A rostro-caudal dissociation in the dorsal and ventral striatum of the juvenile SHR suggests an anterior hypo- and a posterior hyperfunctioning mesocorticolimbic system

• Published in: Behavioural brain research Vol. 130; no. 1; pp. 171 - 179
• Main Authors: Papa, M., Diewald, L., Carey, M.P., Esposito, F.J., Gironi Carnevale, U.A., Sadile, A.G.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 10.03.2002
• Subjects: ADHD; Animals; Autoradiography; c-FOS; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; CaMKII; Cannabinoid Receptor Modulators; Cerebral Cortex - physiology; Dopamine - physiology; Dopamine receptors; Dorsal striatum; Frontal cortex; Genetic models; Immunocytochemistry; Immunohistochemistry; Limbic System - physiology; Neostriatum - physiology; Perfusion; Postnatal handling; Proto-Oncogene Proteins c-fos - metabolism; Proto-Oncogene Proteins c-jun - metabolism; Quinpirole binding; Raclopride binding; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Dopamine D1 - physiology; Receptors, Dopamine D2 - physiology; SCH-23390; SHR rat; Transcription Factors - genetics; Ventral striatum; ADHD; Quinpirole binding; Immunocytochemistry; c-FOS; Frontal cortex; Postnatal handling; Dorsal striatum; Raclopride binding; Autoradiography; CaMKII; Genetic models; SCH-23390; SHR rat; Ventral striatum; Dopamine receptors
• ISSN: 0166-4328; 1872-7549
• DOI: 10.1016/S0166-4328(01)00421-1

Functional molecular neuroimaging techniques have been applied to the study of the neural substrates of Attention-Deficit Hyperactivity Disorder (ADHD) in an animal model, the juvenile SHR rat. They include quantitative receptor autoradiography and immunocytochemistry for neuronal markers such as Ca 2+/Calmodulin Dependent Kinase II (CaMKII) and transcription factors. Multiple evidence emerges for a rostro caudal dissociation within the dorsal (DS) and ventral striatum (VS) (n. accumbens) and olfactory tubercle (OT). It consists in (i) a higher density of dopamine (DA) D-1/D-5 receptor binding sites in a discrete segment of the anterior forebrain that comprises the DS, VS and OT, (ii) a lower density of DA D-2/D-3 autoreceptors in the caudal portion of the n. accumbens shell subterritory, (iii) a reduced number of CaMKII and c-FOS positive elements only in the anterior portion of DS and VS (iv) reversal by repeated injections of methylphenidate (MP) (3 mg/kg, 14 days) with ‘downregulation’ in SHR and ‘up-regulation’ in the WKY control rats of DS and VS of DA D-1/D-5 receptors. Thus, under basal conditions the mesocorticolimbic (MCL) DA system appears to be hyperfunctioning rather than hypofunctioning, as demonstrated (i) by subsensitivity of presynaptic D-3 autoreceptors and (ii) by phasic inhibition of MCL activity induced by acute blockade of endocannabinoid reuptake using AM404. Following MP treatment, the hyperfunctioning MCL DA system turns into a hypofunctioning one, as earlier suggested by Solanto [32]. Since the target neurons of MCL fibers seem to be uncoupled to D-1 receptors, the medium spiny GABA neurons projecting to the ventral pallidum and ventral tegmental area (VTA) exert a weak feedback inhibition on the neurons of origin of MCL system. Therefore, MCL neurons maintain a high basal activity with consequences on the cortico–striato–pallido–thalamo–cortical system and amygdala complex through the ‘extended amygdala system’. While the former explains the attention, motivation and activity alterations of this rat model of ADHD, the latter explains the emotional symptoms of the syndrome. It remains to be ascertained the starting point in the network leading eventually to the segmental defect as well as its significance in humans.