Differential distribution, affinity and plasticity of dopamine D-1 and D-2 receptors in the target sites of the mesolimbic system in an animal model of ADHD.
The distribution of dopamine (DA) D-1 and D-2 receptors has been studied by autoradiography in the anterior forebrain of the pre-hypertensive spontaneously hypertensive rat (SHR) as an animal model of attention-deficit hyperactivity disorder (ADHD) in children. Juvenile male SHR and Wistar Kyoto (WKY) controls were given either vehicle or the DA re-uptake blocker methylphenidate (MP; 3 mg/kg, i.p.), daily during a 2-week period. A saturation analysis for the D-1 receptor subfamily was carried out with 0.1-5.0 nM of [3H]SCH23390 and two competition studies for the D-2 receptor subfamily with 4 nM of [3H]raclopride or 5 nM of [3H]quinpirole were carried out with unlabelled spiperone and 7-OH-DPAT as unlabelled displacers on cryostat coronal sections of the anterior forebrain. Quantitative receptor autoradiography and computer-assisted image analysis with reference to co-exposed 3H-microscale standards showed in vehicle-treated SHR higher density of DA D-1/D-5 receptor subtypes in the caudate-putamen (CPU), the nucleus accumbens (ACB) core and shell and the olfactory tubercle (OT), which was associated to a lower affinity. MP treatment normalised the DA D-1/D-5 receptors by decreasing the number of binding sites and increasing the affinity to control level. In addition, MP treatment 'down-regulated' DA D-2/D-4 subtypes in the CPU, ACB and OT, and 'up-regulated' mostly D-3 subtype in CPU, ACB, OT in both rat lines and in the globus pallidus, ventral pallidum and lateral septum in WKY rats only. In contrast, D-3 receptors were 'down-regulated' in the islands of Calleja in both rat lines. Moreover, regional cross-correlative analyses revealed a modulatory influence of DA receptors in the cross-talk within the anterior forebrain, which was altered in the SHR. Thus, the differential distribution and regulation of DA receptor subtypes following DA re-uptake blocker as well as the different regional cross-talk in the target sites of nigrostriatal and mesolimbic DA systems lend support to the DA hypothesis of ADHD in children.
Carey
M P
MP
Laboratory Neurophysiology, Behaviour and Neural Networks, Department of Human Physiology F. Bottazzi, Napoli, Italy.
Diewald
L M
LM
Esposito
F J
FJ
Pellicano
M P
MP
Gironi Carnevale
U A
UA
Sergeant
J A
JA
Papa
M
M
Sadile
A G
AG
D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000473:pathology / Q000503:physiopathology*; D001345:Autoradiography; D001931:Brain Mapping; D004195:Disease Models, Animal; D008032:Limbic System / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008636:Mesencephalon / Q000473:pathology / Q000503:physiopathology*; D009473:Neuronal Plasticity / Q000502:physiology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D020239:Receptor Cross-Talk / Q000502:physiology; D017447:Receptors, Dopamine D1 / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000502:physiology*
D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2