Cocaine Receptors on Dopamine Transporters Are Related to Self-Administration of Cocaine

Ritz, Mary C.; Lamb, Richard; Goldberg, Steven R.; Kuhar, Michael J.

doi:10.1126/science.2820058

Cited by 2,112 publications

(1,526 citation statements)

References 53 publications

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“…As has been reported for DAT ligands (Bergman et al, 1989;Ritz et al, 1987), cocaine, WIN 35428, RTI 31, and RTI 51 functioned as positive reinforcers. WIN 35428 has been previously found to function as a positive reinforcer in squirrel monkeys and rats responding under a second-order and a fixed-ratio schedule, respectively (Spealman et al, 1991;Norman et al, 2004, respectively).…”

Section: Discussionsupporting

confidence: 71%

“…Drugs that inhibit the DAT, for instance, functioned as positive reinforcers (Bergman et al, 1989;Tella et al, 1997). Moreover, the potency of cocaine-like drugs in selfadministration was positively correlated with binding affinity at the DAT in vitro (Ritz et al, 1987;Bergman et al, 1989). Simple potency as a reinforcer, however, does not seem to predict abuse potential particularly well.…”

Section: Introductionmentioning

confidence: 99%

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A Reduced Rate of In Vivo Dopamine Transporter Binding is Associated with Lower Relative Reinforcing Efficacy of Stimulants

Wee

2005

Neuropsychopharmacol

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A slow onset of action has been hypothesized to weaken the reinforcing effects of drugs. The present study evaluated this hypothesis with slow-onset cocaine analogs, WIN 35428, RTI 31, and RTI 51. When cocaine or a cocaine analog was made available to rhesus monkeys (n ¼ 4 or 5) for self-administration under a progressive-ratio (PR) schedule with a 1-h time-out between injections, all the drugs functioned as positive reinforcers. The maximum number of injections was in the order of cocaine4WIN 354284RTI 314RTI 51. In in vivo binding in rat striatum, equipotent doses of cocaine, WIN 35428, RTI 31, and RTI 51 were estimated to displace 25% of [ 3 H]WIN 35428 binding at the dopamine transporters (DAT), respectively, 5.8, 22.4, 30.8, and 44.1 min after the intravenous injection. Further, relative reinforcing efficacy was correlated with rate of DAT binding such that slower displacement of [ 3 H]WIN 35428 was associated with a weaker reinforcing effect. In in vitro binding in monkey brain tissue, the cocaine analogs had higher affinity for monoamine transporter sites, but similar affinity ratios of 5-HTT/DAT, compared to cocaine. Lastly, RTI 31 was shown to function as a positive reinforcer in drug-naïve rhesus monkeys under a fixed-ratio 1 schedule. Collectively, the data support the hypothesis that a slow onset at the DAT is associated with reduced reinforcing efficacy of DAT ligands. The data under both the PR and FR schedules, however, suggest that a slow onset at the DAT influence reinforcing effect only to a limited extent.

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Section: Discussionsupporting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

A Reduced Rate of In Vivo Dopamine Transporter Binding is Associated with Lower Relative Reinforcing Efficacy of Stimulants

Wee

2005

Neuropsychopharmacol

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“…The rats persistently and repeatedly chose to stimulate the VTA mesolimbic DA pathway (but not other brain areas), often to the exclusion of other behaviors. Behavioral studies in rodents also indicate that DA is essential for the self-administration of drugs of abuse for which the mesolimbic pathway has been identified as a crucial substrate [114,128]. Drug self-administration is the ‘gold standard’ of animal models of drug abuse [122,129].…”

