Roy Wise -A Dopamine History

ViDA 2021 - Thur June 24th 2021
Roy Wise
NIH/NIDA
A Dopamine History
The history of dopamine is over 100 years. It began when Sir Henry Dale first tested a compound in 1910; he eventually named the compound dopamine in 1951. A handful of investigators took steps to develop and use the compound, and the major clinical ending was when dopamine depletion was iidentifed in Parkinsonian patients and when L-DOPA was found to alleviate its symptoms. The lack of movement in Parkinsonian patients—particularly those who had been infected in the 1919 flu epidemic—suggested that dopamine was involved in motor function; dopamine-depleted animals were akinetic and failed to seek food or water or other rewards and failed to avoid predictable punishment. These animals had reflex responses to rewards and punishers but could not learn to search for rewards—or to avoid predictable punishers. In normal animals, excitatory environmental stimuli cause burst-firing of dopaminergic neurons. This burst-firing is required for learning to respond to predictive stimuli; this learning involves two mechanisms. First, burst-responses must develop, through experience, to reward-predictors. This happens by a Hebbian process; rewards enable the development of burst-firing in response to stimuli that immediately precede them. Second, burst-firing in response to predictors enables the cellular basis for long-term potentiation (LTP) or long-term depression (LTD) in nearby sensory—glutamatergic—inputs to medium-spiny—GABAergic—output neurons in the striatum. By enabling LTP and LTD, burst-firing of dopamine neurons enables the stamping-in of learned responses to external stimuli; this is one of dopamine’s two major behavioral effects. A second behavioral function is the modulation of motivation. The level of pacemaker firing of the dopamine system drives or helps drive motivation; low levels of baseline dopamine are associated with low motivation, and moderate levels are associated with activation. High levels of dopamine—apparently caused only by addictive drugs—are associate with drug-satiety. The driving of dopaminergic burst-firing is induced by glutamate input (a correlate of, but separate from, glutamate input to the striatum). The driving of pacemaker firing is under the control of hormones and the modulation of inhibitory GABAergic input to the dopamine neurons. These two functions—reinforcement and motivation—are the major behavioral effects of dopamine in the brain, and they appear to account for its secondary effects.

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https://docs.google.com/document/d/1I...