Morehead State University

Acute Withdrawal from Drugs of Abuse in an Animal Model: Biomarkers and Mechanisms

Institution

Morehead State University

Abstract

Amphetamine and morphine are commonly abused. Animal models help us understand how drugs of abuse affect behavior and the brain, as well as enable us to identify biomarkers for abuse liability and develop more effective treatments for drug abuse. Amphetamine and morphine produce activation and positive affect in the short-term, that is, for several hours after administration. The current study examined whether they also produced acute withdrawal later in the day, and whether the acute withdrawal could be prevented by co-administration of a dopamine D1 receptor antagonist. The latter result would suggest that acute withdrawal was a longer-term effect of activating the pathway that produces the short-term reinforcing effects of drugs. Different groups of rats were given amphetamine, morphine, amphetamine coadministered with a D1 antagonist, or morphine co-administered with a D1 antagonist. Activity was monitored in open fields for 24 hours after treatments. Amphetamine and morphine were followed by reduced activity approximately 16 to 21 hours after treatment, an indicator of an acute withdrawal. A couple of animals had a negligible reduction in activity during this time, suggesting a different susceptibility to drugs of abuse. D1 antagonist prevented the reduction in activity. An animal accomplishes most functional behaviors (eating, drinking, exploration, etc.) via activity, and so blockade of the reduction in activity suggested blockade of acute withdrawal generally. The study identified new biomarkers that could be relevant for susceptibility to drugs of abuse. The study also suggested a novel and simple conceptualization of acute withdrawal: The cascade of events by which different drugs of abuse produce withdrawal symptoms may be initiated through the mesolimbic dopamine system, the same pathway responsible for the shortterm reinforcing effects of drugs. Supported by NIH grant DA015351.

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Acute Withdrawal from Drugs of Abuse in an Animal Model: Biomarkers and Mechanisms

Amphetamine and morphine are commonly abused. Animal models help us understand how drugs of abuse affect behavior and the brain, as well as enable us to identify biomarkers for abuse liability and develop more effective treatments for drug abuse. Amphetamine and morphine produce activation and positive affect in the short-term, that is, for several hours after administration. The current study examined whether they also produced acute withdrawal later in the day, and whether the acute withdrawal could be prevented by co-administration of a dopamine D1 receptor antagonist. The latter result would suggest that acute withdrawal was a longer-term effect of activating the pathway that produces the short-term reinforcing effects of drugs. Different groups of rats were given amphetamine, morphine, amphetamine coadministered with a D1 antagonist, or morphine co-administered with a D1 antagonist. Activity was monitored in open fields for 24 hours after treatments. Amphetamine and morphine were followed by reduced activity approximately 16 to 21 hours after treatment, an indicator of an acute withdrawal. A couple of animals had a negligible reduction in activity during this time, suggesting a different susceptibility to drugs of abuse. D1 antagonist prevented the reduction in activity. An animal accomplishes most functional behaviors (eating, drinking, exploration, etc.) via activity, and so blockade of the reduction in activity suggested blockade of acute withdrawal generally. The study identified new biomarkers that could be relevant for susceptibility to drugs of abuse. The study also suggested a novel and simple conceptualization of acute withdrawal: The cascade of events by which different drugs of abuse produce withdrawal symptoms may be initiated through the mesolimbic dopamine system, the same pathway responsible for the shortterm reinforcing effects of drugs. Supported by NIH grant DA015351.