Application of Drug Discrimination With Drugs of Abuse To Develop New Therapeutic Agents

Meert, T. F.

doi:10.1037/e496182006-019

Cited by 7 publications

(6 citation statements)

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“…Although the discriminative-stimulus effects of d-amphetamine after pretreatment with various atypical antipsychotics have been widely studied in laboratory animals (Kilbey and Ellinwood, 1979;Nielsen and Jepsen, 1985;Meert, 1991Meert, , 1996Arnt, 1992Arnt, , 1996Mechanic et al, 2002), we are unaware of any published studies in which a similar strategy was used with humans. The results of the present human laboratory experiment are concordant with those from previous studies in which the discriminative-stimulus effects of d-amphetamine were assessed alone and after risperidone pretreatment in amphetamine-trained rats (Meert, 1991(Meert, , 1996. In these experiments, rats were trained to discriminate 1.25 mg/kg damphetamine.…”

Section: Discussionmentioning

confidence: 99%

“…The results of these studies might guide the development of a pharmacotherapy for the treatment of amphetamine abuse/ dependence. The results of preclinical behavioral pharmacology experiments suggest that atypical antipsychotics such as risperidone, olanzapine, and clozapine consistently attenuate the discriminative-stimulus effects of amphetamine (Kilbey and Ellinwood, 1979;Nielsen and Jepsen, 1985;Meert, 1991Meert, , 1996Arnt, 1992Arnt, , 1996Mechanic et al, 2002). The discriminative-stimulus effects of drugs in animals are thought to be a model of the self-reported effects of drugs in humans.…”

Section: Introductionmentioning

confidence: 99%

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Risperidone Attenuates the Discriminative-Stimulus Effects of d-Amphetamine in Humans

Rush

Stoops²,

Hays³

et al. 2003

J Pharmacol Exp Ther

120

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Studies conducted with nonhuman laboratory animals have consistently shown that atypical antipsychotics that are mixed dopamine and serotonin antagonists attenuate the discriminative-stimulus effects of amphetamine. In the present experiment, eight healthy humans learned to discriminate 15 mg of oral d-amphetamine. After acquiring the discrimination (i.e., Ն80% correct responding on four consecutive days), the effects of a range of doses of d-amphetamine (0, 2.5, 5, 10, and 15 mg), alone and after pretreatment with risperidone (0 and 1 mg), a D 2 dopamine and 5-hydroxytryptamine (5-HT) 2 serotonin antagonist, were assessed. d-Amphetamine alone functioned as a discriminative stimulus and produced stimulant-like selfreported drug effects (e.g., increased ratings of "like drug"). These effects were generally a function of dose. Risperidone alone did not occasion d-amphetamine-appropriate responding, but impaired performance. Risperidone pretreatment significantly attenuated the discriminative-stimulus effects of damphetamine, and some of the self-reported drug effects. The results of the present experiment suggest that combining drugdiscrimination and self-reported drug-effect questionnaires may be an effective strategy for assessing the behavioral effects of agonist-antagonist interactions. Future studies should compare the behavioral effects of d-amphetamine after pretreatment with a selective D 2 dopamine (e.g., haloperidol) or 5-HT 2 serotonin (e.g., ritanserin) antagonist to determine the relative contribution of dopamine and serotonin systems in mediating the behavioral effects of stimulants in humans. The results of these studies might guide the development of a pharmacotherapy for the treatment of amphetamine abuse/ dependence. The results of preclinical behavioral pharmacology experiments suggest that atypical antipsychotics such as risperidone, olanzapine, and clozapine consistently attenuate the discriminative-stimulus effects of amphetamine (Kilbey and Ellinwood, 1979;Nielsen and Jepsen, 1985;Meert, 1991Meert, , 1996Arnt, 1992Arnt, , 1996Mechanic et al., 2002). The discriminative-stimulus effects of drugs in animals are thought to be a model of the self-reported effects of drugs in humans. In one experiment, the discriminative-stimulus effects of d-amphetamine (1.0 mg/kg) were tested alone and after pretreatment with risperidone (0.04 -2.5 mg/kg), olanzapine (0.0025-2.5 mg/kg), and clozapine (0.08 -2.5 mg/kg) in rats trained to discriminate 1.0 mg/kg d-amphetamine (Arnt, 1996). Risperidone, olanzapine, and clozapine dose dependently decreased

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Risperidone Attenuates the Discriminative-Stimulus Effects of d-Amphetamine in Humans

