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Meth binge. Dopamine decline. And poor choices.

Izquierdo’s research shows drug-induced deficiencies appear to make it harder for rats to change behavior

Regions of the brain. Source: NIH.

Behavior from the brain

The Laboratory of Cognitive Neuroscience at Cal State L.A., established in 2006 by Alicia Izquierdo, focuses on the brain regions and mechanisms that help us make decisions.

More specifically: How are we able to modify our behavior when given new information?

The lab’s current projects are seeking answers on two main fronts:

The neural basis of adaptive decision-making

The effects of drugs of abuse on flexible behavior

Izquierdo is the first Cal State L.A. researcher with the Drug Enforcement Agency license and registration required for research that uses controlled substances, such as methamphetamine.

Brain regions and their function. Source: NIH.

How rat model might help

A recently established rat model may help scientists understand the mechanisms behind diminished decision-making ability among humans using methamphetamines.

But just how much alike are the brains of rats and of humans?

Decades of research have established many solid, clear correlations, said Alicia Izquierdo, director of The Laboratory of Cognitive Neuroscience at Cal State L.A.

“The animal model has informed us about neurobiological mechanisms of disease. This is true not only for addiction but for a multitude of diseases. This is possible because we can empirically test the effects of (for example) drugs on brain anatomy and chemistry. We therefore learn about what the neural circuitry does to support behavior.”

“There’s a lot of overlap,” she said. “Once you have a model in the rat, you can begin to theorize how it would work in humans.”

Why she studies cognitive flexibility

Alicia Izquierdo summarizes the reasons for studying the effect of methamphetamine on cognitive flexibility, (adapted from her National Institute of Drug Abuse grant abstract):

Methamphetamine (mAMPH) is a highly addictive psychostimulant and a growing public health concern, with a record of nearly 1.4 million people over the age of 12 using methamphetamine in the United States in 2005. In many regions of the United States, it is surpassed only by alcohol and marijuana as the most frequently used drug, often outpacing both heroin and cocaine abuse. Those addicted to methamphetamine make poor, disadvantageous choices and relapse often.

The long-term goal of this project is to provide knowledge about the effects of methamphetamine on decision-making and the brain.

Despite an increased number of studies recently devoting attention to measuring mAMPH effects on learning and memory, no systematic investigation has been conducted on mAMPH's impact on cognitive flexibility in either an animal model or in humans. Cognitive flexibility is of vital importance to the success of an organism and refers to the ability to shift strategy given a new set of circumstances....

We propose to study the effects of mAMPH on flexible cognition using a touch screen-based operant procedure sensitive to pharmacological manipulation in rodents....

Our long-term goal is to reconcile our understanding of the neural circuitry that subserves flexible cognition with the pathological effects of drugs of abuse....

Results arising from this project will enhance our understanding of the impact of mAMPH on flexible cognitive processes and increase our ability to identify therapeutic targets to ameliorate the poor decision-making arising from mAMPH abuse.

Pictured: (l-r) Photo-research assistant Alisa Kosheleff and co-authors Lori Matti, Dr. Alicia Izquierdo and Jack Chen in the La Kretz Hall lab.

Methamphetamine wreaks havoc upon the brain, damaging an addict’s ability to learn and remember. That much researchers have known.

Now, from an examination of laboratory rats high on meth and later low on dopamine, come signs that the damage may go further. The study indicates that binge meth use may also restrict users’ ability to alter their destructive behavior and, ultimately, may diminish their ability to make healthier decisions.

In short, meth has effects on the brain that make it difficult to control or stop use of the drug.

Definitions from the research

Reversal learning is the ability to inhibit a choice that no longer brings about a reward. It is a task often examined in animals to assess inhibitory control and flexible behavior. In humans it usually means inhibiting inappropriate, non-rewarding responses. This task is thought to require the prefrontal cortex in rodents, monkeys, and man.

