Cocaine, Reward, Movement and Monoamine Transporters GR Uhl1, FS Hall1 and I Sora1,2

Molecular Psychiatry (2002) 7, 21–26  2002 Nature Publishing Group All rights reserved 1359-4184/02 $15.00 www.nature.com/mp REVIEW ARTICLE Cocaine, reward, movement and monoamine transporters GR Uhl1, FS Hall1 and I Sora1,2

1Molecular Neurobiology Branch, NIDA-IRP, NIH, Baltimore, MD 21224, USA

Recent evidence enriches our understanding of the molecular sites of action of cocaine reward and locomotor stimulation. Dopamine transporter blockade by cocaine appears a suf- ﬁcient explanation for cocaine-induced locomotion. Variation in DAT appears to cause differences in locomotion without drug stimulation. However, previously-held views that DAT blockade was the sole site for cocaine reward have been replaced by a richer picture of multitransporter involvement with the rewarding and aversive actions of cocaine. These new insights, derived from studies of knockout mice with simultaneous deletions and/or blockade of multiple transporters, provide a novel model for the rewarding action of this heavily-abused substance and implicate multiple monoamine systems in cocaine’s hedonic activities. Molecular Psychiatry (2002) 7, 21–26. DOI: 10.1038/sj/mp/4000964 Keywords: reward; cocaine; aversion; knockout mouse; reinforcement; polygenic

