The Affect of Haliperidol and Amphetamine on Trophic Relationships Potentially Relevant to TS

Grant Type
Basic
Grant Year
1993
Institution Location
IL
Institution Organization Name
Rush-Presbyterian-St. Luke’s Med. Ctr
Investigators Name
Carvey, Paul, PhD

The regions of the brain responsible for producing TS symptoms are unknown. Recent studies point to the possible involvement of a brain region called the n. accumbens. The neurons of the n. accumbens appear to play a role in the integration of emotional activity with motor expression, and may participate in the regulation of impulsive behavior as well. Neuronal activity in the n. accumbens appears to be hypoactive in children with TS (Stoetter, et al., Adv. Neurol. 58:213; 1992). The brain activity changes resulting from a hypoactive n. accumbens could therefore result in motor tics and impulsiveness. The n. accumbens receives a large number of fibers from the inferior regions of the frontal cortex (part of the paleolimbic region). A developmental abnormality in this projection may lead to the hypoactivity observed in the n. accumbens of TS children. We have recently demonstrated that the striatum, a region of the brain closely related to the n. accumbens, contains chemicals (trophic substances) that regulate the growth of cortical neurons. It is reasonable to assume that the n. accumbens likewise contains a trophic activity that regulates the growth of paleolimbic cortex. Disruption of the trophic relationship that exists between the paleolimbic cortex and the n. accumbens could underlie the hypoactivity of the n. accumbens in TS. We have previously demonstrated that drugs which affect the dopamine (DA) neurotransmitter system alter brain trophic activity. Thus, reducing DA neurotransmission with various drugs increases trophic activity in the striatum and n. accumbens directed at DA neurons growing in culture. Increasing DA neurotransmission has the opposite effect. We have also demonstrated that blocking DA neurotransmission reduces the striatal trophic activity directed at frontal cortical neurons while increasing the trophic activity directed at DA neurons. These data suggest that alterations in neurotransmission within the striatum may influence the trophic relationships that exist among several brain structures that project to it. TS is often treated with the dopamine (DA) blocking drug haloperidol. Drugs such as amphetamine, that increase the release of the neurotransmitter DA, often worsen TS. We plan to use these drugs to study the trophic relationships that exist among the n. accumbens, the DA neuron, and the paleocortex. Adolescent rats will be treated chronically with these 2 drugs. Following treatment, the n. accumbens and the striatum from these animals will be introduced into cultures of DA neurons or cultures of the cortex (superior and inferior frontal cortex). After 2 weeks various indices of culture growth will then be collected from those cultures. Striatal extracts from haloperidol treated animals should reduce the growth of superior cortical cultures whereas the opposite response will be observed with extracts from amphetamine treated animals. The effects of n. accumbens extracts on inferior cortical culture growth are unknown. By studying the effects of DA neurotransmission on trophic activity directed at DA neurons and cortical neurons, wehope to learn more about the way trophic factors influence the development of the connections between the paleolimbic cortex and the n. accumbens. Finding this trophic relationship disrupted by alterations in DA neurotransmission would lend support to the hypothesis that trophic factors play a role in the development and treatment of TS. Paul Carvey, Ph.D. Rush-Presbyterian/St. Lukes Medical Center, Chicago, IL Award $24,853 Tourette Association of America Inc. – Research Grant Award 1993