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Declines in a dopamine receptor parallel deficits in vigilance and mental flexibility.

November 01, 2009
Lori Whitten, NIDA Notes Staff Writer

Do chronic cocaine abusers score lower than their peers on tests of concentration, short-term memory, and decisionmaking because the drug has impaired them? Or might they have done just as poorly before they ever took the drug?

NIDA-supported researchers Dr. Terry Robinson and colleagues at the University of Michigan recently presented strong evidence that cocaine causes cognitive deficits that can persist well into abstinence. In their study, rats that self-administered the stimulant performed worse than they had before taking the drug and worse than unexposed animals on a task requiring sustained attention and mental flexibility. The severity and persistence of the deficits correlated directly with the amount of drug exposure and inversely with levels of a neurotransmitter receptor that the drug suppresses.

Persistent Problems on a Demanding Task

The question of the etiology of cocaine abusers' cognitive deficits has important implications for prevention and treatment, but it is difficult to resolve through research with human subjects. To answer definitively, researchers would need to compare chronic abusers' current cognitive ability with baseline measures obtained before their first exposure to the drug. Yet such baseline measures are rarely, if ever, available. To obtain them, researchers would have to either accurately predict which unexposed young people are going to become chronic abusers or subject many young people to cognition tests.

Tests of Vigilance and Mental Flexibility

illustration of rat lever pressing during signal task and non-signal task - see caption

Signal Task (left images)

After a half-second flash of light (top image), two levers emerge from the cage wall (bottom image). To receive a food pellet, the rat must press the lever on the left. This task requires sustained attention—the rat must remember and respond to a simple cue.

Non-Signal Task (right images)

No light flashes, but two levers emerge from the cage wall. To receive a food pellet, the rat must press the lever on the right. This is considered harder than the signal task. The rat must apply a rule that is contingent on something not happening—i.e., the light not flashing—which requires cognitive flexibility.

The Michigan team avoided this obstacle by studying rats. They established baseline cognitive measures by training their animals up to a predetermined skill level on an experimental task. The task challenges the rat to choose correctly between two levers that are introduced simultaneously into its cage. Pushing on one lever is rewarded with a food pellet if a light flashed just prior to the appearance of the levers; pushing on the other lever is rewarded if the light did not flash (see illustration).

Once each rat's lever responses reached roughly 70 percent overall accuracy, the researchers stopped the task and trained the animal to poke its nose into a hole to activate a mechanism that dispensed an infusion of cocaine. Six days every week for the next 3 weeks, some rats self-administered cocaine in this way for 1 hour per day and others for 6 hours per day. Three weeks in a rat's average lifespan is roughly proportional to a year or more in a human's. During this time, the rats in the 6-hour self-administration sessions progressively increased their intake to very high doses of the drug.

One day after a rat's final cocaine infusion, the researchers reintroduced the animal to the light-and-levers task. Animals that had self-administered the drug for 6 hours daily now pushed the wrong lever markedly more often than they had prior to taking the drug, and more often than a control group that had not been exposed to the drug. In contrast, animals that had self-administered cocaine for only 1 hour daily made roughly the same number of errors as the control group. Retested again on post-cocaine days 14 through 21 or 28, the heavily exposed rats continued to exhibit impaired performance while those with less exposure scored as well as the control group.

Chronic Cocaine Self-Administration Increases Proportion of High-Sensitivity D2 Receptors in Rats

Rats exposed to cocaine display a heightened sensitivity to stimuli that trigger dopamine release in the brain's striatum. When treated with a dopamine-promoting drug or test compound, for example, they increase their locomotor activity more than similarly treated cocaine-naïve animals do. These observations would be expected if cocaine increased the number of dopamine 2 (D2) receptors, proteins that provide the primary points of access for the neurotransmitter to influence cellular activity in the striatum—a brain region that processes rewards and helps control movement. However, cocaine-exposed rats in laboratory studies have not consistently shown such increases. Moreover, imaging studies of people with histories of chronic cocaine abuse have found reduced, rather than augmented, striatal D2 receptors.

Dr. Terry Robinson of the University of Michigan and colleagues, in collaboration with Dr. Philip Seeman of the University of Toronto, recently proposed a solution to this conundrum: On the basis of results they obtained in a recent study, the NIDA-funded researchers suggest that cocaine renders the rat striatum more sensitive to dopamine primarily by making some individual D2 receptors more responsive, rather than by increasing their number.

Brain receptors, including the D2 receptors, can change rapidly back and forth between two shapes. When the D2 receptors are in the high-affinity shape (D2High), they bind more readily to dopamine and are more likely to become activated and affect brain function. "Our findings suggest that it's the functional state of the D2 receptor that contributes to increased sensitivity and not the overall D2 levels," says Dr. Seeman.

To assess cocaine's impact on D2 functional states, rats in Dr. Robinson's lab were first trained to self-administer the drug and then allowed to do so for either 1 hour or 6 hours daily, 6 days per week. At the end of 4 weeks, Dr. Seeman and colleagues measured the rats' levels of D2High receptors. They found that both of these groups had more than double the proportion of D2High receptors in the dorsal striatum than a third group that had never received the drug.

The D2High receptor elevation persisted at least 30 days after the last exposure to cocaine.

