Category: Cocaine

 Addicts, even those who have been abstinent for long periods of time, are often still vulnerable to their own memories of prior drug use.  For example, exposure to the same environment in which they commonly used drugs – a contextual memory – can increase their craving for the drug dramatically and can lead to relapse.

A new study has evaluated a novel compound that may ease the power of those memories.

“In this study, we found that after repeatedly giving cocaine injections to rats within a particular environment, the rats developed a strong preference for that environment over another environment where a placebo was given,” explains M. Foster Olive, Ph.D., co-author and senior investigator.  “Next, we treated the animals with an experimental drug called CDPPB, and found that it decreased the rats' preference for the cocaine-associated environment during subsequent tests.”

This is a process called extinction learning, whereby the compound helps the brain to create new associations instead of retrieving the old associations, in this case between the cocaine and the environment.  Dr. Olive also notes that this promising finding may aid the development of new therapeutic treatments that could be used in conjunction with exposure therapy, a technique used to desensitize individuals to stimuli that invoke negative responses or emotions.

John Krystal, M.D., Editor of Biological Psychiatry agrees and hopes that these findings can be expanded to other areas of work.  “It will be interesting to see whether this approach extends to the treatment of cocaine abuse or other addictions.  Further, it will be important to see whether mGluR5 agonists [like CDPPD] might play a role in the treatment of the extinction of other forms of maladaptive learning, such as the traumatic memories associated with posttraumatic stress disorder.”

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Journal Reference:

1. Gass et al. Positive Allosteric Modulation of mGluR5 Receptors Facilitates Extinction of a Cocaine Contextual Memory. Biological Psychiatry, 2009; 65 (8): 717 DOI: 10.1016/j.biopsych.2008.11.001

 Drug addiction affects millions of people around the world, causing numerous problems ranging from emotional and psychological difficulties to physical and health issues. Initial drug use can be motivated by curiosity or peer pressure, but in some animals, such as rats, it can also be the result of a stressful early life event, such as social isolation. A new study examines the impact of social isolation on the animal’s response to cocaine.

The study, Social Isolation During Perinatal Development Alters the Behavioral Response to Cocaine in Juvenile Rats, was conducted by Natasha Lugo-Escobar, Nicole Carreras and Annabell C. Segarra, University of Puerto Rico, School of Medicine, Rio Piedras, PR. The team will present its findings at the 122nd Annual Meeting of the American Physiological Society, which is part of the Experimental Biology 2009 scientific conference. The meeting will be held April 18-22, 2009 in New Orleans.

The Study

Drugs of abuse act on the reward centers of the brain.  These areas are normally involved in mediating pleasure, and also regulate the psycho-stimulant effects of drugs such as cocaine. Stress is known to enhance drug seeking behavior, as well as the psychostimulant effects of cocaine. Since rats are social animals, isolation was used as a stressor to explore the association between stress during development and susceptibility to the psychostimulant effects of drugs of abuse, such as cocaine. 

Rats were stressed: (1) as fetuses (by housing the pregnant mother alone), (2) as neonates (by isolating newborn rats for 1 hr daily during the first 9 days of life) or as adolescents (by housing each rat separately during days 21-35).  Two additional groups: (4) isolated as fetuses, neonates and adolescents and (5) controls – not isolated during any developmental period, comprised the 5 groups studied. When rats reached 21 days of age, they were weaned from their mothers and tested for the psychostimulant response to cocaine as well as for the development of sensitization, a phenomenon characterized by an increase response to the same amount of a drug over time.  For 5 days, half of the rats from all groups were injected with saline and the other half with cocaine (15 mg/kg).  This was followed by a 7 day drug free period and an additional cocaine injection on day 13.  Locomotor activity was measured on days 1, 5 and 13 immediately after injection. 

Results

The researchers found that:

• SEQ CHAPTER \h \r 1Rats that were isolated during all three developmental periods, showed a higher locomotor response to cocaine than control rats.
• The study indicates that the developmental period most susceptible to isolation stress, particularly in males, is the neonatal period, since males isolated as neonates show an increase in the locomotor, and sensitized  response to cocaine, compared to male control and to female rats.  

