Illicit dopamine transients: Reconciling actions of abused drugs

doi:10.1016/j.tins.2014.02.002

Trends in Neurosciences

Volume 37, Issue 4, April 2014, Pages 200-210

https://doi.org/10.1016/j.tins.2014.02.002 Get rights and content

Highlights

•
Natural rewards reinforce behavior by eliciting phasic increases in dopamine (DA transients).
•
Abused drugs pharmacologically evoke DA transients and thus mimic natural rewards.
•
We propose a reclassification of addictive DA transporter inhibitors (DAT-Is).
•
Reclassification based on their ability to elicit DA transients via DA cell bursting.
•
This bursting could be basis for initial reinforcement of drug-seeking/-taking.

Phasic increases in brain dopamine are required for cue-directed reward seeking. Although compelling within the framework of appetitive behavior, the view that illicit drugs hijack reward circuits by hyperactivating these dopamine transients is inconsistent with established psychostimulant pharmacology. However, recent work reclassifying amphetamine (AMPH), cocaine, and other addictive dopamine-transporter inhibitors (DAT-Is) supports transient hyperactivation as a unifying hypothesis of abused drugs. We argue here that reclassification also identifies generating burst firing by dopamine neurons as a keystone action. Unlike natural rewards, which are processed by sensory systems, drugs act directly on the brain. Consequently, to mimic natural rewards and exploit reward circuits, dopamine transients must be elicited de novo. Of available drug targets, only burst firing achieves this essential outcome.

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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Trends in Neurosciences

OpinionIllicit dopamine transients: Reconciling actions of abused drugs

Highlights

Section snippets

Dopamine, psychostimulants, and reinforcement

Phasic dopamine signaling plays a crucial role in appetitive behavior

Abused drugs hijack reward circuits by hyperactivating dopamine transients

Actions of abused drugs on dopamine neurons: traditional view

Actions of abused drugs on dopamine neurons: new view

Abused drugs augment extant dopamine transients and elicit dopamine transients de novo

Generating burst firing by dopamine neurons is the keystone action of abused drugs

Concluding remarks

Acknowledgments

Prog. Neurobiol.

Neuron

Trends Neurosci.

Neuron

Mol. Cell. Neurosci.

Neuron

Neurosci. Lett.

Neuron

Neuroscience

Neurosci. Lett.

Neuropharmacology

Eur. J. Pharmacol.

Biochem. Pharmacol.

Behav. Brain Res.

Neuron

Int. Rev. Neurobiol.

Neuron

Neuron

Neuropharmacology

Trends Neurosci.

Neuron

Neuron

Curr. Opin. Pharmacol.

Neuron

Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats

Proc. Natl. Acad. Sci. U.S.A.

Dopaminergic modulation of limbic and cortical drive of nucleus accumbens in goal-directed behavior

Nat. Neurosci.

The mechanistic classification of addictive drugs

PLoS Med.

Neural mechanisms of addiction: the role of reward-related learning and memory

Annu. Rev. Neurosci.

Dopamine signaling in the nucleus accumbens of animals self-administering drugs of abuse

Curr. Top. Behav. Neurosci.

Influence of phasic and tonic dopamine release on receptor activation

J. Neurosci.

Input-specific control of reward and aversion in the ventral tegmental area

Nature

Monitoring rapid chemical communication in the brain

Chem. Rev.

Multiple dopamine functions at different time courses

Annu. Rev. Neurosci.

Discrete coding of reward probability and uncertainty by dopamine neurons

Science

Adaptive coding of reward value by dopamine neurons

Science

Dissociable cost and benefit encoding of future rewards by mesolimbic dopamine

Nat. Neurosci.

Delays conferred by escalating costs modulate dopamine release to rewards but not their predictors

J. Neurosci.

A cellular mechanism of reward-related learning

Nature

Two dimensions of value: dopamine neurons represent reward but not aversiveness

Science

A selective role for dopamine in stimulus–reward learning

Nature

The debate over dopamine's role in reward: the case for incentive salience

Psychopharmacology (Berl.)

Disruption of NMDAR-dependent burst firing by dopamine neurons provides selective assessment of phasic dopamine-dependent behavior

Proc. Natl. Acad. Sci. U.S.A.

Phasic firing in dopaminergic neurons is sufficient for behavioral conditioning

Science

Cannabinoids enhance subsecond dopamine release in the nucleus accumbens of awake rats

J. Neurosci.

Phasic dopamine release evoked by abused substances requires cannabinoid receptor activation

J. Neurosci.

Disparity between tonic and phasic ethanol-induced dopamine increases in the nucleus accumbens of rats

Opinion
Illicit dopamine transients: Reconciling actions of abused drugs