Abstract
BackgroundAttention-deficit/hyperactivity disorder (ADHD) is a highly heritable developmental disorder resulting from complex gene-gene and gene-environment interactions. The most widely used animal model, the spontaneously hypertensive rat (SHR), displays the major symptoms of ADHD (deficits in attention, impulsivity and hyperactivity) and has a disturbance in the noradrenergic system when compared to control Wistar-Kyoto rats (WKY). The aim of the present study was to determine whether the ADHD-like characteristics of SHR were purely genetically determined or dependent on the gene-environment interaction provided by the SHR dam.MethodsSHR/NCrl (Charles River, USA), WKY/NCrl (Charles River, USA) and Sprague Dawley rats (SD/Hsd, Harlan, UK) were bred at the University of Cape Town. Rat pups were cross-fostered on postnatal day 2 (PND 2). Control rats remained with their birth mothers to serve as a reference for their particular strain phenotype. Behavior in the open-field and the elevated-plus maze was assessed between PND 29 and 33. Two days later, rats were decapitated and glutamate-stimulated release of [3H]norepinephrine was determined in prefrontal cortex and hippocampal slices.ResultsThere was no significant effect of "strain of dam" but there was a significant effect of "pup strain" on all parameters investigated. SHR pups travelled a greater distance in the open field, spent a longer period of time in the inner zone and entered the inner zone of the open-field more frequently than SD or WKY. SD were more active than WKY in the open-field. WKY took longer to enter the inner zone than SHR or SD. In the elevated-plus maze, SHR spent less time in the closed arms, more time in the open arms and entered the open arms more frequently than SD or WKY. There was no difference between WKY and SD behavior in the elevated-plus maze. SHR released significantly more [3H]norepinephrine in response to glutamate than SD or WKY in both hippocampus and prefrontal cortex while SD prefrontal cortex released more [3H]norepinephrine than WKY. SHR were resilient, cross-fostering did not reduce their ADHD-like behavior or change their neurochemistry. Cross-fostering of SD pups onto SHR or WKY dams increased their exploratory behavior without altering their anxiety-like behavior.ConclusionThe ADHD-like behavior of SHR and their neurochemistry is genetically determined and not dependent on nurturing by SHR dams. The similarity between WKY and SD supports the continued use of WKY as a control for SHR and suggests that SD may be a useful additional reference strain for SHR. The fact that SD behaved similarly to WKY in the elevated-plus maze argues against the use of WKY as a model for anxiety-like disorders.
Highlights
Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable developmental disorder resulting from complex gene-gene and gene-environment interactions
A two-way analysis of variance (ANOVA) revealed a significant effect of "pup strain" (F(2,100) > 6, P < 0.005) for all parameters investigated and a significant interaction between "strain of dam" and "pup strain" for various behavioral parameters including latency to enter the inner zone of the open-field (F(4,100) = 2.81, P < 0.05, Figure 1), frequency of entries into the inner zone of the open-field (F(4,100) = 3.96, P < 0.005, Figure 1) and frequency of entries into the open arms of the elevated-plus maze (F(4,100) = 3.67, P < 0.01, Figure 2), as well as glutamate-stimulated release of [3H]norepinephrine in rat pup hippocampus (F(4,100) = 2.55, P < 0.05, Figure 3)
The evidence presented in this paper provides support for the use of Wistar-Kyoto rats (WKY) as a control strain for spontaneously hypertensive rat (SHR)
Summary
Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable developmental disorder resulting from complex gene-gene and gene-environment interactions. The most widely used animal model, the spontaneously hypertensive rat (SHR), displays the major symptoms of ADHD (deficits in attention, impulsivity and hyperactivity) and has a disturbance in the noradrenergic system when compared to control Wistar-Kyoto rats (WKY). Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous disorder resulting from complex gene-gene and gene-environment interactions which give rise to variable expression of the defining symptoms of impaired sustained attention, impulsivity and hyperactivity [1,2,3,4,5]. To explain the heterogeneous nature of ADHD, it has been suggested that different combinations of genetic and environmental factors may be required to produce individual clusters of behavioral symptoms [1115]. Environmental risk factors that contribute significantly to ADHD, include prenatal exposure to drugs such as alcohol and nicotine, obstetric complications, head injury and psychosocial adversity, suggesting that the early postnatal environment may be an important contributory factor [16,17,18]
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