Heroin versus cocaine: opposite choice as a function of context but not of drug history in the rat.

RATIONALE: Previous studies have shown that rats trained to self-administer heroin and cocaine exhibit opposite preferences, as a function of setting, when tested in a choice paradigm. Rats tested at home prefer heroin to cocaine, whereas rats tested outside the home prefer cocaine to heroin. Here, we investigated whether drug history would influence subsequent drug preference in distinct settings. Based on a theoretical model of drug-setting interaction, we predicted that regardless of drug history rats would prefer heroin at home and cocaine outside the home. METHODS: Rats with double-lumen catheters were first trained to self-administer either heroin (25 µg/kg) or cocaine (400 µg/kg) for 12 consecutive sessions. Twenty-six rats were housed in the self-administration chambers (thus, they were tested at home), whereas 30 rats lived in distinct home cages and were transferred to self-administration chambers only for the self-administration session (thus, they were tested outside the home). The rats were then allowed to choose repeatedly between heroin and cocaine within the same session for seven sessions. RESULTS: Regardless of the training drug, the rats tested outside the home preferred cocaine to heroin, whereas the rats tested at home preferred heroin to cocaine. There was no correlation between drug preference and drug intake during the training phase. CONCLUSION: Drug preferences were powerfully influenced by the setting but, quite surprisingly, not by drug history. This suggests that, under certain conditions, associative learning processes and drug-induced neuroplastic adaptations play a minor role in shaping individual preferences for one drug or the other.

Differential vulnerability to relapse into heroin versus cocaine-seeking as a function of setting.

RATIONALE: Previous studies have shown that the effect of setting on drug-taking is substance specific in both humans and rats. In particular, we have shown that when the setting of drug self-administration (SA) coincides with the home environment of the rats (resident rats), the rats tend to prefer heroin to cocaine. The opposite was found in nonresident rats, for which the SA chambers represented a distinct environment. OBJECTIVES: The aim of the present study was to investigate the influence of setting on the ability of different doses of cocaine and heroin to prime cocaine- versus heroin-seeking in rats that had been trained to self-administer both drugs and had then undergone an extinction procedure. METHODS: Resident (N = 62) and nonresident (N = 63) rats with double-lumen intra-jugular catheters were trained to self-administer cocaine (400 µg/kg/infusion) and heroin (25 µg/kg/infusion) on alternate days for 10 consecutive daily sessions (3 h each). After the extinction phase, independent groups of rats were given a noncontingent intravenous infusion of heroin (25, 50, or 100 µg/kg) or cocaine (400, 800, or 1600 µg/kg), and drug-seeking was quantified by counting nonreinforced lever presses. RESULTS: All resident and nonresident rats acquired heroin and cocaine SA. However, cocaine primings reinstated cocaine-seeking only in nonresident rats, whereas heroin primings reinstated heroin-seeking only in resident rats. CONCLUSIONS: We report here that the susceptibility to relapse into drug-seeking behavior is drug-specific and setting-specific, confirming the crucial role played by drug, set, and setting interactions in drug addiction.

The role of setting for ketamine abuse: clinical and preclinical evidence.

Drug abuse is often seen as a unitary phenomenon, partly as a result of the discovery over the past three decades of shared mechanisms of action for addictive substances. Yet the pattern of drug taking is often very different from drug to drug. This is particularly evident in the case of 'club drugs', such as ketamine. Although the number of ketamine abusers is relatively small in the general population, it is quite substantial in some settings. In particular, ketamine abuse is almost exclusively limited to clubs and large music parties, which suggests a major role of context in modulating the reward effects of this drug. This review focuses on recent preclinical and clinical findings, including previously unpublished data, that provide evidence that, even under controlled conditions, ketamine reward is a function of the setting of drug taking.

Ketamine self-administration in the rat: evidence for a critical role of setting.

RATIONALE: The abuse of ketamine has been reported to be on the rise over the past 15 years, but its abuse appears to be limited almost exclusively to the context of music and dance settings, indicating a major role of context in modulating its reinforcing effects. We have previously reported that amphetamine, cocaine, and heroin self-administration (SA) in the rat are differentially influenced by the setting in which testing takes place. The aim of the present study is to extend this pre-clinical model to ketamine. MATERIALS AND METHODS: Independent groups of rats with intravenous catheters were given the possibility to self-administer different doses of ketamine (125, 250, and 500 µg/kg per infusion) under two environmental conditions. Some animals were housed in the SA chambers (resident rats) whereas other rats were transported to the SA chambers only for the test sessions (non-resident rats). After training, within-subject dose effect curves (125, 250, 500, and 1,000 µg/kg per infusion) and break-point (during a progressive ratio session) were calculated. RESULTS: Non-resident rats readily acquired ketamine self-administration. In contrast, resident rats self-administered only the highest dose of ketamine (500 µg/kg), but still four times less than non-resident rats (11.0 ± 6.0 vs 44.4 ± 5.2 infusions during the last training session). No significant differences in break-point were found during the progressive ratio session. CONCLUSIONS: The present study confirms at a preclinical level the importance of setting for ketamine SA and further validates a previously described animal model of drug-environment interaction.