A 2015 Biological Psychiatry study of AZD8529, a positive allosteric modulator of the metabotropic glutamate receptor 2 (a compound that enhances the receptor's response to endogenous glutamate), introduced a widely used rat model of incubation of methamphetamine craving — the time-dependent increase in cue-induced drug seeking over weeks of abstinence — after choice-based voluntary abstinence, and observed that its rats strongly preferred palatable food over methamphetamine throughout, leaving open whether a vulnerable minority would eventually switch preference. Later literature directly resolved that study's two headline questions: heroin craving does not incubate after food-choice voluntary abstinence (it does after forced abstinence), and the mechanisms and circuits controlling relapse after voluntary versus forced abstinence are in several identified respects different. The subpopulation question, however, remains untested. The surviving open problem is to determine, in adequately powered experiments combining the long-term training procedure used to identify addiction-like rats with repeated discrete food-drug choice tests, whether a minority of rats switches its preference from palatable food to drug over extended training, and to identify that subpopulation at the level of the individual animal — its prevalence and whether the switching animals are the ones (on the order of 15-20%) that meet the addiction-like criteria.

Background

In rat self-administration models, 'incubation of drug craving' refers to the time-dependent increase in cue-induced drug seeking (lever pressing for drug-paired cues in extinction tests) that emerges over weeks of abstinence. Classically this abstinence is 'forced': the experimenter removes the animal from the drug environment. The source study (Caprioli et al., 2015) instead imposed 'voluntary abstinence' using a discrete-choice procedure: in daily sessions, rats choose between a lever delivering an intravenous methamphetamine infusion and a lever delivering palatable food pellets, and almost all choices go to food, so drug taking stops while the drug remains available. This mimics human abstinence maintained by contingency management — a clinical intervention in which abstinence is rewarded with non-drug reinforcers such as vouchers or privileges — and in that model cue-induced methamphetamine seeking still incubates, and the metabotropic glutamate receptor 2 (mGluR2) positive allosteric modulator (a compound that enhances the receptor's response to endogenous glutamate) AZD8529 selectively reduced the incubated seeking.

A long-standing puzzle in this literature is that rats overwhelmingly prefer palatable food or other non-drug rewards over cocaine, methamphetamine, or heroin, even after extended drug access, whereas human addiction is characterized by diminished control over behavior by non-drug rewards. Two precedents frame the specific question asked here. First, in the long-term training procedure for identifying 'addiction-like' rats (Deroche-Gamonet et al., 2004), rats self-administer cocaine over many weeks and are scored on criteria adapted from the DSM-IV psychiatric diagnostic manual for addiction — high motivation under progressive-ratio schedules (where the response requirement for each reward grows until the rat stops), continued drug taking despite footshock punishment, and persistent drug seeking when the drug is no longer available (high non-reinforced responding); only a minority, roughly 15-20%, meet criteria. The source study describes the same indices as progressive-ratio responding, resistance to shock-induced suppression of drug-reinforced responding, and high non-reinforced responding. Second, Perry et al. (2013) found that the minority of rats that develops a cocaine-over-food preference in choice sessions also shows an addiction-like profile, with females more likely to switch. The source study used both the extended-access and long-term training procedures and, with n=17 and no explicit phenotyping, saw no shift toward methamphetamine preference, and explicitly asked whether a switch would emerge in the 15-20% of rats that develop the addiction phenotype in a larger study.

The source study's other two stated questions have since been answered. Venniro et al. (2017) showed that heroin craving incubates after forced but not food-choice voluntary abstinence in both sexes, so incubation after voluntary abstinence does not generalize to opioids under this procedure; conversely, oxycodone craving does incubate — and is potentiated — after voluntary abstinence induced by an electrified barrier near the drug lever (Fredriksson et al., 2020), indicating the outcome depends on abstinence modality as well as drug class. On mechanisms, reviews of the voluntary-abstinence literature conclude that the neuropharmacological mechanisms of relapse after voluntary abstinence are often different from those after forced abstinence (Fredriksson et al., 2021); a direct dissociation is the ventral subiculum (a hippocampal output structure) neuronal ensembles (small co-activated populations of neurons that can be selectively silenced) that are critical for incubated oxycodone seeking after electric-barrier voluntary abstinence but not after forced abstinence (Fredriksson et al., 2023), alongside methamphetamine-specific mappings after voluntary abstinence in the dorsomedial striatum (a dorsal striatal region implicated in habitual drug seeking) (Caprioli et al., 2017) and the nucleus accumbens core (a ventral striatal region central to reward seeking) (Rossi et al., 2020). What has not been done is the experiment the source called for: a large-sample study that combines addiction-index phenotyping with longitudinal food-drug choice tracking.

Problem Statement

Determine, for an adequately powered experiment of this kind that measures preference repeatedly using a discrete-choice procedure (each trial offering one intravenous drug infusion versus palatable food pellets), both its design and the expected outcome of each of the following parts: (i) whether any subpopulation of rats switches its preference from palatable food to drug as extended training proceeds; (ii) the prevalence of any such subpopulation in the full sampled population; and (iii) whether that subpopulation is the minority — on the order of the 15-20 percent — that meets the addiction-like criteria under the long-term drug self-administration training procedure (high motivation under progressive-ratio schedules, continued drug taking despite punishment, and persistent drug seeking when the drug is unavailable). Because the experiment has not been run, the expected outcome of each part is a reasoned prediction from the existing evidence rather than an empirical result. The question, posed by the AZD8529 incubation study of Caprioli et al. (2015) after its small sample (n=17) showed no such switch for methamphetamine, requires: (1) an adequately powered sample (substantially larger than the source's n=17, sufficient to detect a subpopulation at roughly this prevalence) with explicit, prospective measurement of the addiction-like indices in the same animals; and (2) longitudinal tracking of food-drug choice across extended training so that switches, their timing, and their stability can be identified at the individual-animal level rather than inferred from group means. A 'switch' is operationalized as a reversal to a majority of drug choices (over the alternative food pellets) sustained across consecutive discrete-choice sessions, with its timing taken as the first session of that majority and its stability as whether the majority of drug choices persists thereafter.

References

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