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NEW ORLEANS — In explaining the difficulty of changing habitual behavior, the psychologist William James rebutted the drunken Rip Van Winkle's excuse for every new fall from the wagon: “I won't count this time!” “He may not count it,” James said in 1892, “but it is being counted nonetheless. Down among his nerve-cells and fibers the molecules are counting it, registering and storing it up to be used against him when the next temptation comes.”

One of the key questions in drug addiction research is what the nature of that “counting” is: what changes among the nerve cells help make the transition from using drugs to being addicted to them? In an exegesis on James's formulation that drew on psychology, neuroanatomy, and molecular genetics, Terry E. Robinson, PhD, explored the role of neuroplasticity in the development of addiction in a lecture here at the Annual Meeting of the Society for Neuroscience in November.


“There has been good evidence for a long time that the effects of drugs change as a consequence of repeated administration,” said Dr. Robinson, who has joint appointments as Professor of Behavioral Neuroscience and Psychology at the University of Michigan in Ann Arbor. While the most familiar example is tolerance – the requirement for increased doses to achieve the same effect – another feature, well characterized in animal models, is sensitization, or an increase in some effect with repeated administration.

“The most studied example of sensitization is psychomotor sensitization,” he said, which refers to the ability of a wide variety of drugs of abuse to enhance locomotion. “This is usually associated with psychostimulant drugs, but many kinds of drugs of abuse have this effect.” In the simplest demonstration of the effect, rats receiving repeated doses of amphetamine become more active from a given dose of drug if they have been exposed to it in the past.

One of the most remarkable features of psychomotor activation is its persistence. “Once you've induced this kind of hypersensitivity, the effects can last for a very long time,” Dr. Robinson said. Sensitized rats left undisturbed for a year still show the effect.

Psychomotor activation is not the only component of the drug experience to undergo sensitization. “We also see sensitization of drug rewards,” he said, so that past treatment with cocaine, morphine, or amphetamine will later on facilitate self administration, increase the preference for places associated with drugs, and increase how hard the animal will work to get drugs.


Dr. Terry E. Robinson: “We tend to think about the neuropsychological effects in addicts as a kind of functional lesion effect, but maybe some effects are due to impaired plasticity.”

A third phenomenon undergoing sensitization, said Dr. Robinson, is “incentive salience, or the ability of stimuli paired with rewards to acquire incentive value, and exert control over behavior.”


What do these three phenomena have in common? “They share some common circuitry, including the ventral tegmental area, the nucleus accumbens, and the dopamine system,” Dr. Robinson said. “The literature is huge” implicating changes in these areas in the process of addiction. “If you measure almost anything, it changes,” he said.

“But what is this telling us about the nature of the neuroplastic adaptation that is taking place?” he asked. “Is this form of drug experience-dependent neuroplasticity just another form of experience-dependent plasticity?”

To answer these questions, Dr. Robinson's group quantified branching following drug addiction in two cell types: medium spiny neurons, which make up more than 90 percent of the output neurons in the nucleus accumbens, and pyramidal neurons in the prefrontal cortex.

“Treatment with amphetamine and cocaine increases dendritic branching,” he said. “There seems to be more surface available to receive inputs on these cells, as a consequence of past experience with these drugs.” The highest increase in branching density occurs on the distal portions, where dopamine and glutamate converge on these cells; these two transporter systems are the ones most commonly implicated in psychomotor sensitization.

But the effect of this drug-dependent increase in branching is not benign, Dr. Robinson explained. “Having had drugs in the past may impair the potential for this kind of plasticity later in life.” Evidence for this comes from rats, in which living in a complex environment leads to just the same increases in dendritic branching in pyramidal cells in the parietal cortex. However, prior treatment with amphetamine “completely blocks the ability of experience in a complex environment to increase dendritic branching in this brain region,” he said.

“What is important about this kind of result is that it suggests another way to think about the cognitive and behavioral deficits we see in addicts. We know that addicts have a variety of neuropsychological symptoms. We tend to think about the neuropsychological effects in addicts as a kind of functional lesion effect,” Dr. Robinson said, “but maybe some effects are due to impaired plasticity.”


