Abstract
Although animals cannot be used to study complex human behaviour such as language, they do have similar basic functions. In fact, human disorders that have animal models are better understood than disorders that do not. ADHD is a heterogeneous disorder. The relatively simple nervous systems of rodent models have enabled identification of neurobiological changes that underlie certain aspects of ADHD behaviour. Several animal models of ADHD suggest that the dopaminergic system is functionally impaired. Some animal models have decreased extracellular dopamine concentrations and upregulated postsynaptic dopamine D1 receptors (DRD1) while others have increased extracellular dopamine concentrations. In the latter case, dopamine pathways are suggested to be hyperactive. However, stimulus-evoked release of dopamine is often decreased in these models, which is consistent with impaired dopamine transmission. It is possible that the behavioural characteristics of ADHD result from impaired dopamine modulation of neurotransmission in cortico-striato-thalamo-cortical circuits. There is considerable evidence to suggest that the noradrenergic system is poorly controlled by hypofunctional α2-autoreceptors in some models, giving rise to inappropriately increased release of norepinephrine. Aspects of ADHD behaviour may result from an imbalance between increased noradrenergic and decreased dopaminergic regulation of neural circuits that involve the prefrontal cortex. Animal models of ADHD also suggest that neural circuits may be altered in the brains of children with ADHD. It is therefore of particular importance to study animal models of the disorder and not normal animals. Evidence obtained from animal models suggests that psychostimulants may not be acting on the dopamine transporter to produce the expected increase in extracellular dopamine concentration in ADHD. There is evidence to suggest that psychostimulants may decrease motor activity by increasing serotonin levels. In addition to providing unique insights into the neurobiology of ADHD, animal models are also being used to test new drugs that can be used to alleviate the symptoms of ADHD.
Highlights
Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed psychiatric disorder of childhood [1,2]
A transmembrane protein involved in DRD1/ DRD5 signalling, has been implicated in ADHD [69]
Calcyon enables the typically Gs-linked DRD1/DRD5 to switch from Gs to Gq coupling, thereby stimulating inositol 1,4,5-triphosphate (IP3) turnover with resultant release of calcium from intracellular stores
Summary
Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed psychiatric disorder of childhood [1,2]. The increase in DRD1 density observed in SHR striatum is reversed by methylphenidate treatment suggesting that psychostimulants reduce ADHD-like behaviour of SHR by increasing dopamine activation of DRD1 [51,81,82] thereby enabling dopamine-mediated LTP and reinforcement mechanisms to take place. In vitro findings provided further support, where methylphenidate released significantly less dopamine from SHR nucleus accumbens slices than WKY [58], and chronic methylphenidate treatment (3 mg/kg for 2 weeks) increased endogenous dopamine activation of DRD2 in WKY striatum but did not alter DRD2 function in SHR probably because DRD2 were already up-regulated in SHR and no longer responsive to increases in extracellular dopamine [141] These results suggest that neural circuits have been altered in SHR and that psychostimulant drugs affect SHR and WKY brains differently. Future research on animal models of human disorders will undoubtedly promote a better understanding of the contribution of specific neurobiological factors to behavioural components like attention, reinforcement and extinction that seem to be important for understanding ADHD
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