Developmental Plasticity of Basal Ganglia dopamine Systems

Grant Type
Grant Year
Institution Location
Institution Organization Name
University of Pennsylvania
Investigators Name
Neal, Bethany, PhD

Tourette Syndrome (TS) is a developmental disorder, as it generally occurs during the first decade of life, with a higher incidence in males compared to females (3 or 4:1), and shows improvement during adulthood. Drugs which reduce the synaptic transmission of the neurotransmitter dopamine or block its effects at receptors (e.g., haloperidol) have been shown to be clinically effective in the treatment of TS. The Syndrome is exacerbated by drugs such as amphetamines (which increase dopamine activity in•the brain), and patients with TS have evidence of a dopaminergic overactivity within the brain. These findings suggest that dopamine may play a role in the etiology and symptomatology of TS. Therefore, experimentally-induced disruptions of the development of dopamine systems within the brain may provide an animal model of this Syndrome. The striatum, a brain region which contains a high concentration of dopamine, is an important relay area for both sensorimotor and cognitive information. It is known that destruction of dopamine neurons with the neurotoxin 6-hydroxydopamine (6-0H DA) results in a loss of dopamine within the striatum, causes a number of behavioral deficits and alters the responsitivity to dopaminergic drugs. However, the types and degree of behavioral alterations depend upon the age at which the lesioning occurs. In adult rats, extensive lesions of dopamine neurons produce profound behavioral impairments (e.g., rats do not eat or drink), while neonatal 6-OHDA lesions have little effect on eating or drinking, and cause no sensory impairment, suggesting that different effects on dopamine inputs or receptors occur in the neonate. Interestingly, neonatally-lesioned rats do exhibit self-biting behavior and other abnormal oral movements following treatment with drugs which mimic dopamine. Those behaviors are not observed in adult-lesioned rats. We and others have shown that neonatal dopamine depletion also produces cognitive impairments — some of which appear to be due to attentional deficits. This phenomenon is of interest in Tourette Syndrome research because TS individuals are known to have an increased incidence of learning and attention deficits compared to the general population. We believe that this differential vulnerability to 6-OHDA treatment between neonates and adults involves the development of the organization of the striatum. We have shown that striatal dopamine systems develop in three distinct stages during early life, and these stages are linked to the organization of neurons and receptors within the striatum. There may be differential neurochemical and behavioral consequences of dopamine depletion at various stages of development because of the ontogeny of this striatal organization. We will compare the neurochemical and functional consequences of 6-OHDA lesions at various early time points with lesions made in adulthood to examine the consequences of disruption of the development of dopamine systems and how the plasticity of the systems differ depending upon their maturity. We hope to use these results to better understand the underlying mechanisms of developmental disorders involving deficits in motor control with concurrent learning and attentional deficits (e.g., Tourette Syndrome). Bethany S. Neal, Ph.D. University of Pennsylvania School of Medicine, Philadelphia, PA Award $25,000 Tourette Association of America Inc. – Research Grant Award 1990