Rush

Stoops²,

Hays³

et al. 2003

J Pharmacol Exp Ther

120

View full text Add to dashboard Cite

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“…Typically, researchers determine an entire dose-effect curve for each drug examined, including the training drug (e.g., see results in Figure 6). Drug discrimination is a unique method for predicting abuse liability of candidate medications that focuses on subjective effects of the drug and provides insight into the mechanism of action (Meert, 1991). …”

Section: Behavioral and Dependence Pharmacologymentioning

confidence: 99%

Prediction and Prevention of Prescription Drug Abuse: Role of Preclinical Assessment of Substance Abuse Liability

Marusich

Lefever²,

Novak³

et al. 2013

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In 2011, the prevalence of prescription drug abuse exceeded that of any other illicit drug except marijuana. Consequently, efforts to curtail abuse of new medications should begin during the drug development process, where abuse liability can be identified and addressed before a candidate medication has widespread use. The first step in this process is scheduling with the Drug Enforcement Agency so that legal access is appropriately restricted, dependent upon levels of abuse risk and medical benefit. To facilitate scheduling, the Food and Drug Administration (FDA) has published guidance for industry that describes assessment of abuse liability. The purpose of this paper is to review methods that may be used to satisfy the FDA’s regulatory requirements for animal behavioral and dependence pharmacology. Methods include psychomotor activity, self-administration (an animal model of the rewarding effects of a drug), drug discrimination (an animal model of the subjective effects of a drug), and evaluation of tolerance and dependence. Data from tests conducted at RTI with known drugs of abuse illustrate typical results, and demonstrate that RTI is capable of performing these tests. While using preclinical data to predict abuse liability is an imperfect process, it has substantial predictive validity. The ultimate goal is to increase consumer safety through appropriate scheduling of new medications.

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“…Drug discrimination procedures have become an increasingly important behavioral assay in the preclinical development and testing of drugs [e.g., Meert, 1991;Arnt and Skarsfeldt, 1998], and drug discrimination can be used both to classify drugs and to identify underlying pharmacological mechanisms that are important for the discriminative stimulus properties of the drugs being studied [e.g., Overton, 1984;Winter and Rabin, 1989;Kelley and Porter, 1997;]. Early studies with antipsychotic drugs typically reported that it was difficult to establish these drugs as discriminative stimuli [e.g., Overton, 1966 (chlorpromazine, T maze); Harris and Balster, 1971 (chlorpromazine, two-lever operant); Colpaert et al, 1976 (haloperidol, two-lever operant)]; however, other studies have reported more success.…”

Section: Introductionmentioning

confidence: 99%

Chlorpromazine as a discriminative stimulus in rats: Generalization to typical and atypical antipsychotics

et al. 1999

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The discriminative stimulus properties of the typical antipsychotic chlorpromazine were examined in a two‐lever drug discrimination procedure for food reward. Six of nine rats readily acquired the discrimination between 1.0 mg/kg chlorpromazine (i.p.) and vehicle in a mean of 29.7 training sessions. The chlorpromazine generalization curve was dose‐dependent and yielded an ED50 of 0.305 mg/kg (95% confidence interval (CI) = 0.201–0.463 mg/kg). The chlorpromazine cue generalized to the atypical antipsychotics clozapine (ED50 for the clozapine curve was 0.258 mg/kg [95% CI = 0.047–1.420 mg/kg]) and olanzapine (ED50 for the olanzapine curve was 0.199 mg/kg [95% CI = 0.076–0.522 mg/kg]) and to the typical antipsychotic thioridazine (ED50 for the thioridazine curve was 3.103 mg/kg [95% CI = 1.993–4.832 mg/kg]). Haloperidol (a typical antipsychotic) and raclopride (an atypical antipsychotic) did not substitute for chlorpromazine. It is clear from the present results that the discriminative stimulus properties of chlorpromazine share similarities both with the atypical antipsychotics clozapine and olanzapine and with the typical antipsychotic thioridazine. The extent to which the discriminative stimulus properties of antipsychotic drugs reflect or are predictive of their therapeutic effects in schizophrenic patients remains unclear. Drug Dev. Res. 48:38–44, 1999. © 1999 Wiley‐Liss, Inc.

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Application of Drug Discrimination With Drugs of Abuse To Develop New Therapeutic Agents

Cited by 7 publications

References 0 publications

Risperidone Attenuates the Discriminative-Stimulus Effects of d-Amphetamine in Humans

Risperidone Attenuates the Discriminative-Stimulus Effects of d-Amphetamine in Humans

Prediction and Prevention of Prescription Drug Abuse: Role of Preclinical Assessment of Substance Abuse Liability

Chlorpromazine as a discriminative stimulus in rats: Generalization to typical and atypical antipsychotics

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