Modulation of drug choice by extended drug access and withdrawal in rhesus monkeys: Implications for negative reinforcement as a driver of addiction and target for medications development

Abstract

Chronic drug exposure is hypothesized to recruit negative reinforcement processes that increase the magnitude and alter the mechanisms of drug reinforcement. Candidate substrates of negative reinforcement include increased signaling via stress-related neurotransmitters such as corticotropin releasing factor (CRF, acting at CRF receptors) or dynorphin (acting at kappa opioid receptors) and/or decreased signaling via reward-related neurotransmitters such as dopamine. Determinants of drug reinforcement can be examined with choice procedures, in which subjects choose between a drug of interest (e.g. heroin or cocaine) and a non-drug alternative reinforcer (e.g. food). This review summarizes evidence collected from studies of drug choice in rhesus monkeys to address the negative reinforcement hypothesis. In monkeys choosing between heroin and food, chronic heroin exposure and subsequent withdrawal produces a robust increase in heroin choice. This withdrawal-associated increase in heroin choice is blocked by morphine and by other mu opioid agonists used to treat opioid use disorder (methadone, buprenorphine); however, withdrawal-associated increases in heroin choice are not reliably blocked by antagonists of CRF or kappa opioid receptors or by an indirect dopamine agonist. In monkeys choosing between cocaine and food, chronic cocaine exposure and withdrawal fail to increase cocaine choice or alter sensitivity of cocaine choice to treatment with candidate therapeutics including an indirect dopamine agonist and a kappa opioid receptor antagonist. These results support a role for negative reinforcement in self-administration of heroin but not cocaine. The constellation of neurobiological changes that constitutes the negative reinforcing stimulus in opioid-dependent rhesus monkeys remains to be determined.

Figure 1. Illustrative data from studies of heroin vs. food choice in rhesus monkeys

Panel A shows the timing of daily choice and extended-access sessions. During choice sessions (11am–1pm), subjects could choose between food and increasing heroin doses. During extended-access sessions (1pm-10am), food was not available, but subjects could respond for 0.1 mg/kg/injection heroin. During time-out periods, neither food nor heroin was available. Panel B shows heroin choice dose-effect curves when heroin was available only during daily choice sessions (“Choice Alone”), during both choice sessions and extended-access sessions (“Choice + Extended Access”), or on the first day after termination of extended-access sessions (“Choice + Withdrawal Day 1). Abscissa: Unit heroin dose in mg/kg/injection, log scale. Ordinate: Percent of total choices allocated to heroin choice during each component of the choice session. Panel C shows effects of morphine treatment on withdrawal-associated increases in heroin choice over the entire choice session. Abscissa: Treatment conditions during extended heroin access (Ext Acc), after 1 day of withdrawal from extended heroin access (WD), or after 1 day of withdrawal during which subjects were also treated with continuous infusions of morphine (dose in mg/kg/hr). Ordinate: Percent of total choices allocated to heroin choice for the entire choice session. Asterisks indicate significantly different from WD (p<0.05). All points show mean ± SEM from three (B) or four (C) monkeys. Data adapted from Negus, 2006; Negus and Rice, 2009.

Figure 2. Illustrative data from studies of cocaine vs. food choice in rhesus monkeys

Panel A shows cocaine choice dose-effect curves when cocaine was available only during daily choice sessions (“Choice Alone”), during both choice sessions and extended-access sessions (“Choice + Extended Access”), or the first day after termination of extended-access sessions (“Choice + Withdrawal Day 1). Abscissa: Unit cocaine dose in mg/kg/injection, log scale. Ordinate: Percent of total choices allocated to cocaine choice during each component of the choice session. Panel B shows effects of treatment with the kappa opioid receptor antagonist norbinaltorphimine on cocaine choice during withdrawal from extended cocaine access. Abscissa: treatment conditions during extended cocaine access (Ext Acc), after 1 day of withdrawal from extended cocaine access (WD), or after 1 day of withdrawal from extended cocaine access during which subjects were also treated with 10 mg/kg intramuscular norbinaltorphimine. Ordinate: Percent of total choices allocated to heroin choice for the entire choice session. All points show mean ± SEM from four monkeys. Data adapted from Banks and Negus, 2010; Hutsell et al., 2016a.