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.
A Dopamine Nerve Terminal Innervating Neurons in the Nucleus Accumbens
Three major sites of dopamine binding are shown: the D1 postsynaptic receptor, the D2 receptor, and the dopamine-reuptake transporter, which helps regulate synaptic levels of dopamine by carrying the transmitter back into the nerve terminal. Levels of dopamine at the synapse increase when cocaine inhibits the reuptake of dopamine by binding to the dopamine-reuptake transporter. In mice whose dopamine transporters have been eliminated by knockout of the gene for this molecule, synaptic dopamine levels are increased. Cocaine does not induce some biochemical or behavioral responses in these animals, because they have no functional dopamine transporters. The D1 receptors are mainly located on different neurons from the D2 receptors. D1 and D2 receptors have opposing intracellular and behavioral effects, probably mediated by multiple pathways (indicated here by letters A through E) and may differentially affect craving and satiety. Antibodies against cocaine appear to block the effects of the drug by keeping it from entering the central nervous system.
A third major discovery, reported by Carrera et al., demonstrates how immunologic techniques and a well-defined behavioral model can be successfully used in combination. These workers repeatedly injected rats over a 35-day period with a protein-conjugated analogue of cocaine that triggers the immune system to produce anti-cocaine antibodies. They then tested the animals’ responses to injected cocaine. The immunized rats had significantly lower psychomotor responses to the stimulant effects of cocaine than control animals, showing that immunization against the behavioral effects of cocaine is possible. In addition, cocaine concentrations in the brains of immunized animals were 52 percent lower in striatal tissue and 77 percent lower in cerebellar tissue than those in the brains of controls, suggesting that anti-cocaine immunization prevents the uptake of cocaine into critical sites in the brain. This work suggests that it may be possible to vaccinate against the action of cocaine. Other researchers on the immunotherapy of drug abuse are exploring the use of antibodies and other external agents that affect the rate and direction of cocaine metabolism once the drug has been taken. A number of questions, including how long the immunization will remain effective and what risks are entailed in immunizing human subjects, need to be explored before any immunotherapy for cocaine addiction is ready for clinical trials.
Alan I. Leshner, Ph.D.
National Institute on Drug Abuse
Rockville, MD 20857
1. Giros B, Jaber M, Jones SR, Wightman RM, Caron MG. Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 1996;379:606-612.
2. Self DW, Barnhart WJ, Lehman DA, Nestler EJ. Opposite modulation of cocaine-seeking behavior by D1- and D2-like dopamine receptor agonists. Science 1996;271:1586-1589.
3. Carrera MR, Ashley JA, Parsons LH, Wirsching P, Koob GF, Janda KD. Suppression of psychoactive effects of cocaine by active immunization. Nature 1995;378:727-730.