Cocaine hydrolase encoded in viral vector blocks the reinstatement of cocaine seeking in rats for 6 months.
BACKGROUND
Cocaine dependence is a pervasive disorder with high rates of relapse. In a previous study, direct administration of a quadruple mutant albumin-fused butyrylcholinesterase that efficiently catalyzes hydrolysis of cocaine to benzoic acid and ecgonine methyl ester acutely blocked cocaine seeking in an animal model of relapse. In the present experiments, these results were extended to achieve a long-duration blockade of cocaine seeking with a gene transfer paradigm using a related butyrylcholinesterase-based cocaine hydrolase (CocH).


METHODS
Male and female rats were allowed to self-administer cocaine under a fixed-ratio 1 schedule of reinforcement for approximately 14 days. Following the final self-administration session, rats were injected with CocH vector or a control injection (empty vector or saline), and their cocaine solutions were replaced with saline for 14 days to allow for extinction of lever pressing. Subsequently, they were tested for drug-primed reinstatement by administering intraperitoneal injections of saline (S), cocaine (C) (5, 10, and 15 mg/kg), and d-amphetamine according to the following sequence: S, C, S, C, S, C, S, d-amphetamine. Rats then received cocaine-priming injections once weekly for 4 weeks and, subsequently, once monthly for up to 6 months.


RESULTS
Administration of CocH vector produced substantial and sustained CocH activity in plasma that corresponded with diminished cocaine-induced (but not amphetamine-induced) reinstatement responding for up to 6 months following treatment (compared with high-responding control animals).


CONCLUSIONS
These results demonstrate that viral transfer of CocH may be useful in promoting long-term resistance to relapse to cocaine addiction.
Department of Psychiatry, University of Minnesota, Minneapolis, MN 55455, USA. anke0022@umn.edu
Justin J
JJ
Anker
Stephen
S
Brimijoin
Yang
Y
Gao
Liyi
L
Geng
Natalie E
NE
Zlebnik
Robin J
RJ
Parks
Marilyn E
ME
Carroll
D000818:Animals; D002091:Butyrylcholinesterase / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage; D003042:Cocaine / Q000378:metabolism*; D019970:Cocaine-Related Disorders / Q000628:therapy*; D003913:Dextroamphetamine / Q000008:administration & dosage; D058999:Drug-Seeking Behavior; D005108:Extinction, Psychological; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use*; D008297:Male; D051381:Rats; D012054:Reinforcement, Psychology; D055502:Secondary Prevention; D019076:Transgenes
D000697:Central Nervous System Stimulants; D002091:Butyrylcholinesterase; D003042:Cocaine; D003913:Dextroamphetamine