Whether altered plasticity at the neural level is expressed in behavior, however, “is under strong contextual control,” he said. This can be demonstrated by comparing the psychomotor-activating effects in rats that receive the same drug training regimen, but different challenge doses afterwards. Those that receive the challenge in the same environment as their original exposure show the typically strong increase in motion. However, rats receiving the challenge dose in a novel environment “act as if they've never gotten drugs before,” said Dr. Robinson. “We think they're perfectly sensitized, their brains are changed. But they express no sensitization.” This may be relevant to relapse in addicts, he noted: “People tend to relapse when they are back in the environment where they have experienced drugs in the past.”

Context can even play a role in sensitization itself. “The probability of inducing plasticity depends on the conditions under which you experience drugs,” said Dr. Robinson. Rats exposed to drugs in a novel environment are more likely to become sensitized than those receiving drugs in their home cages, where there are no environmental cues to predict the drug is coming.

In experiments performed by Dr. Robinson's group, there is a 23-fold difference in sensitization between the two groups, despite receiving exactly the same drug in exactly the same dosing regimen. It is not that it is impossible to get sensitized to drug effects at home – it just requires a much greater dose. “The environment is shifting the dose-effect function,” he said. “I chide my pharmacologist colleagues that perhaps what is really important in variation of drug response is not pharmacology, but psychology.”


What accounts for these differences on the cellular level? Work in Dr. Robinson's lab has shown that the answer lies in differential levels of gene expression. In rats receiving drugs in a novel environment, expression of cfos, one of the “immediate early” genes in signal transduction pathways, is highly elevated, especially in the caudate. Furthermore, these changes are most significant in those medium spiny neurons that use enkephalin as a neurotransmitter, and are involved in cortical circuits. “In a novel context, the context itself turns on the cortex, activating corticostriatal inputs,” Dr. Robinson said, “pulling in enkephalin-positive cells, engaging cells that are normally not engaged as a consequence of drug administration” in non-novel environments.

Similar changes in cfos expression can be brought about by increasing the rate of drug administration. “This suggests another way of thinking about why drugs that enter the brain rapidly can potentially be more addictive. It is not necessarily because they lead to greater euphoria,” he said. “It could be due at least in part to the effect on behavioral plasticity.”

“There is no argument anymore in the field that a wide variety of drugs of abuse can have an enormous and a consistent impact on patterns of synaptic reorganization in many brain regions,” summarized Dr. Robinson. “The wiring diagram in the brain of the addict really is fundamentally different from the wiring diagram of the non-addict.” Taken together, “these drug-induced neuroplastic adaptations promote the transition from taking drugs to compulsively taking drugs in a way that characterizes addiction.”


While there is widespread agreement that addicts are wired differently, not everyone is convinced that the sensitization seen in animal models is reproduced in humans.

“Clearly, addiction is a change in the brain. It is a brain disorder,” said a leading researcher on addiction, Charles O'Brien, MD, PhD, Professor of Psychiatry at the University of Pennsylvania School of Medicine in Philadelphia. “The whole of psychiatry has moved towards behavioral neuroscience, rather than viewing the mind as a black box.”


Dr. Charles OBrien: “We dont have a good measure of sensitization in humans. … We are really hard pressed” to figure out the precise human correlates of what is seen in rats.

However, he said, “we don't have a good measure of sensitization in humans.” Dr. O'Brien speculated that perhaps some forms of stereotyped movements in humans at high drug doses might reflect sensitization, and noted that some people have suggested that psychosis is a form of sensitization. But, he said, “we are really hard pressed” to figure out the precise human correlates of what is seen in rats.

Dr. O'Brien has proposed an alternative hypothesis. “Could it be that those who don't sensitize become addicted? Maybe sensitization protects, and that is why we don't see any evidence of it in humans who become addicted. Those who fail end up getting hooked.”

“It is clearly an important phenomenon,” he said, “and it may have relevance in humans, but it is not a given. We can't just assume that because it occurs in rats, that it is an important component of addiction in humans.” Dr. O'Brien puts more stock in results arising from neuroimaging studies, “the big new area in the study of addiction,” he said.

Article In Brief

  • ✓ In a lecture at the Society for Neuroscience Annual Meeting, leading drug researcher Dr. Terry Robinson, of the University of Michigan, explored the role of neuroplasticity in the development of addiction