作者: Stewart, Adele ; Rabil, Maximilian J ; Gresch, Paul J ; Hahn, Maureen K ; Blakely, Randy D ; Davis, Gwynne L ; Katamish, Rania M ; Gowrishankar, Raajaram ; Peart, Rodeania ; Carroll, F Ivy

Dopamine (DA) signaling dysfunction is believed to contribute to multiple neuropsychiatric disorders including attention-deficit/hyperactivity disorder (ADHD). The rare DA transporter (DAT) coding substitution Ala559Val found in subjects with ADHD, bipolar disorder and autism, promotes anomalous DA efflux in vitro and, in DAT Val559 mice, leads to increased reactivity to imminent handling, waiting impulsivity, and enhanced motivation for reward. Here, we report that, in contrast to amphetamine and methylphenidate, which induce significant locomotor activation, cocaine administration to these mice elicits no locomotor effects, despite retention of conditioned place preference (CPP). Additionally, cocaine fails to elevate extracellular DA. Given that amphetamine and methylphenidate, unlike cocaine, lack high-affinity interactions with the serotonin (5-HT) transporter (SERT), we hypothesized that the lack of cocaine-induced hyperlocomotion in DAT Val559 mice arises from SERT blockade and augmented 5-HT signaling relative to cocaine actions on wildtype animals. Consistent with this idea, the SERT blocker fluoxetine abolished methylphenidate-induced locomotor activity in DAT Val559 mice, mimicking the effects seen with cocaine. Additionally, a cocaine analog (RTI-113) with greater selectivity for DAT over SERT retains locomotor activation in DAT Val559 mice. Furthermore, genetic elimination of high-affinity cocaine interactions at SERT in DAT Val559 mice, or specific inhibition of 5-HT_2C receptors in these animals, restored cocaine-induced locomotion, but did not restore cocaine-induced elevations of extracellular DA. Our findings reveal a significant serotonergic plasticity arising in the DAT Val559 model that involves enhanced 5-HT_2C signaling, acting independently of striatal DA release, capable of suppressing the activity of cocaine-sensitive motor circuits.

2016-06-01·Drug and Alcohol Dependence2区 · 医学

Cocaine withdrawal alters the reward omission effect and enhances traits of negative urgency in rats across multiple days of testing

2区 · 医学

Article

作者: Rebec, G V ; Barker, Alan T

BACKGROUNDThe personality trait of negative urgency, characterized as behaving rashly when emotionally perturbed, is gaining attention as an indicator for susceptibility to problematic substance use. How this trait is influenced by exposure to drugs of abuse is still unclear. Using an animal model of binge cocaine consumption, we tested this relationship in a reward-omission task across multiple days.METHODSAdult, male, Sprague-Dawley rats received seven daily (ip) injections of saline, cocaine (10-20mg/kg), or cocaine (20-40mg/kg). Cocaine doses increased linearly each day from the lower to the higher dose. A separate group received RTI-113 (3.0mg/kg), a selective dopamine transporter inhibitor, for 7 days. Fifteen days after their final injection, rats were trained on a reward-omission task with an operant component to earn further rewards.RESULTSPrevious exposure to cocaine resulted in dose-dependent increases in negative urgency in separate behavioral variables across days of testing. The lower dose range increased negative urgency on the dimension of decreased reaction time to press a lever, while the higher dose range increased the rate of increase in lever presses made per trial. Rats receiving RTI-113 did not resemble either cocaine group and instead showed a decrease in lever pressing across days.CONCLUSIONSOur results indicate that previous binge cocaine consumption enhances behavioral markers of negative urgency in a dose-dependent, time-sensitive manner on discrete behavioral dimensions. The results with RTI-113 suggest the relationship between cocaine exposure and negative urgency is unlikely to be explained solely by inhibition of dopamine reuptake.

2012-08-01·Psychopharmacology3区 · 医学

Interactions between dopamine transporter and cannabinoid receptor ligands in rhesus monkeys

3区 · 医学

Article

作者: F. Ivy Carroll ; David R. Schulze ; Lance Richard McMahon

RATIONALEΔ(9)-tetrahydrocannabinol (Δ(9)-THC) modifies dopamine efflux. However, the extent to which cannabinoid and dopamine drugs modify each other's behavioral effects has not been fully established.OBJECTIVESThis study examined dopamine releasers and/or transport inhibitors alone and in combination with cannabinoids in two drug discrimination assays.METHODSExperimentally and pharmacologically experienced rhesus monkeys (n = 5) discriminated Δ(9)-THC (0.1 mg/kg i.v.) from vehicle while responding under a fixed ratio 5 schedule of stimulus-shock termination. A separate group (n = 6) of monkeys responded under the same schedule, received daily Δ(9)-THC (1 mg/kg/12 h s.c.), and discriminated the cannabinoid antagonist rimonabant (1 mg/kg i.v.), i.e., cannabinoid withdrawal, from vehicle. A sign of withdrawal sign (head shaking) was examined in monkeys receiving Δ(9)-THC daily.RESULTSRimonabant antagonized the Δ(9)-THC discriminative stimulus and a dose of Δ(9)-THC greater than the daily treatment attenuated the rimonabant discriminative stimulus. In monkeys discriminating Δ(9)-THC, the dopamine transporter ligands cocaine, amphetamine, bupropion, RTI 113, and RTI 177 produced a maximum of 2% responding on the drug lever and blocked the discriminative stimulus effects of Δ(9)-THC. In Δ(9)-THC treated monkeys discriminating rimonabant, the dopamine transporter ligands partially substituted for and increased the potency of rimonabant to produce discriminative stimulus effects. The dopamine antagonist haloperidol enhanced the Δ(9)-THC discriminative stimulus without significantly modifying the rimonabant discriminative stimulus. Imipramine and desipramine, which have low affinity for dopamine transporters, were less effective in modifying either the Δ(9)-THC or rimonabant discriminations. The dopamine transporter ligands and haloperidol attenuated head shaking, whereas imipramine and desipramine did not.CONCLUSIONSDopamine release and/or inhibition of dopamine transport blocks detection of Δ(9)-THC and is potentially the mechanism by which some therapeutics (e.g., bupropion) reduce the subjective effects of marijuana and enhance the subjective effects of marijuana withdrawal.

100 项与 RTI-113 相关的药物交易

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