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.
Laboratory Neurophysiology, Behaviour and Neural Networks, Department of Human Physiology F. Bottazzi, Napoli, Italy.
M P
MP
Carey
L M
LM
Diewald
F J
FJ
Esposito
M P
MP
Pellicano
U A
UA
Gironi Carnevale
J A
JA
Sergeant
M
M
Papa
A G
AG
Sadile
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