Model for reduced brain dopamine in Lesch‐Nyhan syndrome and the mentally retarded: Neurobiology of neonatal‐6‐hydroxydopamine‐lesioned rats

Self‐injurious behavior (SIB) remains a serious problem among the mentally retarded because no known pharmacological agents block this behavior. This symptom is especially severe in Lesch‐Nyhan syndrome (LNS), a genetic disorder associated with HPRT deficiency. Because the prominent neurobiological deficit in LNS is a loss of dopaminergic neurons, reduction of dopamine with 6‐hydroxydopamine (6‐OHDA) in rats during their development is proposed as a model of the dopamine deficiency in LNS and in mentally retarded individuals with SIB who may have this neurotransmitter deficiency. In behavioral testing of this model, dopamine agonists that activate D₁‐dopamine receptors induced SIB in adult rats with neonatal 6‐OHDA‐dopamine lesions, a change not seen in rats lesioned as adults. SIB also has been observed when muscimol is microinjected into the substantia nigra reticulata (SNR) of the neonatal‐6‐OHDA lesioned rats. D₁‐dopamine antagonists, as well as NMDA antagonists, have been found to block the SIB induced by L‐DOPA in these neonatally lesioned rats. In addition to the reduced dopamine, LNS patients also have an increased striatal serotonin content, as do rats neonatally lesioned with 6‐OHDA. Activation of serotonergic receptors with m‐chlorophenylpiperazine has increased oral activity in neonatal‐6‐OHDA‐lesioned rats; destruction of serotonin‐containing neurons has blocked this effect caused by a D₁‐dopamine agonist. These data suggest that serotonin and corresponding serotonin receptors contribute to dysfunctions in the neonatal‐6‐OHDA‐lesioned model. This work provides background support for the hypothesis that neonatal reduction of dopamine results in increased vulnerability to SIB as a result of adaptation within a neural circuit in the brain involving D₁‐dopamine receptors, the SNR, and glutamate‐and serotonin‐containing neurons. Functional mapping in neonatally lesioned rats using ¹⁴C‐2‐deoxyglucose (2‐DG) uptake and Fos‐like immunoreactivity (Fos‐L1) has implicated the SNR, entopeduncular nucleus, globus pallidus, and subthalamic nucleus in the action of a D₁‐dopamine agonist. In addition, a generalized increase in Fos‐L1, but not 2‐DG uptake, is also induced in the striatum by a D₁‐dopamine agonist. The action of CGS‐19755 and MK‐801, NMDA antagonists, on the accumulation of Fos‐L1 in the striatum induced by a D₁‐dopamine agonist also has been examined. Whereas CGS‐19755 blocked the increase in striatal Fos‐L1 induced by the D₁‐dopamine agonist, MK‐801 did not. Because both drugs block SIB in the rat model, these findings suggest that the glutamatergic neuronal system that contributes to SIB is not associated with the striatum. The research being undertaken with the model of neonatal dopa‐mine reduction may suggest new therapeutic approaches to the SIB observed in developmental disorders of unknown etiology, as well as the SIB associated with LNS. © 1995 Wiley‐Liss, Inc.