Cocaine self-administration in dopamine-transporter knockout mice (original) (raw)
Related papers
2009
There has been much interest in the relative importance of dopamine and serotonin transporters in the abuse-related-effects of cocaine. We tested the hypotheses that mice lacking the dopamine transporter (DAT Ϫ/Ϫ), the serotonin transporter (SERT Ϫ/Ϫ), or both (DAT Ϫ/Ϫ SERT Ϫ/Ϫ) exhibit decreased reinforcing effects of cocaine. We also assessed whether observed effects on selfadministration are specific to cocaine or if operant behavior maintained by food or a direct dopamine agonist are similarly affected. We used a broad range of experimental conditions that included acquisition without previous training, behavior established with food training and subsequent testing with food, cocaine or a direct dopamine agonist as reinforcers, fixed ratio and progressive ratio schedules of reinforcement, and a reversal procedure. Wild-type mice readily acquired cocaine self-administration and showed dose-response curves characteristic of the schedule of reinforcement that was used. While some DAT Ϫ/Ϫ mice appeared to acquire cocaine selfadministration transiently, almost all DAT Ϫ/Ϫ mice failed to self-administer cocaine reliably. Food-maintained behaviors were not decreased by the DAT mutation, and IV self-administration of a direct dopamine agonist was robust in the DAT Ϫ/Ϫ mice. In contrast to those mice, cocaine's reinforcing effects were not diminished in SERT Ϫ/Ϫ mice under any of the conditions tested, except for impaired initial acquisition of both food-and cocaine-maintained behavior. These findings support the notion that the DAT, but not the SERT, is critical in mediating the reinforcing effects of cocaine.
Lack of Cocaine Self-Administration in Mice Expressing a Cocaine-Insensitive Dopamine Transporter
Journal of Pharmacology and Experimental Therapeutics, 2009
Cocaine addiction is a worldwide public health problem for which there are no established treatments. The dopamine transporter (DAT) is suspected as the primary target mediating cocaine's abuse-related effects based on numerous pharmacological studies. However, in a previous study, DAT knockout mice were reported to self-administer cocaine, generating much debate regarding the importance of the DAT in cocaine's abuse-related effects. Here, we show that mice expressing a "knockin" of a cocaine-insensitive but functional DAT did not self-administer cocaine intravenously despite normal food-maintained responding and normal intravenous self-administration of amphetamine and a direct dopamine agonist. Our results have three implica
Abolished cocaine reward in mice with a cocaine-insensitive dopamine transporter
Proceedings of the National Academy of Sciences, 2006
There are three known high-affinity targets for cocaine: the dopamine transporter (DAT), the serotonin transporter (SERT), and the norepinephrine transporter (NET). Decades of studies support the dopamine (DA) hypothesis that the blockade of DAT and the subsequent increase in extracellular DA primarily mediate cocaine reward and reinforcement. Contrary to expectations, DAT knockout (DAT-KO) mice and SERT or NET knockout mice still selfadminister cocaine and͞or display conditioned place preference (CPP) to cocaine, which led to the reevaluation of the DA hypothesis and the proposal of redundant reward pathways. To study the role of DAT in cocaine reward, we have generated a knockin mouse line carrying a functional DAT that is insensitive to cocaine. In these mice, cocaine suppressed locomotor activity, did not elevate extracellular DA in the nucleus accumbens, and did not produce reward as measured by CPP. This result suggests that blockade of DAT is necessary for cocaine reward in mice with a functional DAT. This mouse model is unique in that it is specifically designed to differentiate the role of DAT from the roles of NET and SERT in cocaine-induced biochemical and behavioral effects.
Journal of Neurochemistry, 2014
Tolerance to the neurochemical and psychoactive effects of cocaine after repeated use is a hallmark of cocaine addiction in humans. However, comprehensive studies on tolerance to the behavioral, psychoactive, and neurochemical effects of cocaine following contingent administration in rodents are lacking. We outlined the consequences of extended access cocaine selfadministration as it related to tolerance to the psychomotor activating, dopamine (DA) elevating, and DA transporter (DAT) inhibiting effects of cocaine. Cocaine self-administration (1.5 mg/kg/inj; 40 inj; 5 days), which resulted in escalation of first hour intake, caused reductions in evoked DA release and reduced maximal rates of uptake through the DAT as measured by slice voltammetry in the nucleus accumbens core. Furthermore, we report reductions in cocaine-induced uptake inhibition and a corresponding increase in the dose of cocaine required for 50% inhibition of DA uptake (K i ) at the DAT. Cocaine tolerance at the DAT translated to reductions in cocaine-induced DA overflow as measured by microdialysis. In addition, cocaineinduced elevations in locomotor activity and stereotypy were reduced, while rearing behavior was enhanced in animals with a history of cocaine self-administration. Here, we demonstrate both neurochemical and behavioral cocaine tolerance in an extended-access rodent model of cocaine abuse, which allows for a better understanding of the neurochemical and psychomotor tolerance that develops to cocaine in human addicts.
Psychopharmacology, 2017
The low self-administration (LS)/Kgras (LS) and high self-administration (HS)/Kgras (HS) rat lines were generated by selective breeding for low- and high-intravenous cocaine self-administration, respectively, from a common outbred Wistar stock (Crl:WI). This trait has remained stable after 13 generations of breeding. The objective of the present study is to compare cocaine preference, neurotransmitter release, and dopamine receptor activation in LS and HS rats. Levels of dopamine, acetylcholine, and cocaine were measured in the nucleus accumbens (NA) shell of HS and LS rats by tandem mass spectrometry of microdialysates. Cocaine-induced locomotor activity and conditioned-place preference were compared between LS and HS rats. HS rats displayed greater conditioned-place preference scores compared to LS and reduced basal extracellular concentrations of dopamine and acetylcholine. However, patterns of neurotransmitter release did not differ between strains. Low-dose cocaine increased lo...
