Systematic review and meta-analysis of the behavioral effects of methylphenidate in the spontaneously hypertensive rat model of attention-deficit/hyperactivity disorder

Douglas T Leffa; Alana C Panzenhagen; Artur A Salvi; Claiton H D Bau; Gabriel N Pires; Iraci L S Torres; Luis A Rohde; Diego L Rovaris; Eugenio H Grevet

doi:10.1016/j.neubiorev.2019.02.019

Systematic review and meta-analysis of the behavioral effects of methylphenidate in the spontaneously hypertensive rat model of attention-deficit/hyperactivity disorder

Neurosci Biobehav Rev. 2019 May:100:166-179. doi: 10.1016/j.neubiorev.2019.02.019. Epub 2019 Feb 28.

Authors

Douglas T Leffa¹, Alana C Panzenhagen², Artur A Salvi³, Claiton H D Bau⁴, Gabriel N Pires⁵, Iraci L S Torres⁶, Luis A Rohde⁷, Diego L Rovaris⁸, Eugenio H Grevet⁹

Affiliations

¹ Post-Graduate Program in Medicine: Medical Sciences, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Laboratory of Pain Pharmacology and Neuromodulation: Pre-clinical studies - Pharmacology Department, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
² Department of Genetics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; ADHD Outpatient Program, Hospital de Clínicas de Porto Alegre, Brazil.
³ Laboratory of Pain Pharmacology and Neuromodulation: Pre-clinical studies - Pharmacology Department, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
⁴ Department of Genetics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; ADHD Outpatient Program, Hospital de Clínicas de Porto Alegre, Brazil; Department of Psychiatry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
⁵ Departamento de Psicobiologia, Universidade Federal de São Paulo, São Paulo, Brazil; Department of Physiological Sciences, Santa Casa de São Paulo School of Medical Sciences, São Paulo, Brazil.
⁶ Laboratory of Pain Pharmacology and Neuromodulation: Pre-clinical studies - Pharmacology Department, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Animal Experimentation Unit - GPPG - Hospital de Clínicas de Porto Alegre - Porto, Alegre, Brazil.
⁷ ADHD Outpatient Program, Hospital de Clínicas de Porto Alegre, Brazil; Department of Psychiatry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; National Institute of Developmental Psychiatry for Children and Adolescents, Brazil.
⁸ Department of Genetics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; ADHD Outpatient Program, Hospital de Clínicas de Porto Alegre, Brazil; Department of Psychiatry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. Electronic address: drovaris@hcpa.edu.br.
⁹ ADHD Outpatient Program, Hospital de Clínicas de Porto Alegre, Brazil; Department of Psychiatry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

PMID: 30826386
DOI: 10.1016/j.neubiorev.2019.02.019

Abstract

The spontaneously hypertensive rats (SHR) are the most widely used model for ADHD. While face and construct validity are consolidated, questions remain about the predictive validity of the SHR model. We aim at summarizing the evidence for the predictive validity of SHR by evaluating its ability to respond to methylphenidate (MPH), the most well documented treatment for ADHD. A systematic review was carried out to identify studies evaluating MPH effects on SHR behavior. Studies (n=36) were grouped into locomotion, attention, impulsivity or memory, and a meta-analysis was performed. Meta-regression, sensitivity, heterogeneity, and publication bias analyses were also conducted. MPH increased attentional and mnemonic performances in the SHR model and decreased impulsivity in a dose-dependent manner. However, MPH did not reduce hyperactivity in low and medium doses, while increased locomotor activity in high doses. Thus, since the paradoxical effect of stimulant in reducing hyperactivity was not observed in the SHR model, our study does not fully support the predictive validity of SHR, questioning their validity as an animal model for ADHD.

Keywords: ADHD; Animal model; Meta-analysis; Methylphenidate; Predictive validity; SHR; Systematic review.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't
Systematic Review

MeSH terms

Animals
Attention / drug effects
Attention Deficit Disorder with Hyperactivity / psychology*
Behavior, Animal / drug effects*
Central Nervous System Stimulants / administration & dosage*
Disease Models, Animal*
Dose-Response Relationship, Drug
Impulsive Behavior / drug effects
Memory / drug effects
Methylphenidate / administration & dosage*
Rats, Inbred SHR
Reproducibility of Results

Substances

Central Nervous System Stimulants
Methylphenidate