Cocaine's Addictive Influence Begins Even Before Euphoria

It has long been known in the addiction field that exposure to drug-associated stimuli, commonly referred to as relapse triggers, is one of the primary causes of relapse in abstinent addicts. Neuroscience studies have added evidential support for this perspective by providing a molecular explanation for it. It is thought to principally involve two neurotransmitters: dopamine and glutamate, and a region of the reward system called the ventral tegmental area (VTA).

The VTA is part of the midbrain, and two major dopamine pathways—the mesolimbic and mesocortical—run through it. It is chock full of dopamine, glutamate, and GABA neurons. When a subject who has acquired the self-administration of a drug like cocaine is exposed to environmental stimuli they have associated with the drug, glutamate and dopamine are released from the VTA. This rush of neurotransmitters activates another area of the reward system, the nucleus accumbens, and usually leads to an attempt to reinstate drug-using behavior.

As might be expected, cocaine use itself also results in increased dopamine and glutamate transmission in the VTA. Interestingly, however, this increased neurotransmitter activity begins before the pharmacological effects of cocaine can occur. While it takes about 10 seconds for cocaine to cross the blood-brain barrier and exert its psychotropic influence, dopamine levels rise almost immediately. Thus, it would seem that the reinforcing qualities of the drug may not be solely attributable to the euphoria it produces.

Roy Wise, Bin Wang, and Zhi-Bing You published an article last week in PloS One that investigates this phenomenon. They injected cocaine methiodide (MI)—an analogue to cocaine that does not cross the blood-brain barrier to have a psychotropic effect—into rats and measured the resultant changes in neurotransmitter levels.

In rats that had never been exposed to cocaine, the MI had no effect. But in those that had previously acquired cocaine self-administration, the MI caused VTA glutamate release. It was also enough to cause these rats to reacquire cocaine-seeking behavior that had been rendered extinct.

This study speaks to the complexity and potency of the inclination toward relapse. While it has been known that external cues can cause changes in brain chemistry that predispose one toward relapse, this is the first evidence that internal cues (besides the actual rewarding mental influences of the drug) may also play a role in reinstating drug use. Fortunately, these added influences can be avoided by continued abstinence from the drug. But once a drug is used, how pleasurable the resultant experience is may have little to do with the re-emergence of drug cravings.


Roy A. Wise, Bin Wang, Zhi-Bing You, Antonio Verdejo García (2008). Cocaine Serves as a Peripheral Interoceptive Conditioned Stimulus for Central Glutamate and Dopamine Release. PLoS ONE, 3 (8) DOI:10.1371/journal.pone.0002846