Dataset Information

Behavioural effects of methylphenidate in the spontaneously hypertensive rat model of attention-deficit/hyperactivity disorder: a systematic review and meta-analysis protocol.

ABSTRACT:

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent condition related to several negative outcomes, and its pathophysiology is still poorly understood. The spontaneously hypertensive rats (SHRs) are the most commonly used animal model of ADHD. How ever, its validity, and especially its predictive validity, has been questioned. Therefore, the current protocol discloses the background, aims and methods of a systematic review and meta-analysis of studies reporting the behavioural effects of methylphenidate (MPH), the most commonly prescribed treatment for ADHD, in the SHR.

Search strategy

Studies will be identified through a literature search using three different electronic databases: Medline, Embase and Web of Science. There will be no language restrictions. All s tudies that administered MPH to SHR and evaluated locomotion, attention, impulsivity or memory will be included.

Screening and annotation

Studies will be prescreened based on title and abstract, and a full-text review will be performed if necessary. Screening will be performed by two authors, and any disagreement will be discussed with a third author.

Data management and reporting

Data extraction will be performed by two independent authors according to a standardised form. Studies will be grouped according to the behavioural outcomes reported, and a meta-analysis will be performed for each group. The influence of predefined covariates on the effects of MPH will be evaluated using meta-regression and sensitivity analyses. Data will be reported following PRISMA guidelines.

SUBMITTER: Leffa DT

PROVIDER: S-EPMC8715948 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.