Trends in Neurosciences
OpinionIllicit dopamine transients: Reconciling actions of abused drugs
Section snippets
Dopamine, psychostimulants, and reinforcement
A long-held tenet in the pharmacology of abused drugs is that, despite marked differences in cellular targets, all classes of these substances increase brain levels of extracellular dopamine [1]. Drug-induced dopamine elevations occur to the greatest extent in the nucleus accumbens (NAc), a brain region that is crucial for translating motivational input into behavioral output 2, 3. This shared outcome of a hyper-dopamine state is thought to mediate the initial reinforcing properties of abused
Phasic dopamine signaling plays a crucial role in appetitive behavior
Intrinsic properties coupled with converging input from numerous excitatory and inhibitory afferents enable dopamine neurons to signal in two general modes: tonic and phasic 8, 9, 10, 11. During tonic dopamine signaling, slow and irregular firing contributes to a low ambient level of extracellular dopamine that binds to high-affinity D2 dopamine receptors and supports movement, cognition, and motivation. By contrast, during phasic dopamine signaling, rapid and synchronous burst firing elicits
Abused drugs hijack reward circuits by hyperactivating dopamine transients
An emergent hypothesis is that abused drugs activate dopamine transients to a greater degree than natural rewards, leading to overvaluation of cues predicting drug availability 6, 7. Indeed, abused drugs from broad classes, including ethanol, cocaine, nicotine, and cannabinoids, have now been demonstrated to augment dopamine transients (Figure 1E, right) 25, 26, 27, 28. Although drug-evoked dopamine transients resemble those occurring naturally [29], abused drugs evoke a quantitatively greater
Actions of abused drugs on dopamine neurons: traditional view
Abused drugs have traditionally been classified on the basis of three functional targets on dopamine neurons: firing of action potentials, vesicular dopamine release, and dopamine uptake 4, 5. Activation of each target is thought to increase brain levels of extracellular dopamine [1]. In general, (i) ethanol, nicotine, cannabinoids, and opiates increase burst firing by dopamine neurons; (ii) nicotine and opiates upregulate vesicular dopamine release; (iii) cocaine- and AMPH-like
Actions of abused drugs on dopamine neurons: new view
- (i)
Abused drugs generate burst firing by dopamine neurons
We argue here that, similarly to other abused drugs, addictive DAT-Is generate burst firing by dopamine neurons. This postulate is supported by recent evidence demonstrating that cocaine activates burst firing by dopamine neurons in awake animals but suppresses firing in anesthetized animals [43]. Thus, suppression of dopamine cell firing does not appear to be the dominate action of addictive DAT-Is in awake animals, indicating that other
Abused drugs augment extant dopamine transients and elicit dopamine transients de novo
The new view of drug mechanism proposed herein identifies two shared actions of abused drugs. This first common action is to augment extant dopamine transients. These ‘ongoing’ transients are evoked by natural rewards and their predictive cues or occur spontaneously. All three functional targets of abused drugs should contribute to the augmentation of extant dopamine transients. For example, upregulation of vesicular dopamine release and inhibition of dopamine uptake would increase the
Generating burst firing by dopamine neurons is the keystone action of abused drugs
We now bring forward and integrate key ideas developed in preceding sections to argue that generating burst firing is the keystone action of abused drugs. To begin, dopamine transients arise from burst firing by dopamine neurons, and are necessary and sufficient for predictive cues to form cue–reward associations and to promote reward seeking during appetitive behavior. To hijack this process, abused drugs must act robustly on dopamine neurons. For cues to promote drug seeking, abused drugs
Concluding remarks
On the basis of reclassifying addictive DAT-Is with an emphasis on phasic dopamine signaling, we have argued that generating burst firing of dopamine neurons is the keystone action of abused drugs. The essential outcome of this action is eliciting dopamine transients de novo. Reclassifying DAT-Is thus reconciles dopamine theories of appetitive behavior with a mechanistic understanding of how abused drugs hijack reward circuits, leading to an overlearning of cues predicting drug availability.
Acknowledgments
The authors gratefully thank the National Institute of Drug Abuse (grants DA021770 and DA024036 to P.A.G. and DA025634 to M.F.R.) and National Science Foundation (grant DBI0754615 to P.A.G.) for funding their research on amphetamine.
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