Cocaine mechanisms: enhanced cocaine, fluoxetine and nisoxetine place preferences following monoamine transporter deletions
Section snippets
Subjects
DAT (Sora et al., 1998), SERT (Bengel et al., 1998), NET (Xu et al., 2000) and NET/SERT knockout mice were bred by heterozygote crosses as previously described. The background strain of the three knockout strains was a chimera of C57BL/6J with 129/Sv or 129Svj, which was the result of the original knockout derivation. Mice were genotyped using polymerase chain reaction (PCR) amplifications using oligonucleotide primers targeted at neomycin genomic sequences found in the knockout constructions,
Subjects
No gross abnormalities or behavioral phenotypes were found in these individual or combined knockouts beyond those already reported for the single knockouts. SERT/NET combined knockout mice were produced at nearly expected ratios from double-heterozygote crosses and were normal in their fertility, baseline locomotor responses, habituation, screen hang time and rotarod performance (data not shown).
Fluoxetine CPP in DAT knockout mice
Fluoxetine failed to produce significant place preferences in either wildtype or heterozygote DAT KO
Discussion
The simplest hypotheses that explain current and previous data are that lifelong deletion of DAT, SERT, NET or combined transporter deletions each provide a distinctive pattern of alteration in the reward resulting from blockade of SERT or NET or of all three transporters. The current results are consistent with the idea that cocaine may normally work as a dirty drug that provides both rewarding and aversive properties by distinct actions at these three transporters. The combined observations
Acknowledgements
We acknowledge that financial support of the NIDA-IRP; the substantial contributions to this work from the Charles River animal care staff, Triad division, as well as comments by Drs. Elliot Gardner and Roy Wise.
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Present address: Psychopharmacology Laboratory, Tokyo Metropolitan Institute of Psychiatry, Tokyo, Japan.