conditioned place preference (CPP) and self-administration. Thereafter, the differentially expressed genes in the prefrontal cortex (PFC) and striatum of representative methylphenidate-treated SHRs, which showed CPP to and self-administration of methylphenidate, were analyzed.ResultsGenome-wide transcriptome profiling analyses revealed 30 differentially expressed genes in the PFC, which include transcripts involved in apoptosis (e.g. S100a9, Angptl4, Nfkbia), transcription (Cebpb, Per3), and neuronal plasticity (Homer1, Jam2, Asap1). In contrast, 306 genes were differentially expressed in the striatum and among them, 252 were downregulated. The main functional categories overrepresented among the downregulated genes include those involved in cell adhesion (e.g. Pcdh10, Ctbbd1, Itgb6), positive regulation of apoptosis (Perp, Taf1, Api5), (Notch3, Nsbp1, Sik1), mitochondrion organization (Prps18c, Letm1, Uqcrc2), and ubiquitin-mediated proteolysis (Nedd4, Usp27x, Ube2d2).ConclusionTogether, these changes indicate methylphenidate-induced neurotoxicity, altered synaptic and neuronal plasticity, energy metabolism and ubiquitin-dependent protein degradation in the brains of methylphenidate-treated SHRs, which showed methylphenidate CPP and self-administration. In addition, these findings may also reflect cognitive impairment associated with chronic methylphenidate use as demonstrated in preclinical studies. Future studies are warranted to determine the clinical significance of the present findings with regard to long-term recreational methylphenidate use or abuse in individuals with ADHD.

Dataset Information

N-methyl-d-aspartate receptor dysfunction in the prefrontal cortex of stroke-prone spontaneously hypertensive rat/Ezo as a rat model of attention deficit/hyperactivity disorder.

Publications

N-methyl-d-aspartate receptor dysfunction in the prefrontal cortex of stroke-prone spontaneously hypertensive rat/Ezo as a rat model of attention deficit/hyperactivity disorder.

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