COMMENTS: First study to show that drug use causes a decline in dopamine (D2) receptors. Important because addicts have a low number of such receptors, which may contribute to addiction. Also shows that receptors can bounce back, but rate is highly varaible and not related to baseline D2 receptors.
Cocaine Abuse And Receptor Levels: PET Imaging Confirms Link
14 Jul 2006
Using positron emission tomography (PET), researchers have established a firm connection between a particular brain chemistry trait and the tendency of an individual to abuse cocaine and possibly become addicted, suggesting potential treatment options.
The research, in animals, shows a significant correlation between the number of receptors in part of the brain for the neurotransmitter dopamine – measured before cocaine use begins – and the rate at which the animal will later self-administer the drug. The research was conducted in rhesus monkeys, which are considered an excellent model of human drug users.
Generally the lower the initial number of dopamine receptors, the higher the rate of cocaine use, the researchers found. The research was led by Michael A. Nader, Ph.D., professor of physiology and pharmacology at Wake Forest University School of Medicine.
It was already known that cocaine abusers had lower levels of a particular dopamine receptor known as D2, in both human and animal subjects, compared to non-users. But it was not known whether that was a pre-existing trait that predisposed individuals to cocaine abuse or was a result of cocaine use.
“The present findings in monkeys suggest that both factors are likely to be true,”
Nader and colleagues write in a study published online this week in the journal Nature Neuroscience. “The present findings also suggest that more vulnerable individuals are even more likely to continue using cocaine because of the cocaine-induced reductions in D2 receptor levels.”
This was the first study ever to measure the baseline D2 levels of animals that had never used cocaine and compare those levels to changes in D2 receptors after the animals had started using. This kind of comparison is not possible with human subjects, and in previous monkey research, the brain chemistry of animals exposed to cocaine was compared only with non-using “controls.”
The research also showed that starting to use cocaine caused the D2 levels to drop significantly and that continuing to use the drug kept the D2 levels well below the baseline.
“Overall, these findings provide unequivocal evidence for a role of [dopamine] D2 receptors in cocaine abuse and suggest that treatments aimed at increasing levels of D2 receptors may have promise for alleviating drug addition,” the researchers write.
The study suggested that increasing D2 receptors might be done “pharmacologically” or by improving environmental factors, such as reducing stress. But, the study notes, “at present there are no clinically effective therapies for cocaine addiction, and an understanding of the biological and environmental mediators of vulnerability to cocaine abuse remains elusive.”
Dopamine, like other neurotransmitters, moves between nerve cells in the brain to convey certain “messages.” It is released by one nerve cell and taken in by the receptors on the next nerve cell, some of which are D2. Unused dopamine is collected in “transporters” that return it to the sending cell.
Cocaine operates by entering the transporter, blocking the “reuptake” of dopamine and leaving more of it in the space between the cells. It is thought that this overload of dopamine gives the user the cocaine “high.”
But this dopamine overload also overwhelms the D2 receptors on the receiving cells, and those cells eventually react by reducing the number of D2 receptors. Drug researchers hypothesize that it is this change that creates a craving for cocaine: once the receptor level drops, more dopamine is needed for the user even to feel “normal.”
Like cocaine use, stress can also increase the dopamine levels and apparently cause a reduction in the D2 receptors. Earlier research by Nader’s team at Wake Forest showed a connection between stress and a tendency to abuse cocaine.
The current study also observed differences in the time it took for the D2 receptors to return to normal levels once cocaine use ended. Monkeys that used only for one week had only a 15 percent reduction in D2 receptors and recovered completely within three weeks.
But monkeys that used for a year averaged a 21 percent reduction in D2 receptors. Three of those monkeys recovered within three months, but two of those monkeys still had not returned to their baseline D2 levels after one year of abstinence.
Lack of recovery was not related to initial baseline D2 levels. The study suggests that “other factors, perhaps involving other neurotransmitter systems, mediate the recovery of D2 receptor function.”
THE STUDY: PET imaging of dopamine D2 receptors during chronic cocaine self-administration in monkeys.
Nader MA, Morgan D, Gage HD, Nader SH, Calhoun TL,
Buchheimer N, Ehrenkaufer R, Mach RH.
Nat Neurosci. 2006 Aug;9(8):1050-6. Epub 2006 Jul 9.
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Medical
Center Boulevard, Winston-Salem, North Carolina 27157, USA. [email protected]
Dopamine neurotransmission is associated with high susceptibility to cocaine abuse. Positron emission tomography was used in 12 rhesus macaques to determine if dopamine D2 receptor availability was associated with the rate of cocaine reinforcement, and to study changes in brain dopaminergic function during maintenance of and abstinence from cocaine. Baseline D2 receptor availability was negatively correlated with rates of cocaine self-administration. D2 receptor availability decreased by 15-20% within 1 week of initiating self-administration and remained reduced by approximately 20% during 1 year of exposure. Long-term reductions in D2 receptor availability were observed, with decreases persisting for up to 1 year of abstinence in some monkeys. These data provide evidence for a predisposition to self-administer cocaine based on D2 receptor availability, and demonstrate that the brain dopamine system responds rapidly following cocaine exposure. Individual differences in the rate of recovery of D2 receptor function during abstinence were noted.