Scientists have identified a mechanism in the brain that helps to explain why craving for cocaine, and the risk of relapse, seems to increase in the weeks and months after drug use is stopped. The research was supported by the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health.

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The first large-scale analysis of proteins in the brains of monkeys addicted to cocaine reveals new information on how long-term cocaine use changes the amount and activity of various proteins affecting brain function.The identified changes are more numerous and long-lasting than previously thought, which may provide a biological explanation for why cocaine addiction is so difficult to overcome, according to Scott E. Hemby, Ph.D.

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How meth addiction happens. If alcohol’s impact on brain cells is wide-ranging and diffuse, and marijuana’s impact is selective and subtle, the impact of cocaine and amphetamine is much more straightforward. “There is certainly lots of evidence for common neurological mechanisms of reward across a wide variety of drugs,” said Dr. Robert Post, chief of the biological psychiatry branch at NIMH. Animals will readily administer cocaine and amphetamine, Dr. Post once explained to me, but when researchers surgically block out areas of the brain that are dense with dopamine receptors, the picture changes dramatically. “The evidence definitely incriminates dopamine in particular,” said Dr. Post. “In animal models, if you make selective lesions in the dopamine-rich areas of the brain, particularly the nucleus accumbens in the limbic system, the animals won’t self-administer either amphetamine or cocaine.” When you knock out large slices of the nucleus accumbens, animals no longer want the drugs. So, one cure for addiction has been discovered already—but surgically removing chunks of the midbrain won’t do, of course. At the heart of the meth high is a chemical paradox. The entire range of stimulative effects hits the limbic system within seconds of being inhaled or inject, and the focused nature of the impact yields an astonishingly pleasurable high. But the long-term result is exactly the opposite. The body’s natural stock of these neurotransmitters starts to fall as the brain, striving to compensate for the artificial flooding of the reward center, orders a general cutback in production. At the same time, the receptors for these neurotransmitters become excessively sensitive due to the frequent, often unremitting nature of the stimulation. The release of dopamine and serotonin in the limbic structure called the nucleus accumbens lies at the root of active drug addiction. It is the chemical essence of what it means to be addicted. The pattern of neural firing that results from this surge of neurotransmitters is the “high.” Dopamine is more than a primary pleasure chemical—a “happy hormone,” as it has been called. Dopamine is also the key molecule involved in the memory of pleasurable acts. Dopamine is part of the reason why we remember how much we liked getting high yesterday. One reason why amphetamine addicts will continue to use, even in the face of rapidly diminishing returns, is simply to avoid the crushing onset of withdrawal. Even though the drug may no longer be working as well as it once did, the alternative--the psychological and physical cost of withdrawal--is even worse. When addicts talk about “chasing a high,” the metaphor can be extended to the losing battle of neurotransmitter levels. In the jargon used by Alcoholics Anonymous, addicts generally have to get worse before they can get better. Speed, then, is diabolically well suited to the task of artificially stimulating the limbic reward pathway. Molecules of amphetamine displace dopamine and norepinephrine in the storage vesicles, squeezing those two neurotransmitters into the synaptic gap, and keeping them there, where they repeatedly stimulate their receptors. By mechanisms less well identified, cocaine accomplishes the same feat. Speed also interferes with the return of dopamine, norepinephrine, and serotonin molecules to their storage sacs, a procedure known as reuptake blocking—the same mechanism by which the so-called selective serotonin reuptake inhibitors (SSRI) antidepressants increase the availability of serotonin in the brain. Adapted from “Addiction: The Search For A Cure” ©Dirk Hanson

Crack, free-base, and powder. The cocaine high is a marvel of biochemical efficiency. Cocaine works primarily by blocking the reuptake of dopamine molecules in the synaptic gap between nerve cells. Dopamine remains stalled in the gap, stimulating the receptors, resulting in higher dopamine concentrations and greater sensitivity to dopamine in general. Since dopamine is involved in moods and activities such as pleasure, alertness and movement, the primary results of using cocaine--euphoria, a sense of well being, physical alertness, and increased energy—are easily understood. Even a layperson can tell when lab rats have been on a cocaine binge. The rapid movements, sniffing, and sudden rearing at minor stimuli are not that much different in principle from the outward signs of cocaine intoxication among higher primates.

Chemically, cocaine and amphetamine are very different compounds. Psychoactively, however, they are very much alike. Of all the addictive drugs, cocaine and speed have the most direct and most devastatingly euphoric effect on the dopamine systems of the brain. Writing in an issue of Synapse, Jonathan D. Brodie and colleagues at the New York University School of Medicine reported that “A rapid elevation in nucleus accumbens dopamine characterizes the neurochemical response to cocaine, methamphetamine, and other drugs of abuse."

