By David N. Leff

Just as ¿a journey of a thousand miles must begin with a single step,¿ the road to cocaine addiction begins with a single fix. Snorting or shooting up coke for the first time triggers a weeklong surge of neuronal activity in a brain region central to the development of addiction.

This discovery is reported in the May 31, 2001, issue of Nature, under the title: ¿Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons.¿ The paper¿s senior author is neuroscientist Antonello Bonci, a neuroscientist on the neurology faculty of the University of California, San Francisco, and a principal investigator at the Ernest Gallo Clinic and Research Center.

¿The finding,¿ Bonci told BioWorld Today, ¿that a single dose of cocaine is producing the same cellular changes that occur during normal memory formation in the hippocampus ¿ the brain region that normally stores learning and memory ¿ is kind of amazing. This was known to be something happening for totally different reasons in other brain regions.¿

The surprise, he observed, is that ¿the first drug exposure appears to throw open a window of vulnerability that may make the brain acutely responsive to subsequent exposures for around a week. This accelerates the molecular process of memory formation that may underly addiction. It¿s the first direct evidence that a single cocaine exposure ¿ what in humans would be a recreational dose ¿ causes dramatic changes in the brain, like those underlying learning and memory.¿

Bonci explained, ¿The single exposure doubles the responsiveness of dopamine neurons, which are known to play a key role in drug craving and relapse. If you think of cocaine as a drug that might give people pleasure for an hour or two, the fact that this functional change lasts for a week or more is another kind of incredible thing, because it¿s maintained by long-term potentiation ¿ LTP ¿ in a specific region of the brain, called the ventral tegmental area. So this is our Nature article¿s main scientific finding.

¿Apparently,¿ he said, ¿the very first contact with an addictive drug, the long-term potentiation ¿ where interlinked neurons acting simultaneously become more strongly connected ¿ forms the basis for usurping some kinds of memory as a first step toward addiction or relapse.¿

LTP Beefs Up Synapses¿ Memory Messages

Bonci said ¿long-term potentiation is the most widely studied synaptic phenomenon in the brain, because it is so strong. It can last for hours or days, with all these implications for learning and memory. LTP,¿ he explained, ¿is simply a potentiation of the synaptic transmission on one of these excitatory glutamate receptors ¿ the one called the AMPA receptor.¿ (AMPA stands for alpha-amino-3-hydroxy-5-methyl-isoxazole propionic acid.)

When it reaches dopamine neurons, glutamate activates excitatory receptors that in turn activate AMPA. Its activity is converted into electrical impulses that whiz along the neuron, releasing dopamine. This is long-term potentiation ¿ the physiological hallmark of learning.

¿Whenever you hear about LTP,¿ Bonci observed, ¿people mean that there is an increase or strengthening of the transmission in the synapse through this AMPA receptor. This can happen in the hippocampus, which is believed to be the main brain-cell phenomenon that underlies normal memory formation.¿

He and his team focused on a different brain region ¿ the ventral tegmental area (VTA) ¿ which, Bonci noted, ¿has been implicated in several drug-related behaviors. We know that all important drugs of abuse ¿ morphine, ethanol, cocaine, amphetamines, nicotine ¿ increase dopamine levels. If you play video games, you increase your dopamine levels.¿

In their study, the co-authors used electrophysiological tests of brain tissue slices from cocaine-treated mice to demonstrate the dynamics of LTP in the dopamine-rich VTA brain region.

¿Dopamine,¿ Bonci went on, ¿is a confusing kind of neurotransmitter. Neuroscientists are still wondering what are these changes related to acute drug exposure. What exactly does dopamine do? What we know is that dopamine is needed in the learning phase. For example, a model for studying drug addiction is self-administration. If in behavioral experiments with rats we remove their dopamine, the rats won¿t learn to self-administer cocaine in the first place. So it seems to play a major role in the learning phase of this drug-related behavior.

¿Another example: An increase in dopamine neurotransmission seems to be related to relapse in cocaine addiction.¿

Getting Real About Treatment Options

Bonci is now engaged in researching practical applications for his findings, aimed at improved treatment for addiction and relapse. ¿The question,¿ he said, ¿is how to develop drugs that interfere with these cocaine-induced changes, but not with normal memory formation. This is something we are exploring.

¿If we say that a single dose of cocaine can open a window of vulnerability to relapse,¿ he pointed out, ¿and if we can find out exactly what the mechanism for this LTP change is, we may be able to find a way to block the change. Because now we know exactly which receptor to target ¿ the one for AMPA. And we know that that is going to produce a change in transmission.

¿So if we can block the steps from cocaine intake going on to production of LTP,¿ he continued, ¿we might stop the onset of this increased neural transmission. And we think we might just reduce or eliminate the vulnerability, and the changes favoring relapse. We are trying to elucidate the mechanisms that are responsible, from drug exposure to the expression of LTP. There is a whole world in between the two, and that is what we are studying now.

¿We also want to see whether giving our mice multiple injections of cocaine, rather than a single dose, will also produce more long-lasting changes in LTP ¿ and how these are produced as well. So we want to better understand how frequently and how long this effect can last, if we expose the animal to multiple injections of cocaine. And what exactly is the pharmacological kinetic of this phenomenon, and the mechanism. That is what we are doing now.

¿It is very striking,¿ Bonci concluded, ¿that cocaine¿s effects are so long-lasting ¿ and given that we observe such a large effect in an area of the brain known to play a role in addiction ¿ it seems that people may be underestimating the harmlessness of cocaine.¿

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