Cocaine is a prototypical psychomotor stimulant that reward mechanisms. These studies in turn built on increases locomotor activity and elevates mood with prior pharmacologic blockade studies18–22 that revealed rewarding euphoria.1 It also produces fearful and jit- altered psychostimulant self-administration with dopa- tery aversive effects in many who take it.2,3 Cocaine mine depletions or with dopamine receptor blocking blocks monoamine uptake by neuronal plasma mem- drugs. brane transporters for dopamine (DAT), serotonin This ‘DAT-is-it’ hypothesis was a major motivation (SERT) and norepinephrine (NET), and can also block for work that resulted in cloning DAT cDNAs, genes ligand- and voltage-gated channels with somewhat and gene variants in our laboratory and others.23–30 It lower potencies.4 Understanding the relationships drove characterization and study of DAT gene variants between cocaine’s molecular actions and its psycho- in humans29,31–53 and animal models.54,55 It led to the motor stimulant and aversive properties has remained production and characterization of DAT-over- and surprisingly incomplete. This review focuses on recent under-expressing and DAT-knockout mice strains.56–59 advances in our understanding of the complex These studies revealed an exquisite DAT-dependence relationships between cocaine’s molecular actions and of cocaine’s locomotor stimulation. By contrast, they its locomotor stimulant, rewarding and aversive also produced surprising results that refuted the strong properties. ‘DAT-is-it’ hypothesis of cocaine reward. The ‘DAT-is-it’ hypothesis drove thinking about cocaine reward for at least a decade, ideas widely Cocaine-induced locomotion: DAT is it linked to Kuhar, Spealman and their colleagues4–8 who DAT variation in humans and mice links robustly with gathered evidence from structure-activity relationships variation in both baseline locomotion and/or psycho- of transporter-blocking compounds with differential stimulant-induced locomotor activities. Three strains potencies at DAT, SERT and NET. They examined of DAT knockout or knockdown mice produced in sep- relationships between potencies of these compounds arate laboratories each have substantially elevated in tests of reward and binding affinities at each of the locomotor activities in novel environments.56,58,59 Sup- monoamine transporters. They each identified the best ranormal levels of locomotor activity remain elevated correlations for the rewarding effects of cocaine with even after several hours of habituation. When cocaine DAT blockade. These authors also cited prior work is administered, wild-type animals display substantial from lesion studies9–12 and electrical brain stimulation increases in their locomotion that are several times studies13–17 that implicated dopamine pathways in greater than their habituated baseline activity levels. However, DAT knockout mice display no further cocaine-induced increase in activity.56,58,60 Neither Correspondence: GR Uhl, MD, PhD, Molecular Neurobiology, Box SERT nor NET gene knockouts provide any comparable 5180, Baltimore, MD 21224, USA. E-mail: guhlȰintra.nida.nih. reduction in cocaine-induced locomotion.60,61 Knock- gov 2Current address: Psychopharmacology Laboratory, Tokyo Metro- out mice have a lifetime to adapt to loss of a single politan Institute of Psychiatry, Tokyo, Japan gene product, providing cautions in interpretation (see Received 20 June 2001; accepted 27 June 2001 below). Nevertheless, results from these mice clearly Cocaine, reward, movement and monoamine transporters GR Uhl et al 22 indicate that DAT is a necessary and principal site for mouse brain systems that normally expressed the cocaine-induced locomotor stimulation. absent transporters, maintaining cocaine reward. Genetic variation at the mouse and human DAT loci We tested whether DAT- and SERT-expressing sys- also contributes to interesting locomotor phenotypes. tems could each provide such redundancy in the long- Mouse quantitative trait locus (QTL) studies localize a term absence of the other transporter. We constructed portion of the B×D recombinant inbred strain differ- double knockout mice with deletions of both the DAT ence in baseline and psychomotor stimulant-induced and SERT genes, examined their baseline behavioral locomotion near the DAT locus, while additional vari- and biochemical features, and tested their preference ance maps to a second locus that appears to regulate for cocaine.60 Deletions of all of the DAT combined DAT expression.62 Human DAT gene markers have with removal of either half or all of the SERT com- reproducibly linked with attention deficit hyperactiv- pletely eliminated cocaine reward assessed in the CPP ity disorder (ADHD).29,63–68 DAT polymorphisms can paradigm. These results defined, for the first time, a be linked more strongly to the hyperactivity than to the minimal set of gene deletions necessary for elimination attention deficits in this disorder.65 Variation in DAT of cocaine reward. More recent evidence underscores activity is thus a significant contributor to ‘baseline’ the specificity of these observations. Double knockouts locomotor activity levels, while DAT is absolutely of both SERT and NET fail to reduce cocaine reward.70 necessary for cocaine-induced locomotor stimulation. In fact, SERT/NET double knockouts dramatically enhance cocaine place preference. While we have thus identified a specific group of Cocaine, reward and aversion: rich patterns of multi- sites whose elimination can totally block measures of transporter involvement cocaine reward, we have also identified potential sites This simple story for DAT and cocaine locomotion for some of the aversive effects reported by cocaine contrasts strikingly with results for rewarding proper- users. Data from reduced or enhanced cocaine reward ties of cocaine. We have tested DAT knockout mice in in the absence of specific transporters or transporter the conditioned place preference (CPP) paradigm58 that combinations can be tentatively assembled with prior measures preference for an environment paired with a data from other transporter blocking drugs as follows drug. Homozygous DAT knockout mice express per- (see also Figure 1): fectly intact cocaine conditioned place preference. DAT appears to be the transporter most associated Another DAT knockout strain was also rewarded by with rewarding properties of cocaine in conditioned cocaine in an operant self-administration paradigm.69 place preference tests. Compounds with substantial Two strains of DAT knockouts thus provided convinc- ing evidence that DAT was not necessary for cocaine reward, results fatal to any strong version of the ‘DAT- is-it’ hypothesis for cocaine reward. Studies of reward in mice with deletions of the other monoamine transporters at which cocaine acts did not provide any clear alternative single transporter site for cocaine’s rewarding actions. Cocaine was no less rewarding in SERT knockouts tested in the CPP para- digm58 or in NET knockout mice.61 The failure of any single monoamine transporter gene knockout strain to eliminate cocaine reinforcement and reward thus left open several possible roles for these transporters in cocaine reward/reinforcement in wild-type mice. These even included the possibility that non-transporter molecular sites of cocaine could be involved in cocaine reward/reinforcement. We chose to pursue a different hypothesis: that cocaine normally works as a ‘dirty drug’, producing rewarding effects through simultaneous actions at Figure 1 Model for the relative contributions of blockade of more than one transporter site. Multiple molecular the transporters for dopamine (DAT), serotonin (SERT) and sites for cocaine’s rewarding/reinforcing actions could norepinephrine (NET) on cocaine reward and aversive fea- provide redundancies so that no one site alone would tures in wild-type animals. DAT: Dopamine transporter block- be absolutely required for cocaine reward. Such redun- ade is drawn as exerting largely rewarding properties. SERT: dancies could even be enhanced by compensatory Serotonin transporter blockade is drawn as exerting a combi- nation of rewarding and aversive properties. Uneven distri- mechanisms active in mice that develop without one butions of these influences (lumps in the figure) are meant or more transporters. If cocaine normally altered activi- to suggest different properties of action at different serotonin ties in several parallel or interactive brain systems with receptor subtypes. NET: Norepinephrine transporter blockade substantial redundancies, the systems expressing the is drawn as exerting largely aversive properties. These contri- remaining transporter(s) might thus compensate for butions change significantly in knockout mice, as noted in loss of cocaine-modulated activities in knockout the text.