These results suggest a mechanism by which chronic cocaine may promote a return to drug seeking. A cocaine-induced increase in the proportion of dopamine-ready D2 receptors could make the brain respond more strongly to the drug and its cues. Dr. Seeman's findings in rat brains indicate that the receptor's altered functional state may be a persistent neurobiological change underlying addiction.

The findings may also influence interpretation of current imaging studies in which cocaine abusers demonstrate lower D2 receptor levels than nonabusers. "Our findings suggest that human imaging studies may not be capturing the complete picture of D2 receptors," says Dr. Robinson. "The state of the receptor matters, so caution is required in interpreting human imaging results."

Currently, there is no way to differentiate the D2 receptor's two forms in people. "Scientists are working on the very difficult task of finding a tracer for human imaging that selectively highlights the D2 high-affinity state, but it will probably take years," says Dr. Seeman. "The implications of developing this tracer would be enormous, however. Appropriate radiotracers will clarify the role of the D2 high-affinity state in cocaine addiction. Furthermore, the proportion of receptors in the high-affinity state may predict vulnerability to addiction." Along with addiction, D2Highreceptors may figure in the pathology of other psychiatric conditions, including schizophrenia.

"We hypothesize that the affinity state of the D2 receptor fully accounts for the hypersensitivity to drug and drug-associated cues and explains why relapse is such a persistent problem," says Dr. Seeman. He and colleagues plan to examine the biochemical underpinnings of the shift from a low- to high-affinity state, and their findings may suggest future directions for therapy.

Source: Briand, L.A. et al. Cocaine self-administration produces a persistent increase in dopamine D2High receptors. European Neuropsychopharmacology 18(8):551-556, 2008. [Abstract]

The mistakes the rats made at the later retests primarily consisted of pushing the wrong lever when the light did not flash. This is reasonable, Dr. Robinson says, because choosing correctly in these instances calls on more complex cognitive abilities, particularly flexibility. "Making the correct choice after the light flashes requires attentiveness and the ability to respond to a simple cue. When there is no light flash, the rat has to register its absence and recall an alternative rule for action. That's an ambiguous situation and therefore more cognitively demanding."

D2 Receptor Levels Parallel Performance

Examination of brain tissue 4 days after their final cocaine infusion revealed fewer D2 receptors in the prefrontal cortex (PFC) of those animals that had self-administered the drug in 6-hour daily sessions than of rats in the 1-hour-access and no-drug groups. In the medial area of the PFC, rats in the 6-hour-access group had D2 receptor levels that were only about 85 percent those of the unexposed rats. Rats from the 6-hour-access group demonstrated continuing depression of D2 receptor levels a month after cocaine self-administration stopped.

The D2 receptor is one of several proteins that alter brain cell activity when stimulated by the neurotransmitter dopamine. Dopamine stimulation of D2receptors in the PFC contributes to a variety of cognitive functions, including attention, that come into play during decisionmaking. Although the results of Dr. Robinson's study suggest that cocaine may diminish cognitive functions by disrupting D2 receptors, the larger picture of the drug's influence on these receptors is more complicated (see box).

The Importance of Protocol

Dr. Robinson's team is the first to investigate cocaine's effects on cognition using a self-administration protocol that results in drug intake comparable to that of human abusers. This feature of their study, says Dr. Robinson, is the reason they were able to demonstrate persistent cocaine-induced cognitive deficits. Other studies in which researchers gave animals more limited access to the drug have also observed deficits, but only transient ones. Also, previous research has shown that only extended access to cocaine is likely to induce behavioral and neural changes that are linked with addiction and relapse.

bar graph showing persistent attention deficits in extended cocaine use rats  Extended Cocaine Access Leads to Persistent Attention Deficits: One day after their final cocaine infusion, rats that had self-administered the drug in repeated, long bouts (6 hours daily for 3 weeks) were less accurate on a test of sustained attention than those that had short access (1 hour daily for 3 weeks) to the drug. One month after the last cocaine infusion, the performance of rats in all three groups was similar in responding to a half-second flash of light. Rats in the long-access group, however, were less accurate when presented with the more difficult problem of reacting to the absence of a light flash.

"Our findings suggest that extended cocaine self-administration changes the brain in a way that impairs the ability to be attentive—a capacity that is important in making decisions in real life," says Dr. Robinson. "The trials with flashes tested relatively simple cognitive processes, while the trials without flashes drew on more complex processes. Moreover, the mixing of trials with flashes and trials without flashes also taps into cognitive flexibility: The rats learned two different responses and had to execute the right one in each trial."

"This animal study used a well-designed, rich task to demonstrate persistent cocaine-induced deficits in important cognitive functions—sustained attention and cognitive flexibility—and link them to a neurobiological change," says Dr. Susan Volman of NIDA's Division of Basic Neuroscience and Behavioral Research. "Similar impairments in people would likely influence judgment and the ability to respond flexibly to the environment."


Briand, L.A. et al. Persistent alterations in cognitive function and prefrontal dopamine D2 receptors following extended, but not limited, access to self-administered cocaine. Neuropsychopharmacology 33(12):2969-2980, 2008. [Full Text (PDF, 274KB)]