Effects of Environmental Manipulations and Treatment with Bupropion and Risperidone on Choice between Methamphetamine and Food in Rhesus Monkeys

Abstract

Preclinical and human laboratory choice procedures have been invaluable in improving our knowledge of the neurobiological mechanisms of drug reinforcement and in the drug development process for candidate medications to treat drug addiction. However, little is known about the neuropharmacological mechanisms of methamphetamine vs food choice. The aims of this study were to develop a methamphetamine vs food choice procedure and determine treatment effects with two clinically relevant compounds: the monoamine uptake inhibitor bupropion and the dopamine antagonist risperidone. Rhesus monkeys (n=6) responded under a concurrent schedule of food delivery (1-g pellets, fixed-ratio (FR) 100 schedule) and intravenous methamphetamine injections (0-0.32 mg/kg/injection, FR10 schedule) during 7-day bupropion (0.32-1.8 mg/kg/h) and risperidone (0.001-0.0056 mg/kg/h) treatment periods. For comparison, effects of removing food pellets or methamphetamine injections and FR response requirement manipulations were also examined. Under saline treatment conditions, food was preferred over no methamphetamine or small unit methamphetamine doses (0.01-0.032 mg/kg/injection). Larger methamphetamine doses resulted in greater methamphetamine preference and 0.32 mg/kg/injection methamphetamine maintained near exclusive preference. Removing food availability increased methamphetamine choice, whereas removing methamphetamine availability decreased methamphetamine choice. Methamphetamine choice was not significantly altered when the FR response requirements for food and drug were the same (FR100:FR100 or FR10:FR10). Risperidone treatment increased methamphetamine choice, whereas bupropion treatment did not alter methamphetamine choice up to doses that decreased rates of operant behavior. Overall, these negative results with bupropion and risperidone are concordant with previous human laboratory and clinical trials and support the potential validity of this preclinical methamphetamine vs food choice model.

Effects of 7-day repeated treatment with the 5-HT2A inverse agonist/antagonist pimavanserin on methamphetamine vs. food choice in male rhesus monkeys

“…The present behavioral results suggest this may not be a therapeutically advantageous treatment option for methamphetamine addiction. The present results are consistent with previous methamphetamine vs. food choice studies in nonhuman primates evaluating “antagonist-like” pharmacological treatments such as dopamine antagonists PG01037, buspirone, and risperidone or the dopamine D3 partial agonist PG619 (Banks and Blough, 2015; John et al, 2015a, 2015b). Furthermore, both the dopamine partial agonist aripiprazole and the dopamine antagonist risperidone have failed to reduce methamphetamine choice in the human laboratory (Stoops et al, 2013) or methamphetamine use in clinical trials (Coffin et al, 2013; Nejtek et al, 2008; Tiihonen et al, 2007).…”

“…Studies were conducted in three adult male rhesus monkeys ( Macaca mulatta ) surgically implanted with a double-lumen catheter (0.76 mm ID × 2.36 mm OD, STI Flow, Morrisville, NC) inserted into a femoral or jugular vein and who had methamphetamine self-administration histories (Banks and Blough, 2015; Schwienteck and Banks, 2015). Monkeys were maintained on a diet of fresh fruit and food biscuits (Lab Diet High Protein Monkey Biscuits #5045, PMI Nutrition Inc., St. Louis, MO) delivered after the behavioral session.…”

“…Daily experimental sessions were conducted from 0900 to 1100 h in each monkey’s home chamber as described previously (Banks and Blough, 2015). The terminal choice procedure consisted of five 20-min components, with a different unit methamphetamine dose available during each successive component (0, 0.01, 0.032, 0.1, and 0.32 mg/kg/injection during components 1–5, respectively).…”

Insights from Preclinical Choice Models on Treating Drug Addiction

“…To date, preclinical drug versus nondrug choice procedures have been established for the abused drugs cocaine [20–22], methamphetamine [23,24], 3,4-methylenedioxymethamphetamine [25], heroin [26,27], remifentanil [28], secobarbital and chlordiazepoxide [29], and nicotine [30] in either nonhuman primates or rats. With the exception of one heroin versus electrical brain stimulation choice study [31], all other preclinical drug versus nondrug choice procedures have used some food variant as the alternative nondrug reinforcer.…”

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

“…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.…”