Molecular Psychiatry Cocaine, reward, movement and monoamine transporters GR Uhl et al 23 selectivity for DAT can produce place preferences and aversive features in some animal models.78–80 They fit are self-administered by animals, although often less with the failure of mazindol, a widely used combined avidly than cocaine (for review see Rothman and DAT/NET blocker, to exhibit any striking human clini- Glowa).71 However, as noted above, DAT is not ‘it’, cal abuse liability and with its not-infrequent discon- since DAT deletion alone does not eliminate cocaine tinuation due to jitteriness and sleep disturbances.81–83 reward.58 Data from DAT knockouts are also tempered by Caveats: brain changes in knockout mice and cocaine results examining the role of SERT and NET in the reward maintenance of cocaine reward in these mice. The The precise neuroadaptive changes that may contribute selective SERT blocker fluoxetine and the selective to the differences in the rewarding consequences of NET blocker nisoxetine both produce strong place pref- monoamine transporter blockade in single and mul- erences in DAT knockouts but not in wild-type mice tiple transporter knockout mice are unknown. The or in heterozygote mice with one knockout DAT allele, brains of mice of each of these knockout strains appear one wild-type DAT allele and half wild-type levels of grossly normal, although the smaller brains of DAT KO DAT expression.70 These data clearly indicate that mice are consistent with the smaller overall size of blockade of SERT or NET can acquire rewarding these mice.84 Each single transporter knockout exhibits properties in DAT’s lifelong absence. How much DAT a distinctive pattern of brain neurochemical rearrange- removal and how long this removal needs to be carried ments,58,60,61,85,86 many of which can be tentatively out to achieve these striking effects remain interesting linked to homeostatic mechanisms triggered by current questions. The adaptive mechanisms that make increased tonic levels of extracellular neurotransmit- fluoxetine and nisoxetine rewarding in DAT knockouts ters. Thus, the DAT knockouts that display enhanced could well contribute to the reward that cocaine con- extracellular dopamine levels56,87 and reduced DA fers in DAT knockout mice, since cocaine retains its clearance56,87,88 also display altered levels of ability to block both SERT and NET in these animals. expression of dopamine D1, D2 and D3 receptors levels Recent reports that the NET blocker roboxetine tyrosine hydroxylase, dopamine-modulated neuropep- enhances nucleus accumbens dopamine in DAT tides, and other features.89,90 Microarray studies of knockout but not in wild-type mice72 could contribute mRNA from the brains of DAT and of SERT knockouts one biochemical substrate for the nisoxetine reward also identify dozens of genes whose expression is con- found in DAT knockouts. Such mechanisms may not sistently altered more than two-fold.91 None of these be relevant for fluoxetine reward, however, since a characterizations provide evidence for large supra- selective SERT blocker did not increase nucleus additive knockout influences on any brain neurochem- accumbens dopamine levels in the same study. ical, microdialysis or gene expression profile when SERT blockade could well contribute to both mice with multiple knockouts have been examined to rewarding and aversive properties of cocaine. Such date, however. No current known neurochemical alter- explanations seem among the most plausible current ation follows the pattern of retained or absent cocaine explanations for otherwise apparently contradictory reward across these multiple knockout strains. data that demonstrate: (1) enhanced cocaine reward in In DAT knockouts, cocaine could also acquire novel SERT knockout mice;58 (2) enhanced fluoxetine reward properties by modulating dopamine acting as a ‘false in DAT and in NET knockout mice;70 and (3) ablated transmitter’ in cells in which it is not synthesized. cocaine reward in DAT/SERT combined knockout Since NET has good affinities for dopamine and SERT mice.60 can even accumulate dopamine with lower affinity, SERT blockade might normally produce a combi- some of the dopamine that is synthesized in dopami- nation of rewarding and aversive features by aug- nergic neurons of DAT knockout mice could become a menting serotonin actions at different serotonin recep- ‘false transmitter’ at adjacent norepinephrine or sero- tor subtypes expressed differentially in distinct tonin terminals. In a similar fashion norepinephrine serotonergic circuits. If these rewarding and aversive could be a false transmitter at adjacent dopaminergic features normally balanced each other to produce little or serotonergic terminals in NET knockouts, and/or net reward or aversion with SERT blockade, fluoxetine serotonin a false transmitter in SERT knockout dopa- or other selective serotonin reuptake inhibitors would mine or norepinephrine terminals.92,93 While some display minimal aversion and also little abuse liability false transmission thus seems likely in these knock- in humans, as has been observed.73–75 The fluoxetine outs, it seems an unlikely explanation for all of the cur- reward acquired by DAT and by NET knockout mice rent data derived from these mice. NET and SERT is consistent with the idea that each of these knockouts blockade by cocaine fails to provide the robust shifts the balance between rewarding and aversive ser- enhancements of striatal dopamine efflux in DAT otonergic components, although not necessarily in knockouts that would be expected if false transmission identical ways. were widespread in these mice.85 Although cocaine NET blockade may well contribute less to rewarding and the NET blocker reboxetine do enhance dopamine and more to aversive properties of cocaine in wildtype efflux in the nucleus accumbens of DAT knockouts, animals. These observations are consistent with fre- rewarding SERT blockade by fluoxetine fails to quent human clinical self-reports of ‘jitteriness’ with enhance this dopamine efflux.72 Further studies will be cocaine use.76,77 They accord with evidence for cocaine necessary to define how much of the cocaine, fluoxet-

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Molecular Psychiatry