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Discovery of post-stimulus activated release implies new mechanisms for dopamine release

October 16, 2006

The neurotransmitter dopamine continues to be released for nearly an hour after neurons are stimulated, suggesting the existence of secondary mechanisms that allow for sustained availability of dopamine in different regions of the brain including areas critical for memory consolidation, drug induced plasticity and maintaining active networks during working memory, according to a University of Pittsburgh study being presented today at the 36th Annual Meeting of the Society for Neuroscience, held at the Georgia World Congress Center in Atlanta.

Determining the mechanisms that cause what is being called "post-stimulus activated release" and how they maintain dopamine levels could have important implications for understanding and treating neurological and psychiatric disorders caused by an imbalance of dopamine function including schizophrenia, attention deficit hyperactivity disorder, Tourette's syndrome, Parkinson's disease and addiction.

According to Bita Moghaddam, Ph.D., professor of neuroscience and psychiatry, who led the study, in addition to its clinical benefits, post-stimulus activated release can be used to explain how brief events that activate neurons for short periods of time can influence brain function long after the events. For example, it can be used to explain how smelling freshly baked cookies could evoke childhood memories of spending time with a beloved grandparent, leading a person to reminisce long after the smell is gone and take the unplanned or impulsive action of baking or buying cookies.

Dopamine is a neurotransmitter associated with learning and memory, motor control, reward perception and executive functions such as working memory, behavioral flexibility and decision making. When a novel or salient stimulus occurs, the dopamine neurons in the brain increase their firing rate, boosting the release of dopamine. The dopamine is diffused into the extracellular space of the brain until it can be transported or metabolized.

In a rat model, the researchers have been attempting to understand increases in extracellular levels of dopamine during behaviorally active states, such as completing a cognitive task or experiencing stressful situations and in response to the electrical stimulation of neurons. In their studies, they have observed that dopamine levels remain above the baseline long after neurons had been stimulated - from five to 20 minutes in the ventral tegmental area (VTA) and 40 to 100 minutes in the nucleus accumbens and prefrontal cortex.

Attempting to discern the cause of the elevated levels, researchers stimulated the VTA of the brain of a rat model by using an electrode. The VTA is a nucleus in the midbrain where dopamine neurons are located. After stimulating the neurons, the researchers measured the amount of dopamine in the extracellular fluid of the nucleus accumbens and prefrontal cortex - two areas where the VTA is known to send signals. They found that dopamine levels increased during stimulation, and remained elevated for an hour after stimulation.

Dopamine levels wane as dopamine is taken back into cells by an active transport system. Yet this active transport system is not abundant in the ventral striatum and prefrontal cortex areas, leading researchers to think that perhaps the dopamine levels remained elevated due to an excess that had yet to be absorbed. To test this hypothesis, they applied tetrodotoxin (TTX), a neurotoxin that blocks the active release of dopamine, to the nucleus accumbens and prefrontal cortex. TTX caused dopamine levels to drop, indicating that the dopamine levels remained elevated because dopamine was being actively released after the neurons fired and not because there was residual dopamine in the brain.

Dr. Moghaddam and colleagues are currently conducting experiments in efforts to identify the exact mechanism causing post-stimulus activated release.

University of Pittsburgh Medical Center