In the late 1990s, scientists at Johns Hopkins and NIDA had shown that opiate receptors play a role in cocaine addiction as well. PET scans demonstrated that cocaine addicts showed increased binding activity at opiate receptors sites in the brain during active cocaine addiction. Take away the cocaine, and the brain must cope with too many empty dopamine and endorphin receptors.Cocaine and amphetamine produce rapid classical conditioning in addicts, demonstrated by the intense cravings touched off by such stimuli as the sight of a building where the user used to buy or sell. Environmental impacts of this nature can produce marked blood flow increases to key limbic structures in abstinent addicts.

When the crack "epidemic" first became news, it was clear that the old specialty of free-basing was now within reach of existing cocaine users. No paraphernalia needed except for a small pipe; no more butane and mixing; no muss, no fuss. Like basing, smoking crack was a drug dealer’s dream. The “rush” from smoking crack was more potent, but even more transient than the short-lived high from nasal ingestion. Both the cocaine high and the amphetamine high are easily augmented with cigarettes or heroin. These combinations result in “nucleus accumbens dopamine overflow,” a state of neurochemical super saturation similar to the results obtained with the notorious “speedball”—heroin plus cocaine. It has been clear for more than a decade that most cocaine treatment programs are failures. In the case of crack cocaine, relapse rates after formal treatment sometimes approach one hundred percent. Clearly, a piece of the puzzle has been missing. If receptors were the sites that controlled how drugs affected the mind, and if genes controlled how receptors were grown, then one implication of all the receptor theories was that sensitivity to addictive drugs could conceivably have a genetic basis. It was a large step in the right direction, because there were already good reasons for seeing alcoholism and other addictions as inherited dysfunctions in brain chemistry.--Excerpted from Addiction: The Search for a Cure © Dirk Hanson 2007Photo Credit: Legal Drug Alternatives (Source: Addiction Inbox)

Crack, free-base, and powder The cocaine high is a marvel of biochemical efficiency. Cocaine works primarily by blocking the reuptake of dopamine molecules in the synaptic gap between nerve cells. Dopamine remains stalled in the gap, stimulating the receptors, resulting in higher dopamine concentrations and greater sensitivity to dopamine in general. Since dopamine is involved in moods and activities such as pleasure, alertness and movement, the primary results of using cocaine--euphoria, a sense of well being, physical alertness, and increased energy—are easily understood. Even a layperson can tell when lab rats have been on a cocaine binge. The rapid movements, sniffing, and sudden rearing at minor stimuli are not that much different in principle from the outward signs of cocaine intoxication among higher primates. Chemically, cocaine and amphetamine are very different compounds. Psychoactively, however, they are very much alike. Of all the addictive drugs, cocaine and speed have the most direct and most devastatingly euphoric effect on the dopamine systems of the brain. Writing in the November 2004 issue of Synapse, Jonathan D. Brodie and colleagues at the New York University School of Medicine reported that “A rapid elevation in nucleus accumbens dopamine characterizes the neurochemical response to cocaine, methamphetamine, and other drugs of abuse." In the late 1990s, scientists at Johns Hopkins and NIDA had shown that opiate receptors play a role in cocaine addiction as well. PET scans demonstrated that cocaine addicts showed increased binding activity at mu opiate receptors sites in the brain during active cocaine addiction. Take away the cocaine, and the brain must cope with too many empty dopamine and endorphin receptors. Cocaine and amphetamine produce rapid classical conditioning in addicts, demonstrated by the intense cravings touched off by such stimuli as the sight of a building where the user used to buy or sell. Environmental impacts of this nature can produce marked blood flow increases to key limbic structures in abstinent addicts. When the crack "epidemic" first became news, it was clear that the old specialty of free-basing was now within reach of existing cocaine users. No paraphernalia needed except for a small pipe; no more butane and mixing; no muss, no fuss. Like basing, smoking crack was a drug dealer’s dream. The “rush” from smoking crack was more potent, but even more transient, than the short-lived high from nasal ingestion Both the cocaine high and the amphetamine high are easily augmented with cigarettes or heroin. These combinations result in “nucleus accumbens dopamine overflow,” a state of neurochemical super saturation similar to the results obtained with the notorious “speedball”—heroin plus cocaine. It has been clear for more than a decade that most cocaine treatment programs are failures. In the case of the newly arrived crack cocaine, relapse rates after formal treatment sometimes approach one hundred per cent. Clearly, a piece of the puzzle has been missing. If receptors were the sites that controlled how drugs affected the mind, and if genes controlled how receptors were grown, then one implication of all the receptor theories was that sensitivity to addictive drugs could conceivably have a genetic basis. It was a large step in the right direction, because there were already good reasons for seeing alcoholism and other addictions as inherited dysfunctions in brain chemistry. --Excerpted from Addiction: The Search for a Cure © Dirk Hanson 2007 Photo Credit: Legal Drug Alternatives