Conditioned Withdrawal Drives Heroin Consumption and Decreases Reward Sensitivity

Abstract

Aspects of drug withdrawal may become conditioned to previously neutral environmental stimuli via classical conditioning processes. Nevertheless, the significance of conditioned withdrawal effects in motivating drug intake remains largely unexplored. Here, we investigated the effects of conditioned withdrawal in modulating heroin consumption and brain reward sensitivity in rats. Rats intravenously self-administered heroin (20 g/infusion) during 0 h (control), 1 h (nondependent), or 23 h (dependent) sessions and had daily intracranial self-stimulation (ICSS) thresholds assessed. ICSS thresholds remained stable and unaltered in control rats. In nondependent rats, heroin self-administration induced a transient activation of reward systems, reflected in lowering of ICSS thresholds. In dependent rats, heroin intake escalated across sessions and was associated with a gradual decrease in reward sensitivity, reflected in progressively elevated ICSS thresholds. Thus, as dependence develops, heroin may be consumed not only for its acute reward-facilitating effects, but also to counter persistent deficits in reward sensitivity. In nondependent rats, the opioid receptor antagonist naloxone (30 g/kg) increased heroin consumption and reversed heroin-induced lowering of ICSS thresholds, effects resistant to classical conditioning. In contrast, in dependent rats naloxone (30 g/kg) increased heroin consumption and also elevated ICSS thresholds above their already elevated baseline levels (i.e., precipitated withdrawal). Most importantly, stimuli repeatedly paired with naloxone-precipitated withdrawal provoked heroin consumption and elevated ICSS thresholds in dependent rats. Thus, conditioned stimuli predicting the onset of heroin withdrawal, and hence the reward deficits coupled with this state, may play a critical role in provoking craving and relapse in human opiate addicts.

Supply of a Nondrug Substitute Reduces Escalated Heroin Consumption

“…This finding reproduces previous research on prolonged or unlimited access to opiate self-administration in rats (Bozarth and Wise, 1985;Ahmed et al, 2000;Morgan et al, 2002;Walker et al, 2003;Kenny et al, 2006;Chen et al, 2006;, monkeys (Deneau et al, 1969;Woods and Schuster, 1971) and humans (Wikler, 1952). After escalation, increasing heroin prices decreased heroin consumption in both groups of animals.…”

Reward comparison: the Achilles’ heel and hope for addiction

“…Thus, we hypothesize that cue-induced craving and/or withdrawal contribute to avoidance of the taste cue following taste-drug pairings. As discussed, such an interpretation can account for avoidance of the taste cue (withdrawal is associated with anhedonia [82]), blunting of the accumbens dopamine response to the taste cue, elevated circulating corticosterone, and the onset of aversive taste reactivity following the intraoral delivery of the drug-associated cue. Were the animal in a state of cue-induced craving and/or withdrawal, the best correction for the onset of this aversive state would be drug.…”

Reward Sensitization: Effects of Repeated Nicotine Exposure and Withdrawal in Mice

“…Both intravenously self-administered and experimenter-administered nicotine can increase brain reward sensitivity measured by intracranial self-stimulation (ICSS) (Cryan et al, 2003a;Harrison et al, 2002;Kenny and Markou, 2006b). However, unlike other drugs of abuse (Kenny et al, 2003b(Kenny et al, , 2006aCryan et al, 2003b;Paterson et al, 2000), nicotine withdrawal is not consistently characterized by decreases in brain reward sensitivity (Johnson et al, 2008;Kenny and Markou, 2006b;Stoker et al, 2008), and in one case increased brain reward sensitivity lasted for up to 36 days in rats (Kenny and Markou, 2006b). More recently, conditioned withdrawal cues have been shown to directly amplify the incentive properties of cues associated with nicotine (Scott and Hiroi, 2010).…”