Neuropsychopharmacology, 1996
Investigation of residual behavioral states produced by withdrawal from different routes of cocaine administration indicates that depending on the mode of intake, chronic cocaine produces either tolerance or sensitization to subsequent challenge doses of cocaine. We studied the effect of routes of cocaine administration on the dopamine transporter receptors (DATR), the presumed neuronal mediator of cocaine reward, using the diphenyl substituted piperazine derivative, l3H]GBR 12935 and the cocaine analogue [ 3 HJWIN 35,428. Alzet osmotic mini-pumps filled with either cocaine (100 mg/ml) or saline were surgically implanted on rats into a subcutaneous pocket at the dorsal midline, continuously infusing cocaine at the rate of 40 mg/ kg/day. The pumps were removed 14 days later, and the rats were killed 7 days after the removal of pumps. For the intermittent administration, two groups of rats were injected daily either with 40 mg/kg of cocaine or saline for
Cocaine does not produce reward in absence of dopamine transporter inhibition
NeuroReport, 2009
Previously we reported that knock-in mice with a cocaine-insensitive dopamine transporter (DAT-CI mice) do not experience cocaine reward, as measured by conditioned place-preference (CPP). This conclusion has come under scrutiny because some genetically modified mice show cocaineinduced CPP in a narrow dose range, i.e. responding at doses around 10 mg/kg, but not at 5 and 20 mg/kg, the doses we tested in DAT-CI mice. These results raise the possibility that we have missed the optimal dose for cocaine response. Here we report that cocaine does not produce reward in DAT-CI mice at low, moderate, and high doses, including 10 mg/kg. This study strengthens our conclusion that DAT inhibition is required for cocaine reward in mice with a functional dopaminergic system.
Journal of Pharmacology and Experimental Therapeutics, 2014
Previous literature investigating neurobiological adaptations following cocaine self-administration has shown that high, continuous levels of cocaine intake (long access; LgA) results in reduced potency of cocaine at the dopamine transporter (DAT), whereas an intermittent pattern of cocaine administration (intermittent access; IntA) results in sensitization of cocaine potency at the DAT. Here, we aimed to determine whether these changes are specific to cocaine or translate to other psychostimulants. Psychostimulant potency was assessed by fast-scan cyclic voltammetry in brain slices containing the nucleus accumbens following IntA, short access, and LgA cocaine self-administration, as well as in brain slices from naive animals. We assessed the potency of amphetamine (a releaser), and methylphenidate (a DAT blocker, MPH). MPH was selected because it is functionally similar to cocaine and structurally related to amphetamine. We found that MPH and amphetamine potencies were increased following IntA, whereas neither was changed following LgA or short access cocaine self-administration. Therefore, whereas LgA-induced tolerance at the DAT is specific to cocaine as shown in previous work, the sensitizing effects of IntA apply to cocaine, MPH, and amphetamine. This demonstrates that the pattern with which cocaine is administered is important in determining the neurochemical consequences of not only cocaine effects but potential cross-sensitization/cross-tolerance effects of other psychostimulants as well.
Neuropharmacology, 2014
In previous studies, we generated knock-in mice with a cocaine-insensitive dopamine transporter (DAT-CI mice) and found cocaine does not stimulate locomotion or produce reward in these mice, indicating DAT inhibition is necessary for cocaine stimulation and reward. However, DAT uptake is reduced in DAT-CI mice and thus the lack of cocaine responses could be due to adaptive changes. To test this, we used adeno-associated virus (AAV) to reintroduce the cocaine-sensitive wild type DAT (AAV-DATwt) back into adult DAT-CI mice, which restores cocaine inhibition of DAT in affected brain regions but does not reverse the adaptive changes. In an earlier study we showed that AAV-DATwt injections in regions covering the lateral nucleus accumbens (NAc) and lateral caudate-putamen (CPu) restored cocaine stimulation but not cocaine reward. In the current study, we expanded the AAV-DATwt infected areas to cover the olfactory tubercle (Tu) and the ventral midbrain (vMB) containing the ventral tegmental area (VTA) and substantia nigra (SN) in addition to CPu and NAc with multiple injections. These mice displayed the restoration of both locomotor stimulation and cocaine reward. We further found that AAV-DATwt injection in the vMB alone was sufficient to restore both cocaine stimulation and reward in DAT-CI mice. AAV injected in the VTA and SN resulted in DATwt expression and distribution to the DA terminal regions. In summary, cocaine induced locomotion and reward can be restored in fully developed DAT-CI mice, and cocaine inhibition of DAT expressed in dopaminergic neurons originated from the ventral midbrain mediates cocaine reward and stimulation.
The role of the dopamine transporter in cocaine abuse
Neurotoxicity Research, 2004
There have been many studies aimed at understanding the role that the dopamine transporter plays in cocaine abuse. Most studies suggest that inhibition of dopamine uptake by cocaine is the primary mechanism by which its behavioral effects are produced. Because of the strong relationship between binding to the dopamine transporter and the behavioral effects of cocaine, the dopamine transporter has on occasion been referred to as the cocaine binding site. Chronic studies using cocaine or selective inhibitors of dopamine, norepinephrine, or serotonin uptake suggest that while a selective dopamine uptake inhibitor can produce sensitization to cocaine, the long-lasting sensitized response to a cocaine challenge observed in cocaine-pretreated rats is due to cocaine's action on a system other than, or in addition to, dopamine. Thus, while dopamine appears to be important for the behavioral effects of cocaine, it appears that neurochemical systems other than dopamine likely play a role in the behavioral effects of chronic cocaine.