Attentional set shift is a task that requires the animal to shift attentional domains to obtain reward (from attending to scent media to tactile media or vice versa). Importantly, this test of cognitive control was unimpaired following meth administration in the present study—only reversal phases were impaired. This suggests the animals had no problems shifting attention; rather it was in their flexible behavior that the animals were found to make choices that were not the best.

Dopamine is a neurotransmitter, or brain chemical, that is important in learning about reward. All drugs of abuse increase dopamine in areas like the nucleus accumbens. Virtually any behaviors we engage in that we find pleasurable (food, sex, shopping, gambling) increase dopamine in this brain region.

“It’s like the neurobiological consequences of meth use get stacked against you. With each use, you could be tinkering with the intricate balance of dopamine in the brain and leaving yourself more vulnerable to further use and a further inability to quit using,” said Cal State L.A. Assistant Professor of Psychology Alicia Izquierdo.

Izquierdo and UC Irvine Professor of Neurobiology and Behavior John F. Marshall led the study, which will be presented at the first national conference on translational research in methamphetamine addiction in July. The results were recently published in the journal Neuropsychopharmacology.

The nine-member research team conducted a series of three experiments involving 37 rats that were administered binge doses of methamphetamine. Then, according to Izquierdo, the rats were faced with “tasks that required them to engage in flexible behavior to optimize rewards.” It was a deliberate search for evidence of meth-induced changes in “reversal learning” and “attentional set-shifting.”

How dopamine might fit in

The researchers also examined levels and locations of dopamine in the rats’ brains.

The problem, the researchers found, may be rooted in the way meth alters the transport of dopamine in the brain. In rats with heavy meth intakes, they found significant reductions in the chemicals that transport dopamine.

The image shows how neurotransmission works specifically for dopamine. Source: NIH.

According to Izquierdo, the study is also significant because it constitutes the first rat model of the widely reported decision-making deficits observed in human methamphetamine users. (See “How rat model might help” sidebar.)

“Traditionally,” she said, “addiction research focused on learning and memory tasks. This is more about how animals can maximize reward, more about adaptive behavior.”

Addicts, she said, are known to have very poor control over their drug use, which prevents them from changing their behavior, from making good decisions.

Is poor self-control linked to lowered dopamine? Could further research lead to pharmaceutical, behavioral or other types of treatments?

Meet in Montana about meth

Those questions will likely arise next July in Montana at the Translational Research in Methamphetamine Addiction Conference. It will bring together behavioral scientists, pharmacologists, toxicologists, neurobiologists, treatment therapists, and others to examine meth addiction.

“It will cover (from) lab bench to bedside applications,” said Izquierdo.”

The topic gamut will run from basic animal-model research in neurobiology to treatments for humans.

“It’s nice,” she said, “when you see that the research you do might actually have an impact on therapy or treatments for meth addicts.”

Pictured: Co-author/CSULA grad student Victor Cazares in CSULA Cognitive Neuroscience lab.

The team, the lab, the funder

Co-authors on the project with Izquierdo and Marshall were three Cal State L.A. students – graduate students Lori Scott and Victor Cazares, and undergraduate Jack Chen – and four other UCI researchers (Annabelle M. Belcher, Steven J. O’Dell, Melissa Malvaez and Tiffany Wu).

Scott (in Cal State L.A.’s Ed.D. program) and Cazares (at University of Michigan) are now doctoral students. Chen remains active in the Laboratory of Cognitive Neuroscience at Cal State L.A. and is applying to continue his work there as a graduate student.

The study was funded by a National Institutes of Health grant from the National Institute of Drug Abuse, part of UC Irvine Professor Marshall’s decade-long NIH-supported project examining methamphetamine abuse and cortical cell injury. Ongoing and future research on this project is also funded by NIH NIGMS 1SC2MH087974 to Izquierdo.

Cal State L.A. graduate student Alisa Kosheleff conducts the Cal State L.A. effort in the project.



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Last Update: 05/18/2009