Opinion: Differentiating the rapid actions of cocaine

Perspectives
Nature Reviews Neuroscience 12, 479-484 (August 2011) | doi:10.1038/nrn3043

Opinion: Differentiating the rapid actions of cocaine

See also: Correspondence by Aragona | Correspondence by Wise & Kiyatkin
Roy A. Wise1 & Eugene A. Kiyatkin1  About the authors

Abstract
The subjective effects of intravenous cocaine are felt almost immediately, and this immediacy plays an important part in the drug’s rewarding impact. The primary rewarding effect of cocaine involves blockade of dopamine reuptake; however, the onset of this action is too late to account for the drug’s initial effects. Recent studies suggest that cocaine-predictive cues — including peripheral interoceptive cues generated by cocaine itself — come to cause more direct and earlier reward signalling by activating excitatory inputs to the dopamine system. The conditioned activation of the dopamine system by cocaine-predictive cues offers a new target for potential addiction therapies.

The speed with which cocaine activates the reward circuitry of the brain is thought to be an important determinant of the drug’s addictive potency (Box 1). Speed of delivery is important for all rewards1; the effectiveness of a reward can be decreased by half or more if it is delayed by a mere second or two2, 3. It is widely assumed from the short latency of subjective and behavioural responses to intravenous cocaine injections, that the drug almost instantly activates the reward system in the brain. However, experienced users report cocaine-like subjective effects within seconds, before the drug has time to reach the brain, cross the blood–brain barrier and interact with its central pharmacological targets4.

