PEMP lab

Dynamic control of dopamine release in cocaine abuse

R03 DA017155 (NIH/NIDA), PI: Phillips

Dopamine release for complex stimulus patterns. On the left is the best fit of a dynamic mathematical model that captures dopamine fluctuations evoked by repetitive stimulus trains (24 pulses, 60 Hz) spaced regularly at 1-s intervals. Facilitation is apparent. Raw data are shown in the darker color and the model is the lighter trace. The correlation coefficient of the goodness of fit is r²=0.99. On the right, the parameters extracted from the fit to the data on the left (in one animal) were used to predict dopamine fluctuations evoked by the repetitive stimulus delivered (in another animal) at irregular intervals at approximately the same rate (~1 Hz). The prediction is the lighter trace, data are in the darker trace, and r²=0.96 is the correlation coefficient of the goodness of fit. After: Montague et al, 2004.

Rapid dopaminergic neurotransmission in the nucleus accumbens is implicated in the generation of goal directed behaviors, and is central to drug reinforcement. The amplitude of phasic dopamine release on repeated activation of dopaminergic neurons in not static, but undergoes dynamic gain modulation. This may be fundamental to generation of appropriate responses to environmental stimuli. Thus, disruption of the fine balance of mechanisms that dynamically control dopamine release could have dire behavioral consequences, particularly in responding to external cues. This type of abnormal behavior is apparent in addicts who show highly elevated responses to drug-related cues. Furthermore, there are several lines of evidence that key mechanisms that control dopamine release are disrupted following cocaine abuse. Therefore, a better understanding of the dynamic control of dopamine release and its dysfunction following cocaine use should generate important information about the pathophysiology of cocaine addiction.

Real-time electrochemistry, that samples extracellular dopamine with subsecond time resolution, provides a unique opportunity to study these processes efficiently. The dynamics of dopamine release can be exposed using patterned activation of dopaminergic neurons and then quantified with a mathematical model (see figure). The first objective is to determine the mechanisms underlying these dynamics that control dopamine release in the nucleus accumbens in normal animals. This will be achieved by a systematic characterization. First, the locus will be determined for the dynamics by comparing dopamine responses to electrical stimulation of dopaminergic cell bodies with that of their axons. In this way the mechanisms that reside in the terminal will be distinguished from those in the cell body. Next, comparing dopamine responses before and after systemic administration of the dopamine receptor antagonist, haloperidol will establish whether dopamine chemical neurotransmission is a requirement for dynamic control. If it is then more selective antagonists (SCH-23390 and raclopride) will be used to determine whether the transmission is via D1-like or D2-like receptors. The second objective is to re-examine these processes following exposure to cocaine. The impact of acute (single dose) and chronic (seven daily doses) cocaine-exposure will be assessed by comparing dopamine release dynamics in these groups to controls. This data should provide a unique insight into the control of dopamine in behaving animals, and the effect of cocaine exposure on this.

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