Further studies of the reinforcing effects of benztropine analogs in rhesus monkeys

Woolverton, William L.; Hecht, Gerald S.; Agoston, Gregory E.; Katz, Jonathan L.; Newman, Amy Hauck

doi:10.1007/s002130000616

Cited by 57 publications

(58 citation statements)

References 17 publications

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“…Together, these studies demonstrate that JHW007 passes the blood-brain barrier and readily penetrates the brain, slowly achieving significant levels of in vivo DAT occupancy. Interestingly, JHW007 failed to produce appreciable cocaine-like locomotor stimulant effects, despite significant in vivo occupancy, consistent with previous studies indicating decreased efficacy of BZT analogs compared with cocaine (Katz et al, 1999Woolverton et al, 2001).…”

Section: Discussionsupporting

confidence: 87%

“…Analogs of benztropine (BZT), for instance, have high affinity for the DAT and inhibit DA uptake in vitro. However, these drugs compared with cocaine have reduced effectiveness as behavioral stimulants and generally do not share subjective and reinforcing effects of cocaine in drug-discrimination and self-administration animal models (Newman et al, 1995;Katz et al, 1999;Woolverton et al, 2001). These findings suggest that some structural variants of drugs acting at the DAT may have reduced abuse liability compared with cocaine and a potential approach to the discovery of medications for cocaine abuse.…”

Section: Introductionmentioning

confidence: 99%

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Identification of a Dopamine Transporter Ligand That Blocks the Stimulant Effects of Cocaine

Desai¹,

Kopajtic²,

Koffarnus³

et al. 2005

J. Neurosci.

106

120

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There is a large unmet medical need for cocaine addiction treatments. Studies have indicated that the dopamine transporter (DAT) is the primary biological target of cocaine, and most drugs that have DAT affinity have behavioral effects like those of cocaine. However, analogs of benztropine have high DAT affinity and behavioral effects that show varying degrees of similarity to cocaine. We now report the discovery that a benztropine analog, JHW007, with high affinity for the DAT does not have cocaine-like behavioral effects and antagonizes the effects of cocaine. JHW007 occupied the DAT in vivo more slowly than did cocaine and had not reached an apparent plateau up to 270 min after injection. The in vivo binding of cocaine to the DAT suggested rate of DAT occupancy as an important contributor to its behavioral effects, and the slow association with the DAT may provide an explanation for JHW007 being relatively devoid of cocaine-like behavioral effects. The antagonism of cocaine suggests that DAT ligands with reduced cocaine-like activity can function as cocaine antagonists and suggests JHW007 as a lead for discovery of cocaine-abuse pharmacotherapeutics.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Identification of a Dopamine Transporter Ligand That Blocks the Stimulant Effects of Cocaine

Desai¹,

Kopajtic²,

Koffarnus³

et al. 2005

J. Neurosci.

106

120

View full text Add to dashboard Cite

show abstract

“…drug availability (Balster and Schuster, 1973;Griffiths et al, 1978;Risner and Jones 1976;Bergman et al, 1989). In this regard, double alternation schedules like the one used in the present study previously have been used only in single-lever self-administration studies (Woolverton et al, 2001(Woolverton et al, , 2002. It is noteworthy that functions describing the relation between response allocation and unit dose of drug obtained on the first and second days of the double alternation schedule were comparable and, also, were similar to previously reported effects of these drugs under different choice procedures (Iglauer and Woods, 1974;Paronis et al, 2002;Negus, 2003).…”

Section: Discussionsupporting

confidence: 84%

Evaluation of the Reinforcing Effects of Monoamine Reuptake Inhibitors Under a Concurrent Schedule of Food and I.V. Drug Delivery in Rhesus Monkeys

Gąsior

Bergman

Kallman

et al. 2004

Neuropsychopharmacol

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Most medications prescribed for attention-deficit-hyperactivity disorder are psychomotor stimulants with reinforcing effects in laboratory animals (eg methylphenidate). The present studies were conducted to evaluate the reinforcing effects of the recently approved medication atomoxetine in monkeys trained to 'choose' between automated deliveries of either an i.v. injection or food. Rhesus monkeys were trained to lever-press under concurrent schedules of reinforcement; responses on one lever resulted in an injection of either saline or drug, and responses on the alternative lever resulted in food delivery. Data were collected on four measures: response rates, percentage of total responses occurring on the injection-lever (% ILR), number of injections earned, and number of food pellets earned. Dose-effect functions were determined for cocaine (0.003-0.3 mg/kg/inj), methylphenidate (0.003-0.1 mg/kg/inj), amphetamine (0.003-0.1 mg/kg/inj), atomoxetine (0.01-0.3 mg/kg/inj), and desipramine (0.03-1.0 mg/kg/inj) using a double alternation schedule of saline and drug availability. Results indicate that the distribution of behavior changed according to the drug and dose available for self-injection. Saline availability was typically associated with high rates of food-maintained responding. The % ILR increased from 371% when saline was available to 490% when 40.03 mg/kg/inj of cocaine, methylphenidate or d-amphetamine was available. However, no dose of atomoxetine or desipramine maintained self-administration behavior on the injection-lever. The number of food pellets earned per session decreased as the dose of each drug increased, indicative of behavioral activity with all five drugs. The reinforcing effects of cocaine, methylphenidate, and d-amphetamine in these studies are consistent with previous findings in nonhuman primates and with their documented abuse liability. The absence of reinforcing effects of atomoxetine support the view that, like desipramine, it has no evident abuse potential.

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“…Cocaine, for example, has a relatively weak affinity at the DAT, and low potency as a reinforcer, but is one of the most efficacious reinforcers in laboratory animals and is highly abused by humans. This dissociation between potency and efficacy as a reinforcer can also be found in other DAT inhibitors (Roberts et al, 1999;Woolverton et al, 2001). Thus, pharmacological factors other than or in addition to DAT inhibition appear to determine reinforcing efficacy.…”

Section: Introductionmentioning

confidence: 73%

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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Further studies of the reinforcing effects of benztropine analogs in rhesus monkeys

Abstract: This study confirms and extends previous results suggesting that compounds with high DAT affinity can have strong, moderate, weak, or no effectiveness as reinforcers. The mechanisms that may underlie this variation in reinforcing effectiveness of these DAT ligands remain to be established.

Cited by 57 publications

References 17 publications

Identification of a Dopamine Transporter Ligand That Blocks the Stimulant Effects of Cocaine

Identification of a Dopamine Transporter Ligand That Blocks the Stimulant Effects of Cocaine

Evaluation of the Reinforcing Effects of Monoamine Reuptake Inhibitors Under a Concurrent Schedule of Food and I.V. Drug Delivery in Rhesus Monkeys

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

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