Abstract
BackgroundMolecular genetic studies suggest the dopamine D1 receptor (D1R) may be implicated in attention-deficit/hyperactivity disorder (ADHD). As little is known about the potential motor role of D1R in ADHD, animal models may provide important insights into this issue.MethodsWe investigated the effects of a full and selective D1R agonist, SKF-81297 (0.3, 3 and 10 mg/kg), on motor behaviour and expression of the plasticity-associated gene, c-fos, in habituated young adult male Spontaneously Hypertensive Rats (SHR), the most commonly used animal model of ADHD, and Wistar-Kyoto (WKY; the strain from which SHR were derived).ResultsSHR rats were more behaviourally active than WKY rats after injection with vehicle. The 0.3 mg/kg dose of SKF-81297 increased motor behaviour (locomotion, sifting, rearing, and sniffing) in both SHR and WKY rats. Total grooming was also stimulated, but only in WKY rats. The same dose increased c-fos mRNA expression in the piriform cortex of both strains. The 3 mg/kg dose increased sifting and sniffing in both strains. Locomotion was also stimulated towards the end of the testing period. The intermediate dose decreased total rearing in both strains, and produced a significant increase in c-fos mRNA in the striatum, nucleus accumbens, olfactory tuberculum, and in the cingulate, agranular insular and piriform cortices. The 10 mg/kg dose of SKF-81297 produced a biphasic effect on locomotion, which was characterized by an initial decrease followed by later stimulation. The latter stimulatory effect was more pronounced in SHR than in WKY rats when compared to their respective vehicle-injected groups. The 10 mg/kg dose also stimulated sifting and sniffing in both strains. Both the 3 and 10 mg/kg doses had no effect on total grooming. The 10 mg/kg dose induced significantly higher levels of c-fos mRNA expression in the nucleus accumbens and adjacent cortical regions (but not striatum) of SHR when compared to WKY rats.ConclusionThe present results suggest a potential alteration in D1R neurotransmission within the frontal-striatal circuitry of SHR involved in motor control. These findings extend our understanding of the molecular alterations in SHR, a heuristically useful model of ADHD.
Highlights
Molecular genetic studies suggest the dopamine D1 receptor (D1R) may be implicated in attention-deficit/hyperactivity disorder (ADHD)
D1R densities are elevated in the striatum and nucleus accumbens of spontaneously hypertensive rats (SHR) [10,11,12], the most commonly used genetic animal model of ADHD [13] – which is consistent with the hypothesis that D1R neurotransmission may be altered in ADHD
EuFefifgseucatrseos2fhSoKwFn-8a1s2m97ea(n0s.3±, 3S,.Ea.nMd.,1n0 =m4g/–k6g)poern eca-fcohsgmroRuNpA) expression in the striatum and cortex of SHR and Wistar-Kyoto strain (WKY) rats (valEffects of SKF-81297 (0.3, 3, and 10 mg/kg) on c-fos mRNA expression in the striatum and cortex of SHR and WKY rats. **P < 0.0001; * P < 0.05 compared to WKY rats of the same dose
Summary
Molecular genetic studies suggest the dopamine D1 receptor (D1R) may be implicated in attention-deficit/hyperactivity disorder (ADHD). The DA D1 receptors (D1R), which are expressed highly in the striatum and prefrontal cortex (PFC), may be relevant for ADHD These receptors are crucial modulators of the motor and cognitive functions mediated by the frontal-striatal circuitry [5,6], functions which are impaired in patients with ADHD. We investigated potential alterations in the motor stimulatory role of D1R in SHR, and in the normotensive Wistar-Kyoto strain (WKY; from which SHR were derived) For this purpose, we studied the motor responses to the full and selective D1R agonist, SKF81297 (0.3, 3, and 10 mg/kg s.c.), and the expression of the plasticity-associated gene, c-fos, in the striatum and adjacent cortical structures, in habituated young male SHR and WKY rats. SKF-81297 was selected since it appears to be a highly selective D1R ligand in vivo, based on on its lack of inhibition of midbrain DA neurons [14], and its lack of response in DA D1 receptor-deficient mutant mice following systemic administration [15]
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