Pharmacological reversal of behavioral and cellular indices of cocaine sensitization in the rat.
OBJECTIVE
Behavioral sensitization has been proposed as an animal model for the intensification of drug craving in cocaine addiction. Interactions between dopamine and glutamate systems are important for the induction and maintenance of sensitization. The goal of this study was to determine if established cocaine sensitization could be reversed by pharmacological manipulation of these transmitter systems.


METHODS
Rats received 15 mg/kg cocaine (IP) on days 1-10 and were challenged with cocaine (10 mg/kg) on day 13 to verify that sensitization had occurred. On days 14-20, separate groups of sensitized rats received daily injections of dopamine D1- or D2-class agonists, an NMDA receptor antagonist, or a dopamine agonist with an NMDA antagonist. Three days or 2 weeks later, all rats were again tested for their response to cocaine to determine if sensitization had been reversed.


RESULTS
Reversal of sensitization was produced by repeated administration of either a D1-class agonist (SKF 81297) or the combination of an NMDA receptor antagonist and a D2-class agonist. Effective combinations were cocaine+MK-801, quinpirole+MK-801, quinpirole+CGS 19755, and pergolide+memantine. The latter drugs are approved for human use. Reversal of sensitization persisted for at least 2 weeks after cessation of drug treatment. Electrophysiological studies revealed that these drug treatments also reversed dopamine D1 receptor supersensitivity in the nucleus accumbens, a cellular correlate of sensitization.


CONCLUSIONS
These results demonstrate that pharmacotherapy can reverse behavioral and cellular adaptations associated with repeated cocaine administration, and may do so without the need for continued medication.
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Department of Neuroscience, FUHS/The Chicago Medical School, North Chicago, IL 60064-3095, USA. marina.wolf@finchcms.edu
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Wolf
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D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000473:pathology*; D003042:Cocaine / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000187:drug effects; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D012646:Self Administration
D018491:Dopamine Agonists; D018765:Dopamine Uptake Inhibitors; D018691:Excitatory Amino Acid Antagonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D003042:Cocaine