Molecular Mechanisms of Cocaine Addiction

Effective medication for the treatment of cocaine overdose and addiction is a major unmet need of worldwide importance. In contrast to heroin, for which there are effective medications to treat both overdose (naloxone) and addiction (methadone), there are no pharmacologic treatments for any aspect of cocaine addiction. Recent discoveries indicating that an anti-cocaine medication is actually within reach are cause for great optimism. This work is defining specific molecular targets against which such a medication might be directed.

A recent study by Giros et al. affirms the central importance of the dopamine-reuptake transporter in the behavioral and biochemical action of cocaine and defines it as a site on which efforts to develop an anti-cocaine medication should be focused. The dopamine-reuptake transporter controls the levels of dopamine in the synapse by rapidly carrying the neurotransmitter back into nerve terminals after its release (Figure 1). Cocaine, which binds strongly to the dopamine-reuptake transporter, is a classic blocker of such reuptake after normal neuronal activity. Because of this blocking effect, dopamine remains at high concentrations in the synapse and continues to affect adjacent neurons, producing the characteristic cocaine "high."

Giros and his colleagues produced a strain of mice in which the gene encoding the dopamine transporter was disabled. These knockout mice, with no functional dopamine-reuptake transporters, did not respond to cocaine either biochemically or behaviorally. This study demonstrates that the transporter is necessary for cocaine to produce its psychostimulatory effects.

Mice with the same deficiency are also being used to help answer questions about Parkinson's disease and certain psychiatric disorders that, like the effects of cocaine, are linked to a malfunction in the regulation of neurotransmission by dopamine.

Another advance in the identification of systems in the brain that relate to the addictive properties of cocaine was reported by Self et al. There are multiple dopamine receptors on the postsynaptic membrane that respond differently to different compounds and are likely to serve different biologic functions (Figure 1). Self et al. suggest that the D1 dopamine–receptor system is a target for medications to treat cocaine addiction. These investigators studied two compounds that stimulate either the D1 or the D2 dopamine receptor and tested the ability of the compounds to reinstate self-administration of cocaine in rats that had stopped seeking the drug. The rats were allowed to administer intravenous cocaine to themselves for two hours, after which saline was substituted for an equal period, during which self-administration progressively diminished or ceased. The researchers found that administering a D2 agonist led to a dramatic reinstatement of cocaine seeking, whereas a D1 agonist had virtually no effect. In a second test, in which rats were "primed" with cocaine, pretreatment with a D1 dopamine–receptor agonist suppressed cocaine seeking, whereas pretreatment with a D2 agonist increased it. That study clearly shows that D1- and D2-receptor agonists have opposite effects on cocaine-seeking behavior. More important, however, it suggests that D1-receptor agonists may diminish episodes of intense craving for cocaine in humans, preventing relapses in people who have stopped using the drug.