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The Journal of Neuroscience, May 31, 2006, 26(22):5894-5900; doi:10.1523/JNEUROSCI.0740-06.2006

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Behavioral/Systems/Cognitive
Conditioned Withdrawal Drives Heroin Consumption and Decreases Reward Sensitivity

Paul J. Kenny, ^* Scott A. Chen, ^* Osamu Kitamura, Athina Markou, and George F. Koob

Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, California 92037

Correspondence should be addressed to either of the following at their present addresses: Paul J. Kenny, Scripps Florida, 5353 Parkside Drive, Jupiter, FL 33458, Email: pjkenny{at}scripps.edu; or Scott A. Chen, Laboratory of Clinical and Translational Studies, National Institutes of Health Animal Center, P.O. Box 529, Building 112, Poolesville, MD 20837, scott.chen{at}mail.nih.gov

Aspects of drug withdrawal may become conditioned to previously neutral environmental stimuli via classical conditioning processes. Nevertheless, the significance of conditioned withdrawal effects in motivating drug intake remains largely unexplored. Here, we investigated the effects of conditioned withdrawal in modulating heroin consumption and brain reward sensitivity in rats. Rats intravenously self-administered heroin (20 µg/infusion) during 0 h (control), 1 h (nondependent), or 23 h (dependent) sessions and had daily intracranial self-stimulation (ICSS) thresholds assessed. ICSS thresholds remained stable and unaltered in control rats. In nondependent rats, heroin self-administration induced a transient activation of reward systems, reflected in lowering of ICSS thresholds. In dependent rats, heroin intake escalated across sessions and was associated with a gradual decrease in reward sensitivity, reflected in progressively elevated ICSS thresholds. Thus, as dependence develops, heroin may be consumed not only for its acute reward-facilitating effects, but also to counter persistent deficits in reward sensitivity. In nondependent rats, the opioid receptor antagonist naloxone (30 µg/kg) increased heroin consumption and reversed heroin-induced lowering of ICSS thresholds, effects resistant to classical conditioning. In contrast, in dependent rats naloxone (30 µg/kg) increased heroin consumption and also elevated ICSS thresholds above their already elevated baseline levels (i.e., precipitated withdrawal). Most importantly, stimuli repeatedly paired with naloxone-precipitated withdrawal provoked heroin consumption and elevated ICSS thresholds in dependent rats. Thus, conditioned stimuli predicting the onset of heroin withdrawal, and hence the reward deficits coupled with this state, may play a critical role in provoking craving and relapse in human opiate addicts.

Key words: heroin; opiate; conditioned withdrawal; classical conditioning; pavlovian conditioning; addiction; craving; relapse

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Received Feb. 18, 2006; revised April 24, 2006; accepted April 24, 2006.

Correspondence should be addressed to either of the following at their present addresses: Paul J. Kenny, Scripps Florida, 5353 Parkside Drive, Jupiter, FL 33458, Email: pjkenny{at}scripps.edu; or Scott A. Chen, Laboratory of Clinical and Translational Studies, National Institutes of Health Animal Center, P.O. Box 529, Building 112, Poolesville, MD 20837, scott.chen{at}mail.nih.gov

Related articles in J. Neurosci.:

Heroin Addiction: Anticipating the Reward of Heroin or the Agony of Withdrawal?

Magalie Lenoir and Ronald Keiflin
J. Neurosci. 2006 26: 9080-9081. [Full Text]  

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				G. Koob and M. J. Kreek Stress, Dysregulation of Drug Reward Pathways, and the Transition to Drug Dependence Am J Psychiatry, August 1, 2007; 164(8): 1149 - 1159. [Abstract] [Full Text] [PDF]

				K. G. C. Hellemans, B. J. Everitt, and J. L. C. Lee Disrupting Reconsolidation of Conditioned Withdrawal Memories in the Basolateral Amygdala Reduces Suppression of Heroin Seeking in Rats J. Neurosci., December 6, 2006; 26(49): 12694 - 12699. [Abstract] [Full Text] [PDF]

				M. Lenoir and R. Keiflin Heroin Addiction: Anticipating the Reward of Heroin or the Agony of Withdrawal? J. Neurosci., September 6, 2006; 26(36): 9080 - 9081. [Full Text] [PDF]

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