Conclusions

This study suggests that isolation during early development alters the brain sensitivity to cocaine, such that when the animal reaches adolescence and is exposed to cocaine, it is more sensitive to the psychostimulant effects of the drug.  

These studies contribute to understanding the mechanisms that may lead to greater abuse of drugs during adolescence. 

UC Irvine pharmacological researchers have discovered that blocking a hormone related to hunger regulation can limit cocaine cravings. Their findings could herald a new approach to overcoming addiction.

Led by Shinjae Chung and Olivier Civelli, the study identified how the melanin-concentrating hormone works with dopamine in the brain’s “pleasure center” to create an addictive response to cocaine use. The researchers further found that blocking MCH in these brain cells limited cocaine cravings.

Dopamine is a neurotransmitter essential to the normal functioning of the central nervous system. It also is associated with feelings of pleasure and is released in the brain during eating, sex and drug use. Heightened levels of the neurotransmitter have been detected in the nucleus accumbens of drug addicts.

The study is the first to detail the interaction of MCH and dopamine in cocaine addiction and show that it occurs in the nucleus accumbens, a portion of the forebrain believed to play an important role in addiction and feelings of pleasure and fear. 

“This discovery indicates that MCH is a key regulator of dopamine in a brain area associated with both pleasure and addiction,” says Civelli, the Eric L. and Lila D. Nelson Professor of Neuropharmacology. “We believe that efforts to target MCH may lead to new treatments to break addiction to cocaine and, possibly, other drugs, like amphetamines and nicotine.”

In mammals, MCH is involved with the regulation of feeding behavior and energy balance. High levels of the hormone can intensify feelings of hunger, and researchers worldwide have been seeking compounds to lower MCH for potential use in the treatment of obesity.

Chung and Civelli believe MCH works in the nucleus accumbens to increase the pleasure of eating. They found that dopamine signaling rose when MCH amounts increased in those brain cells.

The UCI researchers found that test mice conditioned to develop cocaine cravings had increased amounts of MCH and dopamine in their nucleus accumbens. When experimental compounds blocking MCH proteins were administered, those cravings disappeared. In addition, Chung and Civelli discovered that mice lacking key receptors for MCH exhibited significantly fewer cocaine cravings.

They hope to learn whether modulating MCH might be beneficial in treating other dopamine-related disorders as well.

Study results appear in this week’s early online edition of the Proceedings of the National Academy of Sciences. Chun-Ying Li and James Belluzzi of UCI, F. Woodward Hopf and Antonello Bonci of UC San Francisco, and Hiroshi Nagasaki of Nagoya University in Japan also worked on the study, which was supported by grants from the National Institutes of Health.

 For decades, finding clues to substance addiction has been much like searching for a needle in a haystack. But researchers may finally be honing in on specific genes tied to all types of addictions – and finding that some of the same genes associated with alcohol dependence are also closely linked with addictions to nicotine, cocaine, opoids, heroin and other substances.

In a new landmark paper to be published in the April 2009 issue of Nature Reviews Genetics, addiction experts at the University of Virginia Health System and the University of Michigan present new insights into the significant progress made within the last several years in understanding the genetics of addiction.

"Addiction researchers have found that several genes are linked with multiple addictions," says co-author Ming Li, Ph.D., professor of psychiatry and neurobehavioral sciences at the UVA School of Medicine. "So, we're narrowing the scope to specific genetic targets. Once researchers can pinpoint exact genetic variants and molecular mechanisms, then we can create much more effective, even personalized, treatments for individuals addicted to a variety of substances."

In the paper, which in part serves as a comprehensive guide to the existing body of addiction genetics research, Li and co-author Margit Burmeister, Ph.D., professor of psychiatry and human genetics at the University of Michigan, present a summary of specific genomic locations on 11 chromosomes where addictions to alcohol, cannabis, cocaine, heroin, nicotine and opoids are clustered together.

