Rendering the Brain More Vulnerable to Environmental Damage

PI: Gary Miller
University of Texas, Austin

Background: Dopamine is a chemical responsible for transmitting messages among the nerve cells of the brain. Disruption of this "neurotransmission" underlies such diverse conditions as Parkinson's Disease, schizophrenia, and Tourette syndrome. Dopamine relies on two transporter proteins to allow it to move into and out of cells. They are the plasma membrane dopamine transporter (DAT) and the vesicular monoamine transporter (VMAT2). DAT stops the action of dopamine by rapidly binding it and removing it. VMAT2 moves intracellular dopamine into vesicles for storage and later release. Recent data suggests that disturbing the tightly controlled balance of these two transporters makes nerve cells vulnerable to damage by a variety of environmental insults including cocaine and organochlorine insecticides such as dieldrin.

Advance: In this article, the authors review recent work which describes the control of DAT and VMAT2 and the implications a disturbance in the control by environmental agents has on Parkinson's disease and neuropsychiatric disorders. Intricate neuroanatomical analyses on brain tissue from Parkinson's patients shows that the highest levels of DAT and VMAT2 are found in the regions of the brain most sensitive to damage in Parkinson's disease. Studies using reserpine, a powerful inhibitor of VMAT2, suggest that disruption of vesicular loading of dopamine may play a role in depression. Control of DAT and VMAT2 has been implicated in other diseases such as Tourette syndrome, schizophrenia, drug and alcohol abuse, and attention deficit hyperactivity disorder.

Implication: These studies suggest that the control of DAT and VMAT2 plays a major role in mediating susceptibility to neurodegenerative and other diseases. It is possible that drugs designed to alter their balance might be beneficial in Parkinson's disease and other disorders. For patients in early stages of Parkinson's disease, reducing DAT activity might not only increase the synaptic dopamine concentration but might also slow the progression of the disease if toxins are present. In the case of VMAT2, drugs or therapies that increased vesicular uptake by VMAT2 would decrease cytosolic dopamine perhaps preventing its oxidation and resulting in storage of more usable dopamine. In conclusion, recent studies indicate that DAT and VMAT2 mediate neuronal damage and may influence susceptibility to a variety of neurological and psychiatric disorders. [Area of Emphasis: Biology of the Nervous System: Development and Disorders; GPRA Goal: Add to the body of knowledge about normal and abnormal biological functions and behavior (Molecular and Cellular Mechanisms)]

Citation: Miller GW, Gainetdinov RR, Levey AI, Caron MG: Dopamine transporters and neuronal injury. Trends in Pharmacological Science 2: 424-429, 2000.