Cocaine mechanisms: enhanced cocaine, fluoxetine and nisoxetine place preferences following monoamine transporter deletions

doi:10.1016/S0306-4522(02)00379-2

Neuroscience

Volume 115, Issue 1, 15 November 2002, Pages 153-161

https://doi.org/10.1016/S0306-4522(02)00379-2 Get rights and content

Abstract

Cocaine blocks uptake by neuronal plasma membrane transporters for dopamine, serotonin and norepinephrine, producing subjective effects in humans that are both euphoric/rewarding and also fearful, jittery and aversive. Mice with gene knockouts of each of these transporters display cocaine reward, manifest by cocaine place preferences that are at least as great as wildtype values. Norepinephrine and serotonin receptor knockouts even display enhanced cocaine reward. One explanation for these observations could be that cocaine produces aversive or anhedonic effects by serotonin or norepinephrine receptor blockade in wildtype mice that are removed in serotonin or norepinephrine receptor knockouts, increasing net cocaine reward. Adaptations to removing one transporter could also change the rewarding valence of blocking the remaining transporters. To test these ideas, drugs that block serotonin transporter (fluoxetine), norepinephrine transporter (nisoxetine) or all three transporters (cocaine) were examined in single- or multiple-transporter knockout mice. Fluoxetine and nisoxetine acquire rewarding properties in several knockouts that are not observed in wildtype mice. Adding serotonin transporter knockout to norepinephrine transporter knockouts dramatically potentiates cocaine reward.

These and previous data provide evidence that serotonin and norepinephrine transporter blockade can contribute to the net rewarding valence of cocaine. They identify neuroadaptations that may help to explain the retention of cocaine reward by dopamine and serotonin transporter knockout mice. They are consistent with emerging hypotheses that actions at the three primary brain molecular targets for cocaine each provide distinct contributions to cocaine reward and cocaine aversion in wildtype mice, and that this balance changes in mice that develop without dopamine, norepinephrine or serotonin transporters.

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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¹: Present address: Psychopharmacology Laboratory, Tokyo Metropolitan Institute of Psychiatry, Tokyo, Japan.

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Published by Elsevier Ltd.

Cocaine mechanisms: enhanced cocaine, fluoxetine and nisoxetine place preferences following monoamine transporter deletions

Abstract

Section snippets

Subjects

Subjects

Fluoxetine CPP in DAT knockout mice

Discussion

Acknowledgements

Neuroscience

Neuropharmacology

Neuropharmacology

Brain Res.

Pharmacol. Biochem. Behav.

Addict. Behav.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Biol. Psychiatry

Pharmacol. Biochem. Behav.

Trends Neurosci.

Pharmacol. Biochem. Behav.

Brain Res.

Neuropsychopharmacology

Pharmacol. Biochem. Behav.

Neuropsychopharmacology

Pharmacol. Biochem. Behav.

Prog. Neurobiol.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Trends Pharmacol. Sci.

Neuropharmacological mechanisms of drug reward: beyond dopamine in the nucleus accumbens

Crit. Rev. Neurobiol.

Conditioned place preference: what does it add to our preclinical understanding of drug reward?

Psychopharmacology (Berlin)

Comorbidity of psychiatric and substance use disorders in late adolescence: a cluster analytic approach

Am. J. Drug Alcohol Abuse

Altered brain serotonin homeostasis and locomotor insensitivity to 3,4-methylenedioxymethamphetamine (‘Ecstasy’) in serotonin transporter-deficient mice

Mol. Pharmacol.

Release and elimination of dopamine in vivo in mice lacking the dopamine transporter: functional consequences [In Process Citation]

Eur. J. Neurosci.

Serotonin 5-HT(2) receptor stimulation of dopamine release in the posterior but not anterior nucleus accumbens of the rat

J. Neurochem.

Effect of baclofen on cocaine self-administration in rats reinforced under fixed-ratio 1 and progressive-ratio schedules

Psychopharmacology (Berlin)

Cocaine and amphetamine increase extracellular dopamine in the nucleus accumbens of mice lacking the dopamine transporter gene

J. Neurosci.

Pharmacotherapies for treatment of cocaine abuse: preclinical aspects

J. Med. Chem.

Approaches to the treatment of cocaine abuse

Pharm. News

Reinforcing and subjective effects of several anorectics in normal human volunteers

J. Pharmacol. Exp. Ther.

Blockade of cocaine reinforcement in rats with the dopamine receptor blocker pimozide, but not with the noradrenergic blockers phentolamine or phenoxybenzamine

Can. J. Psychol.

Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats

Proc. Natl. Acad. Sci. USA

Preferential modulation of mesolimbic vs. igrostriatal dopaminergic function by serotonin(2C/2B) receptor agonists a combined in vivo electrophysiological and microdialysis study

Synapse

Acute administration of amitriptyline and mianserin increases dopamine release in the rat nucleus accumbens: possible involvement of serotonin2C receptors

Psychopharmacology (Berlin)