Section: Reviewmentioning

confidence: 99%

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

Dichter

Damiano

Allen

2012

J Neurodevelop Disord

254

207

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This review summarizes evidence of dysregulated reward circuitry function in a range of neurodevelopmental and psychiatric disorders and genetic syndromes. First, the contribution of identifying a core mechanistic process across disparate disorders to disease classification is discussed, followed by a review of the neurobiology of reward circuitry. We next consider preclinical animal models and clinical evidence of reward-pathway dysfunction in a range of disorders, including psychiatric disorders (i.e., substance-use disorders, affective disorders, eating disorders, and obsessive compulsive disorders), neurodevelopmental disorders (i.e., schizophrenia, attention-deficit/hyperactivity disorder, autism spectrum disorders, Tourette’s syndrome, conduct disorder/oppositional defiant disorder), and genetic syndromes (i.e., Fragile X syndrome, Prader–Willi syndrome, Williams syndrome, Angelman syndrome, and Rett syndrome). We also provide brief overviews of effective psychopharmacologic agents that have an effect on the dopamine system in these disorders. This review concludes with methodological considerations for future research designed to more clearly probe reward-circuitry dysfunction, with the ultimate goal of improved intervention strategies.

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“…The dopamine (DA) system is an obvious starting point in the search for neuroadaptations responsible for the addictive process. Pharmacological, neurochemical, and lesion experiments indicate that cocaine acts as an indirect agonist at DA synapses by blocking the reuptake of DA into the presynaptic terminal in the nucleus accumbens (NAc) and other projection areas of the ventral tegmental area (Heikkila et al, 1975;Ritz et al, 1987, Roberts et al, 1977Koob et al, 1994;Volkow et al, 1997;Bardo, 1998;Di Chiara, 1999). Despite the evidence for the role of DA neurotransmission in the acute reinforcing effects of cocaine, it remains to be determined whether changes in the physiology of this system account for motivational changes associated with cocaine addiction.…”

Section: Introductionmentioning

confidence: 99%

Reduced Dopamine Terminal Function and Insensitivity to Cocaine Following Cocaine Binge Self-Administration and Deprivation

Mateo

Läck

Morgan

et al. 2005

Neuropsychopharmacol

124

139

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Despite large numbers of studies describing neuroadaptations caused by chronic cocaine exposure, there remains considerable uncertainty as to whether alterations in dopamine (DA) neurotransmission are responsible for progression into an addicted state. Highintake, 24-h access cocaine self-administration (SA, 10 days) followed by an extended (7 days), but not 1 day deprivation period produces an increased motivation to SA cocaine as measured by a progressive ratio protocol. Following binge cocaine SA and deprivation, the status of DA terminals in the nucleus accumbens (NAc) was investigated using microdialysis in freely moving rats and voltammetry in brain slices. At 1 and 7 days following binge cocaine SA, baseline extracellular DA concentrations in the NAc core were decreased by 40 and 55% of control levels, in the 1 and 7 day deprivation groups, respectively. Acute cocaine (1.5 mg/kg, i.v.) administration increased extracellular DA (350%) in the NAc core of naïve animals but failed to significantly increase DA at 1 or 7 days following binge cocaine SA. The shell of the NAc showed a similar lack of effect of cocaine. Analysis of DA terminals in brain slices showed that cocaine was markedly less effective in inhibiting DA uptake at 1 and 7 days of cocaine deprivation (max. effect 40% of control). Electrically stimulated DA release was decreased at 1 day and further decreased at 7 days of deprivation (67 and 49% of control, respectively). The rate of DA uptake was increased (150% of control) following binge SA, irrespective of deprivation period. Finally, presynaptic autoreceptors were subsensitive at both time points, as measured by the ability of quinpirole, a D2-like DA receptor agonist, to inhibit DA release. Thus, the NAc was hypodopaminergic and DA terminals were less sensitive to cocaine following binge cocaine SA and deprivation.

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Cocaine Receptors on Dopamine Transporters Are Related to Self-Administration of Cocaine

Cited by 2,112 publications

References 53 publications

A Reduced Rate of In Vivo Dopamine Transporter Binding is Associated with Lower Relative Reinforcing Efficacy of Stimulants

A Reduced Rate of In Vivo Dopamine Transporter Binding is Associated with Lower Relative Reinforcing Efficacy of Stimulants

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

Reduced Dopamine Terminal Function and Insensitivity to Cocaine Following Cocaine Binge Self-Administration and Deprivation

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