A Risk Factor for Attention Deficit Hyperactivity Disorder Induces Marked Long-Term Anatomical Changes at GABAergic-Dopaminergic Synapses in the Rat Ventral Tegmental Area.

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder. However, the core biology of the disorder that leads to the hypofunctioning of the cerebral dopaminergic network requires further elucidation. We investigated midbrain synaptic changes in male rats exposed to repeated hypoxia during the equivalent of extreme prematurity, which is a new animal model of the hyperactive/impulsive presentation of ADHD. We used a novel combination of a lentiviral vector, peroxidase-immunonanogold double-labelling, three-dimensional serial section transmission electron microscopy and stereological techniques to investigate the synapses formed between GABAergic axons of the rostromedial tegmental nucleus (RMTg) and dopaminergic neurons of the posterior ventral tegmental area (pVTA). This is a key site that sends extensive dopaminergic projections to the forebrain. We also compared the results to our previous study on a schizophrenia risk factor that produces cerebral hyperdopaminergia. In total, 117 reconstructed synapses were compared. Repeated hypoxic rats had a significantly thicker (22%) and longer (18%) postsynaptic density at RMTg GABAergic-pVTA dopaminergic synapses compared to their controls. These results were opposite to those previously observed in rats exposed to a schizophrenia risk factor. These findings for repeated hypoxic rats suggest that the enhanced inhibition of pVTA dopaminergic neurons may contribute to hypodopaminergia in ADHD motor hyperactivity. Synaptic triads, a key component of pVTA circuitry, were not detected in repeated hypoxic rats, indicating a marked deficit. The current knowledge may guide development in males of novel, site-specific ADHD drugs, which is necessary due to the rising prevalence of ADHD, the chronic nature of ADHD symptoms and the limitations of the currently available medications.