A dopamine deficiency model of Lesch-Nyhan disease--the neonatal-6-OHDA-lesioned rat.

Lesch-Nyhan syndrome is characterized by a deficiency of the enzyme hypoxanthine phosphoribosyl transferase (HPRT), compulsive self-mutilatory behavior (SMB), and a loss of central dopaminergic neurons. In order to model the loss of central dopamine-containing neurons in this developmental disorder, neonatal rat pups 3 days of age were given the neurotoxin 6-OHDA intracisternally to reduce brain dopamine. Accompanying the profound loss of dopamine produced by this treatment was an increase in striatal serotonin content. When these neonatally lesioned rats were challenged as adults with systemically administered L-DOPA or with muscimol administration into substantia nigra reticulata (SNR), SMB was observed, a response not observed in unlesioned rats. Thus, the neonatally lesioned rats exhibit increased susceptibility for SMB. Since a D1-dopamine antagonist blocked the SMB response to L-DOPA, it was proposed that D1-dopamine receptors were critical to this behavioral response. Basic investigations concerning D1-dopamine receptor mechanisms in the lesioned rats have been performed and these are reviewed. The data in the neonatally lesioned rats provide convincing evidence that the absence of central dopaminergic neurons is responsible for at least some of the neurological symptoms of the Lesch-Nyhan syndrome, a finding consistent with data collected in mice with an HPRT deficiency.