The primary rewarding effects of cocaine result from its ability to augment the actions of dopamine by inhibiting its reuptake by the dopamine transporter5, 6, 7, and thus prolonging its effects in regions to which the dopamine system projects8, 9, 10. However, blockade of the dopamine transporter by intravenous cocaine has a latency of several seconds in the rat, and longer in humans; it takes cocaine about 15 seconds to reach the brain from intravenous injection in the arm. Thus, the acute central actions of cocaine cannot explain the drug’s immediate effects after intravenous injection.
Recent findings indicate that some peripheral action of cocaine — such as the blockade of potassium channels in the sensory nerves of the cardiovascular system11, 12, 13 — is sensed and relayed trans-synaptically to the brain, where, in parallel with external reward-predictive cues, it comes to briefly activate the reward system of cocaine-experienced rats through Pavlovian conditioning14, 15, 16.
Here, we describe and contrast two rewarding effects of cocaine in the dopamine system: the well-known, unconditioned rewarding effect resulting from the blockade of the dopamine reuptake mechanism in the CNS and the more immediate (though weaker), conditioned dopamine-activating effect resulting from cocaine’s ability to trigger conditioned excitatory input to the brain from the periphery. Although attempts to develop pharmacotherapies for cocaine addiction have mainly focused on the effect of the drug within the reward circuitry of the brain17, the fact that reward-predicting stimuli have more immediate effects and can activate the reward system even in the absence of the reward itself14 suggests that peripheral sites of cocaine act as potential targets for addiction medication.
Cocaine’s fast rewarding action
The primary rewarding effects of cocaine and related drugs are unconditioned and can thus be seen in animals that have no prior experience with the drug8, 9, 18. In cocaine-naive animals, the rewarding effect of cocaine results from the drug’s ability to elevate extracellular levels of the neurotransmitter dopamine; dopamine levels are elevated several-fold during periods when rats19 or monkeys20 are allowed to lever-press for intravenous cocaine (cocaine ‘self-administration’). The timing of successive lever-presses in a session can be predicted from the rise and fall of extracellular dopamine in the forebrain; the next response occurs when the elevated dopamine level from the previous injection falls back to a characteristic ‘trigger-point’21. If the postsynaptic signalling effects of extracellular dopamine are blocked22, 23, 24 or if the mesocorticolimbic dopamine system is lesioned25, 26, 27, cocaine loses its ability to maintain the self-administration habit.
Three brain targets for the rewarding actions of cocaine have been identified. Cocaine is rewarding when microinjected directly into the medial prefrontal cortex8, the ventromedial shell of nucleus accumbens9 or the adjacent medial portion of the olfactory tubercle10. Perhaps because it has been suggested to provide an interface between the mechanisms of motivation and motor function28, the nucleus accumbens has received the most extensive study. Although cocaine elevates dopamine levels in both the core and the shell of nucleus accumbens, the elevation is stronger and more immediate in the shell29, 30, where rewarding effects of the drug have been shown9, 10.
Extracellular dopamine levels can be elevated either by an increase in dopamine release or by a decrease in dopamine reuptake. Amphetamine has both effects: it causes dopamine release and it blocks dopamine reuptake31. Cocaine also blocks dopamine uptake but does not cause dopamine release, at least in vitro5. Thus, until recently30, 32, 33, cocaine has been known as a dopamine reuptake inhibitor and not a dopamine releaser5, 34. Consistent with this view, cocaine does not cause the increase in metabolite levels that would be caused by increased dopamine release34. Although an early report suggested that knockout mice lacking the dopamine transporter could still learn to self-administer cocaine35, this finding has not been replicated7. The emerging consensus is that any minimal signs of cocaine self-administration in such mice reflect the ability of cocaine to block dopamine uptake by other monoamine transporters7, 36 that take over the task of dopamine clearance when the dopamine transporter is deleted. Similar mechanisms probably take place in brain regions where the dopamine transporter is sparse37, 38, 39. Thus, the blockade of dopamine uptake remains the widely accepted mechanism for cocaine’s unconditioned rewarding action.
Fast-scan cyclic voltammetry (Box 2) can reveal the dopamine concentration in the brain and has the temporal resolution needed to determine the onset of the central effects of intravenous cocaine. It has been used in two ways, each of which has suggested that cocaine has very rapid effects. In the first approach, spontaneous fluctuations in dopamine level are monitored before and after intravenous cocaine or saline injections in freely moving rats30, 40, 41. This approach shows that intravenous cocaine can cause significant increases in dopamine signalling in the shell of nucleus accumbens in as little as 8 seconds after the onset of the injection30. However, similar early increases are not seen in the core of nucleus accumbens30, where blockade of dopamine reuptake by cocaine should be more evident because the density of dopamine transporters is greater42. Clear evidence of cocaine-induced changes in dopamine levels in the core of cocaine-naive rats are seen only 30–40 seconds after intravenous injection30, 40, and the dopamine elevations seen in the first 10 seconds or so in the shell seem to reflect cocaine’s effects on dopaminergic neuronal firing33 rather than on dopamine reuptake30.
Box 2 | Measuring and accounting for the latency of central drug effects
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In the second approach, dopamine release in the core of nucleus accumbens was triggered by electrical stimulation of the cell bodies in the ventral tegmental area, and the clearance of the stimulated release was estimated from the rate of decay of the voltammetric peak that reflects the dopamine concentration. From this approach it was suggested that intravenous cocaine starts to block dopamine uptake in as little as 4 seconds after the onset of the intravenous injection43. However, this estimate of ultra-fast uptake inhibition is based on a model that assumes the only source of dopamine release to be the stimulation applied by the experimenter44; this assumption is now open to question16, 30, 33. In any case, accumulation of a physiologically significant amount of dopamine, through this or any other mechanism, seems to take at least 8 and up to perhaps 40 seconds in animals having no prior experience with cocaine30, 40. Thus, the fast pharmacological action of cocaine in the central nervous system — the blockade of dopamine reuptake — becomes important after tens of seconds and does not seem to explain the ultra-fast subjective and behavioural effects of the drug, effects that are seen in the initial seconds after onset of an intravenous cocaine injection and unquestionably before the drug reaches the brain in the case of human subjects.
Cocaine’s ultra-fast rewarding action
More immediate activation of the dopamine system occurs when the reward is reliably predicted by environmental stimuli. Electrophysiological studies of food reward in monkeys have revealed that reward predictors can activate the dopamine system before the receipt of the reward itself45. Early in training, the taste of juice or a piece of apple activates the dopamine system of a hungry monkey; however, after sufficient training the dopamine system comes to be activated when the monkey hears a predictor, such as the click associated with the unlatching of the door between the monkey and the piece of apple45. Once its reward-predictive meaning is learned, the click activates the dopamine system and the rewarding food itself fails to do so. This reward-predictive dopamine release occurs a second or two earlier than the actual presentation of the food reward45. Reliable reward-predictors cause an ultra-fast accumulation (1–3 seconds) of extracellular dopamine; this is a conditioned response to what was an initially ineffective stimulus, a stimulus that has gained importance by its Pavlovian association with the reward it predicts40, 46.
Similarly, activation of the dopamine system is seen before each earned cocaine injection in rats that have learned to self-administer cocaine by lever-pressing47, 48. Here, the initial dopamine elevation is seen as a brief peak, 1 or 2 seconds before the lever-press, as the rat starts to move towards the lever (Fig. 1). This initial peak is not in response to any external stimulus change; however, the peak and the movement are both cocaine predictors in their own right.
Figure 1 | Proposed extracellular dopamine fluctuations following cocaine self-administration.
A schematic representation of the proposed components of the extracellular dopamine fluctuations that accompany lever-pressing in intoxicated rats that expect an intravenous cocaine injection. The three idealized peaks are based on selected individual records from fast-scan in vivo voltammetry studies47, 48 The elevation before the lever-press (peak a) arises as the animal starts to move towards the response lever. Peaks b and c (the early and late components of this part of the response) are not so clearly differentiated from one another in all animals and tend to overlap in averaged group data. The early portion (0–2 seconds) of the post-response elevation (idealized here as peak b; Refs 47,48) is suggested to reflect the response to earned reward predictors, such as the click of the response lever or the illumination of a cue light that accompanies activation of the syringe pump that delivers the drug. This elevation of 0–2 seconds continues to be seen in the early phases of extinction testing, when non-rewarding saline has been substituted for the expected cocaine48. This early elevation is progressively lost in late extinction training as the animal forms a new association between the stimuli that once predicted cocaine but now predict saline48. The later portion (2–5 seconds) of the post-response elevation (idealized here as peak c) is absent in even the early phases of extinction training48, presumably because it is a response to cocaine-predictive cues that do not continue into extinction training, such as the interoceptive cues of cocaine itself. Figure is modified, with permission, from Ref. 48 © (2005) Cell Press.
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Correspondence to: Roy A. Wise1 Email: rwise@intra.nida.nih.gov