Effects of 7-day continuous d-amphetamine, methylphenidate, and cocaine treatment on choice between methamphetamine and food in male rhesus monkeys

Annals of the New York Academy of Sciences

2016

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Substance use disorders are diagnosed as a manifestation of inappropriate behavioral allocation towards abused drugs and away from other behaviors maintained by more adaptive nondrug reinforcers (e.g., work and social relationships). Substance use disorder treatment goals include not only decreasing drug-maintained behavior but also promoting behavioral reallocation toward these socially adaptive alternative reinforcers. Preclinical drug self-administration procedures that offer concurrent access to both drug and nondrug reinforcers provide a translationally relevant dependent measure of behavioral allocation that may be useful for candidate medication evaluation. In contrast to other abused drugs, such as heroin or cocaine, preclinical methamphetamine versus food choice procedures have been a more recent development. We hypothesize that preclinical to clinical translatability would be improved by the evaluation of repeated pharmacological treatment effects on methamphetamine self-administration under a methamphetamine versus food choice procedure. In support of this hypothesis, a literature review suggests strong concordance between preclinical pharmacological treatment effects on methamphetamine versus food choice in nonhuman primates and clinical medication treatment effects on methamphetamine self-administration in human laboratory studies or methamphetamine abuse metrics in clinical trials. In conclusion, this literature suggests preclinical methamphetamine versus food choice procedures may be useful in developing innovative pharmacotherapies for methamphetamine use disorder.

Section: Evaluation Of Candidate Medications In Preclinical Drug Verssupporting

confidence: 55%

Utility of preclinical drug versus food choice procedures to evaluate candidate medications for methamphetamine use disorder

Annals of the New York Academy of Sciences

2016

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“…By contrast, an experimental manipulation that produces reinforcement-independent rate-altering effects (e.g., motor impairment) would be expected to decrease rates of behavior and may or may not alter drug choice. An example of this effect is shown (Figure 4) during continuous 7-day treatment with the monoamine uptake inhibitor methylphenidate on methamphetamine versus food choice [15]. Second, as noted above, clinical treatment goals of substance-use disorders include not only decreasing drug-maintained behavior, but also increasing nondrug-maintained behavior [9,11,12,16].…”

Section: Preclinical Drug Choicementioning

confidence: 99%

“…Effects of Continuous Treatment with the Monoamine Uptake Inhibitor (+)-Methylphenidate on Choice between (+)-Methamphetamine and Food in Rhesus Monkeys ( N = 4) [15]. (A,B) Saline and methylphenidate treatment effects on methamphetamine choice dose–effect functions.…”

Section: Figurementioning

confidence: 99%

Insights from Preclinical Choice Models on Treating Drug Addiction

Trends in Pharmacological Sciences

Negus

2017

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116

Substance-use disorders are a global public health problem that arises from behavioral misallocation between drug use and more adaptive behaviors maintained by nondrug alternatives (e.g., food or money). Preclinical drug self-administration procedures that incorporate a concurrently available nondrug reinforcer (e.g., food) provide translationally relevant and distinct dependent measures of behavioral allocation (i.e., to assess the relative reinforcing efficacy of the drug) and behavioral rate (i.e., to assess motor competence). In particular, preclinical drug versus food 'choice' procedures have produced increasingly concordant results with both human laboratory drug self-administration studies and double-blind placebo-controlled clinical trials. Accordingly, here we provide a heuristic framework of substance-use disorders based on a behavioral-centric perspective and recent insights from these preclinical choice procedures. Keywordschoice; addiction; preclinical model; drug self-administration; substance-use disorder Trends Substance-use disorders (i.e., drug addiction) are increasingly being conceptualized as disorders of behavioral misallocation between drug and nondrug reinforcers.Preclinical drug versus food choice procedures are increasingly being utilized to elucidate environmental, pharmacological, and biological mechanisms associated with this behavioral misallocation.Preclinical drug versus food choice procedures provide distinct dependent measures that dissociate drug reinforcement (i.e., allocation of behavior) from motor competence (i.e., rate of behavior). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptAlternative nondrug reinforcer availability and temporal delivery impact behavioral allocation.Preclinical drug versus food choice procedures are being developed for abused drugs other than cocaine.Biological variables are an emerging as important determinants of behavioral allocation between drug and nondrug reinforcers. Drug AddictionDrug addiction is an insidious and global public health problem. . Furthermore, six of the 11 diagnostic criteria used for substance-use disorders are based on the allocation of behavior towards the procurement and use of the substance compared with other behaviors maintained by nondrug and presumably more adaptive alternative reinforcers (e.g., food, money, or social commendation). Thus, the diagnosis of substance-use disorders takes a behavioral-centric perspective and implies that such disorders arise from behavioral misallocat...

“…Overall, the present results and the broader scientific literature cited support DAT inhibitors as candidate ‘agonist’ medications for methamphetamine addiction, based on shared discriminative stimulus effects. However, subchronic DAT inhibitor treatments have so far failed to attenuate methamphetamine vs. food choice in monkeys (Banks and Blough, 2015; Schwienteck and Banks, 2015) or human laboratory methamphetamine self-administration (Stoops et al, 2015), and do not produce reliable and robust decreases in methamphetamine use in double blind, placebo-controlled clinical trials (Elkashef et al, 2008; Miles et al, 2013). Thus, the utility of ‘agonist-based’ DAT inhibitor medications for methamphetamine addiction remains to be fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

Methamphetamine-like discriminative stimulus effects of bupropion and its two hydroxy metabolites in male rhesus monkeys

Behavioural Pharmacology

Smith²,

Blough³

2016

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The dopamine transporter (DAT) inhibitor and nicotinic acetylcholine (nACh) receptor antagonist bupropion is being investigated as a candidate ‘agonist’ medication for methamphetamine addiction. In addition to its complex pharmacology, bupropion also has two distinct pharmacologically active metabolites. However, the mechanism by which bupropion produces methamphetamine-like ‘agonist’ effects remains unknown. The present aim was to determine the role of DAT inhibition, nACh receptor antagonism, and the hydroxybupropion metabolites in the methamphetamine-like discriminative stimulus effects of bupropion in rhesus monkeys. In addition, varenicline, a partial agonist at the nACh receptor, and risperidone, a dopamine antagonist, were tested as controls. Monkeys (n=4) were trained to discriminate 0.18 mg/kg intramuscular methamphetamine from saline in a two-key food-reinforced discrimination procedure. Potency and time course of methamphetamine-like discriminative stimulus effects were determined for all compounds. Bupropion, methylphenidate, and 2S,3S-hydroxybupropion produced full, ≥90%, methamphetamine-like effects. 2R,3R-hydroxybupropion, mecamylamine, and nicotine also produced full methamphetamine-like effects, but drug potency was more variable between monkeys. Varenicline produced partial methamphetamine-like effects, whereas risperidone did not. Overall, these results suggest DAT inhibition as the major mechanism of the methamphetamine-like ‘agonist’ effects of bupropion, although nACh receptor antagonism appeared, at least partially, to contribute. Furthermore, the contribution of the 2S,3S-hydroxybupropion metabolite could not be completely ruled out.