Altered Reinforcement Sensitivity and Dopamine Transporter Function in an Animal Model of Attention Deficit Hyperactivity Disorder

Attention Deficit Hyperactivity Disorder;Reinforcement Sensitivity;Dopamine Transporter;Animal Model;New Zealand Genetically Hypertensive Rat;Spontaneously Hypertensive Rat;In Vivo Electrochemistry

Sutherland, Karen Rachael ; Hyland, Brian I. ; Wickens, Jeffery R. ; Tripp, Gail

University of Otago

关键词: Attention Deficit Hyperactivity Disorder;    Reinforcement Sensitivity;    Dopamine Transporter;    Animal Model;    New Zealand Genetically Hypertensive Rat;    Spontaneously Hypertensive Rat;    In Vivo Electrochemistry;   

Others  :  https://ourarchive.otago.ac.nz/bitstream/10523/408/1/FINAL%20complete%20corrected%20thesis%203.pdf

美国|英语

来源: Otago University Research Archive

【 摘 要 】

Altered reinforcement sensitivity is an important characteristic of Attention Deficit Hyperactivity Disorder (ADHD). In order to elucidate the neurobiological mechanisms behind this characteristic, an appropriate animal model is required. The present thesis aimed to characterise altered reinforcement sensitivity within the New Zealand genetically hypertensive (NZGH) rat model of ADHD (in comparison to the spontaneously hypertensive rat (SHR) model of ADHD), and to investigate dopamine transporter (DAT) function, as dopamine has previously been implicated in both reward and ADHD. Behaviour was characterised using a discrete trial choice procedure in which rats were presented with a choice between two levers, each differing in either frequency or delay of reinforcement. Like children with ADHD, both SHR and NZGH strains showed an equal preference towards a response associated with a greater frequency of reinforcement, but a greater preference for immediate over delayed reinforcement, in comparison to their respective control strains, the Wistar-Kyoto (WKY) and Wistar (WI). Altered sensitivity towards individual instances of reinforcement (similar to that shown by children with ADHD) was shown by the SHR in the reinforcement frequency study, and by the NZGH in the reinforcement delay study. Overall the behavioural results supported the use of the NZGH as a model of ADHD, and suggested that the NZGH were just as good as the SHR, in modelling the altered reinforcement sensitivity characteristic of ADHD. Exogenous dopamine was locally applied into either the caudate putamen or the medial prefrontal cortex, to indirectly assess DAT function (by determining whether there were any differences in the effects of nomifensine (a DAT and norepinephrine transporter (NET) inhibitor) relative to vehicle on the clearance parameters). Although differences in dopamine clearance (independent of drug effects) were observed between the two strains, with the NZGH showing higher clearance values over time, this did not appear to be due to differences in DAT function, as both strains showed similar effects of nomifensine. In addition, no strain differences were observed in the effects of methylphenidate (a DAT and NET inhibitor) or atomoxetine (a specific NET inhibitor), two current pharmacological treatments for ADHD. Given the similarity between strains in the effects of the various drugs used, the differences found in overall dopamine clearance (independent of drug effects) may be due to alterations in other aspects of the dopamine system, or in other neurotransmitter systems.