In spite of massive amounts of work, the neural basis of addiction remains only partly understood. Much progress has been made in recent years in understanding the motivational role of drugs as positive incentives and rewards. Although it has long known that aversive motivation also plays a role in addiction, this role has been less clearly understood. External stimuli associated with environmental stress or drug withdrawal are negative reinforcers that contribute to instrumental drug seeking and consumption responses by strengthening behaviors that allow escape from and/or avoidance of the aversive states elicited by these stimuli. However, little is known about these brain mechanisms;for this reason, the present proposal argues that a detailed understanding of the neural basis of escape/avoidance behavior will provide important information that will allow a deeper understanding of the role of aversive states in substance abuse. While much research was conducted on the neural basis avoidance in the 1950s and 60s, this work fell out of favor, in part because the results did not lead to a clear understanding of the circuitry. However, in the intervening years, the neural basis of the first phase of avoidance, Pavlovian fear conditioning, has been elucidated in detail. This information makes it possible to revisit the neural basis of avoidance in a new light. In particular, given that we now understand in detail the neural mechanisms through which a neutral environmental stimulus associated with an aversive unconditioned stimulus (US) becomes a Pavlovian conditioned stimulus (CS) that elicits aversive states (fear, anxiety and/or stress), we can now build on this information to understand the neural basis of avoidance conditioning, especially if the same stimuli used as CSs and USs (tone an shock) in studies of the neural basis of Pavlovian conditioning are also used in avoidance conditioning. The studies will examine the contribution of the amygdala, a key structure for fear conditioning, to avoidance. The focus will be on the possible role of specific nuclei implicated in fear conditioning in the acquisition and performance of avoidance (especially the lateral, basal and central nuclei), the contribution of anatomical outputs of key amygdala nuclei (especially the projection from the basal amygdala to the nucleus accumbens), whether avoidance becomes an amygdala-independent habit following over-training, and if so whether other areas take over (especially the dorsal striatum), and finally the role of individual differences in fear and avoidance and their value in predicting susceptibility to addiction and relapse.

Public Health Relevance

Substance abuse is a significant problem in modern society. Better understanding of the brain mechanisms underlying addiction and relapse should provide new insights that could lead to better means of prevention and treatment. One area that has received less attention is the role of negative reinforcement and avoidance in addiction and relapse, the main focus of this proposal.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA029053-01
Application #
7863100
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Volman, Susan
Project Start
2010-05-01
Project End
2015-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
1
Fiscal Year
2010
Total Cost
$328,559
Indirect Cost
Name
New York University
Department
Neurology
Type
Schools of Arts and Sciences
DUNS #
041968306
City
New York
State
NY
Country
United States
Zip Code
10012
LeDoux, J E; Moscarello, J; Sears, R et al. (2017) The birth, death and resurrection of avoidance: a reconceptualization of a troubled paradigm. Mol Psychiatry 22:24-36
Madarasz, Tamas J; Diaz-Mataix, Lorenzo; Akhand, Omar et al. (2016) Evaluation of ambiguous associations in the amygdala by learning the structure of the environment. Nat Neurosci 19:965-72
Ramirez, Franchesca; Moscarello, Justin M; LeDoux, Joseph E et al. (2015) Active avoidance requires a serial basal amygdala to nucleus accumbens shell circuit. J Neurosci 35:3470-7
Campese, Vincent D; Kim, Jeanny; Lázaro-Muñoz, Gabriel et al. (2014) Lesions of lateral or central amygdala abolish aversive Pavlovian-to-instrumental transfer in rats. Front Behav Neurosci 8:161
McCue, Margaret G; LeDoux, Joseph E; Cain, Christopher K (2014) Medial amygdala lesions selectively block aversive pavlovian-instrumental transfer in rats. Front Behav Neurosci 8:329
Martinez, Raquel C R; Gupta, Nikita; Lázaro-Muñoz, Gabriel et al. (2013) Active vs. reactive threat responding is associated with differential c-Fos expression in specific regions of amygdala and prefrontal cortex. Learn Mem 20:446-52
Moscarello, Justin M; LeDoux, Joseph E (2013) Active avoidance learning requires prefrontal suppression of amygdala-mediated defensive reactions. J Neurosci 33:3815-23
Campese, Vincent; McCue, Margaret; Lázaro-Muñoz, Gabriel et al. (2013) Development of an aversive Pavlovian-to-instrumental transfer task in rat. Front Behav Neurosci 7:176
LeDoux, Joseph E (2012) Evolution of human emotion: a view through fear. Prog Brain Res 195:431-42
LeDoux, Joseph (2012) Rethinking the emotional brain. Neuron 73:653-76

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