"The comparison of peaks for addictions to multiple substances on certain chromosomal locations confirms that genetic vulnerability to different substances overlaps, in part," Li says. He further points out that variants in several genes, including aldehyde dehydrogenases, GABRA2, ANKK1, and neurexins 1 and 3, have already been associated with addictions to multiple drugs.

In recommending a future direction for research into the genetics of addiction, Li suggests focusing on CHRNA5, CHRNA3 and CHRNB4 clusters, among other variants. "The exact nature of the gene variants and how they function are still unknown, so functional studies as well as studies using additional ethnic population samples may be quite revealing."

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Journal Reference:

1. Ming D. Li & Margit Burmeister. New insights into the genetics of addiction. Nature Reviews Genetics, 2009; DOI: 10.1038/nrg2536

Researchers from Boston University School of Medicine (BUSM) and Yale University School of Medicine and the University of Connecticut School of Medicine, have discovered that variants in the α-endomannosidase (MANEA) gene are associated with cocaine addiction and cocaine-induced paranoia in European American and African American populations. These findings appear in the March issue of the Archives of General Psychiatry.

Cocaine is widely abused in the United States. The 2002 National Survey on Drug Use and Health revealed that nearly six million Americans age 12 or older used the drug during the preceding year. Compulsive use of cocaine is also common with more than one million individuals considered dependent on the drug. Several studies have suggested a substantial genetic contribution to cocaine dependence and related behaviors.

The researchers took a total of 3,992 individuals from two family-based samples (European American and African American) and two case-control samples (European American and African American) enrolled in studies of drug addiction and classified them as either cocaine dependent, suffering from cocaine-induced paranoia or controls. They were then genotyped for 11 markers spanning the MANEA gene. MANEA encodes an enzyme (a-endomannosidase) that metabolizes complex carbohydrates. MANEA was chosen for further study based on evidence from a low-resolution scan of the entire genome the researchers performed previously to search for genes associated with substance dependence.

The researchers found cocaine induced paranoia was associated with six of the 11 markers in the European American family sample. They also found these six markers and three other markers were significant in the African American sample. The strongest evidence for association in either population and in the total sample was observed for marker rs9387522, which is located in the 3' untranslated region of the gene. The A allele for this marker was associated with increased risk of cocaine induced paranoia in all four data sets.

"Our findings suggest that cocaine dependence and associated behaviors may involve biological pathways not typically thought to be associated with brain metabolism and now opens a new pathway to understanding these highly prevalent disorders and their psychopathological manifestations," said lead author Lindsay A. Farrer, PhD, chief of the Genetics Program and professor of medicine, neurology, genetics & genomics epidemiology and biostatistics at BUSM.

According to the researchers, given MANEA's role in carbohydrate metabolism and relatively minor expression in brain, it would not appear initially to be a good biological candidate to modulate susceptibility to cocaine dependence or its associated psychotic complications. "However, insight into the relationship between MANEA, paranoia, and cocaine dependence can be gleaned from studies of mannosidase and other glycoproteins," notes Farrer.

MANEA is one of several glycosidic enzymes that remove oligosaccharide chains of dopamine β-hydroxylase (DBH), the enzyme that converts dopamine to norepinephrine. Low levels of DBH in plasma or cerebrospinal fluid and genetic variants in DBH have been associated with greater vulnerability to psychotic symptoms in several psychiatric disorders including cocaine dependence, schizophrenia, and major depression. MANEA may also influence susceptibility to cocaine dependence by modifying the function of liver carboxylesterase, a glycoprotein of the high mannose type, two forms of which hydrolyze cocaine and other drugs.

"This finding suggests that drug dependence and associated behaviors may involve biological pathways not typically associated with brain metabolism, and opens a new pathway to understanding these highly prevalent disorders and their psychopathological manifestations," added Farrer.

This work was supported by a grant from the National Institutes of Health.