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January 2011

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Aston-Jones explores the biology of addiction

By Negin Martin
January 2011

Gary Aston-Jones Ph.D.

Ashton-Jones' work has been funded by the National Institute on Drug Abuse and Lilly Pharmaceuticals. His research has clear potential in the development of drugs to treat people with a range of addictions, along with adding to the understanding of the interplay of biology and environment in learning. (Photo courtesy of Steve McCaw)

Jau-Shyong Hong, Ph.D.

Among NIEHS scientists drawn to the talk was Jau-Shyong Hong, Ph.D., right whose Parkinson's research also explores the role the neurotransmitter dopamine plays in brain function. (Photo courtesy of Steve McCaw)

Ken Korach, Ph.D.

The Distinguished Lecture Series also attracts specialists in other fields, such as NIEHS Principal Investigator and Chief of Laboratory of Reproductive and Developmental Toxicology Ken Korach, Ph.D., whose principal research interest is the stimulation of estrogenic response. (Photo courtesy of Steve McCaw)

Patricia Jenson, Ph.D.

Host Patricia Jenson, Ph.D., the principal investigator of the NIEHS Developmental Neurobiology Group in the Laboratory of Neurobiology, joined Ashton-Jones for the question and answer session. She said of his research, "This work has really laid the foundation for many researchers to follow in studying the system, including the work in my own lab." (Photo courtesy of Steve McCaw)

Neurobiologist Gary Aston-Jones Ph.D., discussed the role of orexin neurons in reward-seeking behavior and addiction in his 2010-2011Distinguished Lecture Series presentation at NIEHS Nov. 23, "Seeking Rewards: Overdoing It With Orexin Neurons."

Findings by the Aston-Jones laboratory suggest a novel role for orexin in promoting addictive behavior and drug relapse, as well as its involvement in learning and synaptic plasticity. According to Ashton-Jones, chemical manipulation of these neurons may offer a new therapeutic avenue for reprogramming the drug-seeking response, as orexin analogs show pharmacological potential in modifying behavior.

Aston-Jones( Exit NIEHS holds the Murray Chair of Excellence in Neuroscience and is the director of the Center for Cognitive Neuroscience at the Medical University of South Carolina. Research in his lab has unraveled chemical pathways and neurophysiological circuitries responsible for cognitive performance and acquisition of reward-stimulus association.

Aston-Jones' contributions to the field have deepened understanding of the neuromodulatory signals that underlie mammalian behavior and learning. During his lecture at NIEHS, Aston-Jones shared his latest findings about the function and mechanisms of orexin neurons in the reward system, animal responses in Pavlovian and instrumental drug-seeking experiments, and the mapping of additional areas in the brain affected by addiction.

Orexin neurons connect with many parts of the brain

Orexin neurons are exclusively located in the hypothalamus. Despite their small number, these neurons have widespread projections to the cerebral cortex, midbrain, and the spinal cord that position them as key regulators of neurotransmission.

Release of the neuropeptide orexin is generally thought to be involved in arousal, stimulating food and drug intake and maintenance of the waking state. Conversely, mutations in orexin receptors OXR1 and OXR2 have been associated with narcolepsy and cataplexy, a partial or complete loss of muscle tone, in experiments with dogs and rodents.

Orexin aids memory of morphine and cocaine pleasure

The ventral tegmental area (VTA) in the brain manages learning and the formation of stimuli-reward associations innervated by orexin neurons. Using Fos expression in the brains of test animals as an indicator for neuronal activity during cocaine preference, researchers discovered that orexin neurons are activated by reward-associated stimuli.

One of the behavioral assays commonly used in neurobiology to study addictive behavior in rodents is the conditioned place preference (CPP) paradigm. With CPP on drug-free test days, researchers can measure the degree of preference for a stimulus associated with a reward in response to context-induced environmental cues. Assessing behavioral response in rodents, researchers demonstrated that orexin neurons are stimulated during conditioning for learned preferences for stimuli associated with rewards such as morphine, cocaine, and food. In turn, chemical inhibition or stimulation of orexin neurons significantly affected reward-associated behavior in rats during CPP testing.

Dopamine neurons get a boost from orexin

Mood, attention, and memory are all influenced by the function of dopamine neurons. Long-lasting increases in neurotransmission, known as longterm potentiation or LTP, strengthen synaptic connections and affect plasticity.

Changes in synaptic connections and their strengths in VTA dopamine neurons are implicated in drug-related behavior. Each repeated cocaine use, for example, induces a larger LTP in dopamine neurons, strengthening neuronal connections associated with the drug reward.

Orexin neuron projections into the VTA region directly influence LTP in the VTA dopamine neurons. Local administration of orexin enhances the VTA dopamine neuron response to stimulation. Consistent with this result, disruption of orexin input results in extinguished addictive behavior in rodents.

Orexin regulation of dopamine neuron plasticity is complicated by the factors such as the type and source of the stimulation, which directly modulate function of the neurons in the circuitry.

(Negin Martin, Ph.D., is a biologist in the NIEHS Laboratory of Neurobiology Viral Vector Core.)

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